Protocol. This trial protocol has been provided by the authors to give readers additional information about their work.

Transcription

1 Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Schauer PR, Bhatt DL, Kirwan JP, et al. Bariatric surgery versus intensive medical therapy for diabetes 5-year outcomes. N Engl J Med 2017;376: DOI: /NEJMoa

2 This supplement contains the following items: 1. STAMPEDE Protocols / Summary of changes: - Original protocol dated 23 Oct Final protocol (Amend 7) dated 11 Sep Summary of changes for Amendments Original / final statistical analysis plan (STAMPEDE SAP 06 Dec 2011)

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68 Medical vs Surgical Management of T2DM Final Protocol, 23 October 2006, Amendment 1, 30 April, 2007 Amendment 2, 12 September 2007 Amendment 3, 30 October 2007 Amendment 4, 25 February 2008 Amendment 5, 14 April 2008 Amendment 6, 24 September 2008 Amendment 7, 18 August 2009 STAMPEDE Surgical Therapy And Medications Potentially Eradicate Diabetes Efficiently CLINICAL PROTOCOL A Prospective Randomized Controlled Trial Comparing Advanced Practice Medical Management Versus Advanced Practice Medical Management Plus Bariatric Surgery In The Treatment Of Type 2 Diabetes Mellitus. Regulatory Sponsor: Funding Sponsor: Philip R. Schauer, M.D Bariatric & Metabolic Institute Cleveland Clinic 9500 Euclid Avenue, M61 Cleveland, OH (216) Ethicon 4545 Creek Road, ML 20 Cincinnati, OH Robin F. Scamuffa, Clinical Research Director Date: August 18, 2009 Amendment version 7 Approval Date: September 11, 2009 IRB Number CONFIDENTIAL This document is confidential and the property of The Cleveland Clinic. No part of it may be reproduced without written permission from the study sponsor.

69 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August 2009 Table of Contents STUDY SUMMARY...1 INTRODUCTION BACKGROUND REVIEW OF PRIOR STUDIES RATIONALE AND RISK/BENEFITS STUDY OBJECTIVES STUDY DESIGN GENERAL DESIGN PRIMARY STUDY ENDPOINTS SECONDARY STUDY ENDPOINTS SUB STUDIES RANDOMIZATION BLINDING SUBJECT SELECTION INCLUSION CRITERIA EXCLUSION CRITERIA SUBJECT RECRUITMENT AND SCREENING EARLY WITHDRAWAL OF SUBJECTS Data Collection and Follow-up for Withdrawn Subjects STUDY TREATMENTS DESCRIPTION Glycemic Target Self Management education Dietary and Lifestyle Interventions Visit Frequency and Inter-Visit Contacts ADVANCED MEDICAL MANAGEMENT Hypertension Management Lipid management ADVANCED MEDICAL THERAPY PLUS SURGICAL MANAGEMENT STUDY PROCEDURES LABS AND CLINICAL STUDIES SCREENING / VISIT 1 (UP TO 2 MONTHS) BASELINE AND RANDOMIZATION / VISIT 2 (WITHIN 1 MONTH OF DAY 0) POST RANDOMIZATION / VISIT 3 (+ 1 MONTH) FOLLOW-UP VISITS Visit 4 / Month 3 (+ 2 weeks) Visit 5 / Month 6 (+ 2 weeks) Visit 6 / Month 9 (+ 2 weeks) Visit 7 / Month 12 (+ 2 weeks) Visit 8 / Month 15 (+ 2 weeks) Visit 9 / Month 18 (+ 2 weeks) Visit 10 / Month 21 (+ 2 weeks) Visit 11 / Month 24 (+ 4 weeks) Visit 12 / Month 30 (+ 4 weeks) Visit 13 / Month 36 (+ 4 weeks) Visit 14 / Month 42 (+ 4 weeks) Visit 15 / Month 48 (+ 4 weeks) Visit 16 / Month 54 (+4 weeks) End of Study - Visit 17 / Month 60 (+ 4 weeks)...33 ii CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

70 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August STATISTICAL CONSIDERATIONS SAMPLE SIZE DETERMINATION ANALYSIS POPULATIONS STATISTICAL METHODS INTERIM SAFETY ANALYSES COST EFFECTIVENESS ANALYSIS ADVERSE EVENTS DEFINITIONS RECORDING OF ADVERSE EVENTS DATA SAFETY MONITORING BOARD DATA HANDLING AND RECORD KEEPING CONFIDENTIALITY SOURCE DOCUMENTS CASE REPORT FORMS RECORDS RETENTION STUDY TIMELINE PUBLICATION PLAN PROTOCOL SIGNATURES REFERENCES ATTACHMENTS APPENDICES...48 iii CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

71 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August 2009 List of Abbreviations iv ADA AWP BART BMI C Peptide CBC Chem 12 CPT CRF DCCT DEXA DRG DSMB EKG EWL FPG GIP GLP HbA1c HIPAA ICER ICF IGT IRB LSG MMTT NAFLD NASH NDC NIH OTC PHI PYY QALY RYGBP SMBG T2DM TSH TZD UKPDS American Diabetes Association Average Wholesale Price Brachial Artery Reactivity Test Body Mass Index Connecting Peptide Complete Blood Count Comprehensive Metabolic Panel Current Procedural Terminology Case Report Form The Diabetes Control and Complications Trial Dual Energy X-ray Absorptiometry Diagnosis Related Group Data and Safety Monitoring Board Electrocardiogram Excess body Weight Loss Fasting Plasma Glucose Gastric Inhibitory Polypeptide Glucagon-Like Peptide Hemoglobin A1c Health Insurance Portability and Accountability Act Incremental Cost Effectiveness Ratio Informed Consent Form Insulin Glucose Tolerance Institutional Review Board Laparoscopic Sleeve Gastrectomy Mixed Meal Tolerance Test NonAlcoholic Fatty Liver Disease NonAlcoholic Steato Hepatitis National Drug Code National Institute of Health Over The Counter Protected Health Information Peptide YY Quality Adjusted Life Years Roux-en-Y Gastric Bypass Self-Monitoring of Blood Glucose Type 2 Diabetes Mellitus Thyroid Stimulating Hormone Thiazolidinediones The United Kingdom Prospective Diabetes Study CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

72 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August 2009 Study Summary Indication To assess the effects of advanced medical therapy alone or advanced medical therapy combined with bariatric surgery on glycemic control in obese patients with Type 2 Diabetes Mellitus. Rationale Obesity and Type 2 diabetes mellitus (T2DM) are closely interrelated, and are currently listed as two of the most common chronic, debilitating diseases of Western society. The prevalence of obesity has increased epidemically by more than 75% since 1980, with 34% of the US adult population overweight (BMI ), and another 30% classified as obese (BMI > 30). 1, 2 Type 2 Diabetes is estimated to affect at least 8% of the adult population and 19% of the population greater than 65 years of age. 3 Each year, the incidence of new cases increases, with the Center of Disease Control and Prevention estimating 1.5 million new cases diagnosed in people aged 20 years or older in 2005 alone. It is well established that obesity is the critical etiologic factor in the development of T2DM. 4 Weight loss has beneficial effects on T2DM and improves the metabolic pathophysiology that leads to hyperglycemia. With no medical cure for T2DM, the natural course of the disease is characterized by progression to microvascular complications, leading to blindness, renal failure, amputation, and death due to cardiovascular disease. 5, 6 The direct and indirect costs for treating diabetes and its complications in the US continues to rise, and was estimated to be 132 billion dollars in The indirect cost of diabetes and obesity impact work, productivity, quality of life and other family members. The current options for obese, T2DM individuals are limited. Lifestyle modification including improved eating practices and increased physical activity, supplemented by pharmacotherapy, generally achieve modest and transient results. Tight glycemic control with medication (oral agents and insulin) has been shown to decrease the risk of microvascular complications, but continued monitoring of HbA1c and adjustment of therapy to achieve normal levels remains a constant challenge for physicians and patients. Observational studies have reported that surgical intervention of morbid obesity achieved significant improvement or resolution of T2DM, both in the short and long-term, but generally have been reserved for those with a BMI > 40 or a BMI > 35 if co-morbidity is present Direct evidence of the benefits of nonsurgical and surgical therapies in obese T2DM from randomized, controlled trials is lacking. Bariatric surgery is not currently considered a therapeutic option in the management algorithm for T2DM. Also, there is no clear consensus on what is the best treatment for obese T2DM patients with a BMI However, a recently published trial has demonstrated effectiveness of gastric banding in reducing weight and obesity related co-morbidities in subjects with modest obesity with BMI (30-40) 36. The options available to those who seek a solution to T2DM may be divided into two general groups medical and surgical. Current evidence suggests that medical therapy including

73 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August medically induced weight loss plus tight blood sugar control is safe but relatively ineffective in achieving normal or near normal serum glucose levels and HbA1c. On the other hand, evidence suggests that surgical therapy, albeit invasive, painful, and potentially dangerous may be more effective in altering the progressive natural history of T2DM. We propose a reassessment of both strategies for mild to moderately obese patients. The purpose of this study is to evaluate whether advanced medical therapy alone, or advanced medical therapy combined with surgical intervention, is more effective in improving HbA1c and outcome measures in patients with T2DM and a BMI during 5 years follow-up. The hypothesis of the study is that surgical therapy is more effective than advanced medical therapy for the resolution of type 2 diabetes mellitus in patients with a BMI between 27 and 43 kg/m2. Objectives Primary To assess the effects of advanced medical therapy alone or advanced medical therapy combined with either Roux-en-Y gastric bypass (RYGBP) or laparoscopic sleeve gastrectomy on the success rate of biochemical resolution of diabetes at 1 year as measured by HbA1c < 6% in subjects with Type 2 Diabetes Mellitus and BMI between kg/m 2. Secondary Secondary outcomes or measures will be changes in specific metabolic parameters such as insulin secretion and resistance, assessments of end-organ damage (kidney, eye, cardiovascular), weight loss, and body composition. Additionally, changes in obesity-related comorbidities (blood pressure, dyslipidemia), quality of life, and hospitalizations will be examined. The costeffectiveness of each program and the side effects and /or complications will be analyzed. Trial Design This is a 3-arm randomized, controlled, single center study. Male and female subjects between the ages of 20 to 60 years old with clinical diagnosis of Type 2 diabetes mellitus and BMI between kg/m 2, will be included in this study. Approximately 150 eligible subjects who have given their consent to participate will be randomized in a 1:1:1 ratio, with stratification on use of insulin at screening, to one of the following treatments: Advanced medical therapy Advanced medical therapy combined with Roux-en-Y gastric bypass (RYGBP) Advanced medical therapy combined with laparoscopic sleeve gastrectomy Advanced medical therapy is defined as the use of the latest lifestyle guidelines set forth by the American Diabetes Association to optimize weight loss and glycemic management, frequent home monitoring/titration strategies, use of latest FDA approved drug therapy (incretins, insulin sensitizers etc) for treatment of hyperglycemia and restoration of pancreatic B cell function in addition to regular visits to board certified Endocrinologists/Diabetologists at the Cleveland CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

74 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Clinic. Advancement to combination therapy will be done swiftly, and insulin initiated early in the course of therapy to achieve a euglycemic status for the primary endpoint. In addition to glycemic management, all subjects will be treated according to current ADA guidelines for lipids and blood pressure targets. After study randomization, study visits will be scheduled at every 3 months for the first 2 years and every 6 months thereafter. The study will continue until all subjects have had the opportunity for 60 months of follow-up. Endpoints Primary endpoint Success rate of biochemical resolution of diabetes at 12 months as measured by HbA1c 6%. Secondary endpoint See protocol section 3.3 for secondary endpoints Statistical Methods Sample Size Determination The primary end point of the study is defined as biochemical resolution of diabetes at 12 months after entry into the study. Assuming rates of diabetes resolution at 12 months to be 83%, 50% and 20% in the gastric bypass, laparoscopic sleeve gastrectomy and advanced medical therapy arms, respectively, 50 patients will be enrolled into each arm in order to meet the objectives of the study. The expected lost to follow-up rate is 20% of patients, leaving approximately 40 evaluable patients per arm. This will provide > 99% power to detect differences among any of the 3 groups and 80% power to detect a difference between the 2 surgical arms, using a 2-sided alpha of The primary analysis will not be adjusted for multiple comparisons since the probability of diabetes resolution in one group is independent of the probability of diabetes resolution in either of the other two groups; therefore, the comparisons are assumed to be independent. Analysis of the Primary and Secondary Endpoints Data will be analyzed according to the program into which the patients were randomized at baseline (modified intention-to-treat analysis). Data will be summarized using descriptive statistics. Categorical data will be described using frequencies and percentages and the chisquare statistic or fisher s exact test will be used, as appropriate, to compare treatment groups. Continuous variables will be summarized using means, medians, interquartile ranges and minimum and maximum values. For comparison of treatment groups, ANOVA will be used for data that are normally distributed. For non-normal data, the Kruskal-Wallis will be used. CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

75 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Overview of Patient Flow Chart Pre-screening Evaluation Inclusion/Exclusion criteria review Informed Consent Initial screening evaluation History and physical Psychiatric evaluation Nutrition evaluation Screening Lab work Initiate / Continue Standard Medical Therapy Baseline labs Re-evaluation of inclusion/exclusion criteria Anesthesia clearance Initiate Diabetes patient education * Randomization Medical Therapy 50 subjects Medical Therapy Plus Gastric Bypass 50 subjects Medical Therapy Plus Sleeve Gastrectomy 50 subjects Advanced Diabetic Medical Care* If HbA1c > 6.0% Adjustment of medical treatment Per Treatment Algorithm Guidelines Target euglycemia at 12 mos Standard post-op care Advanced Diabetic Medical Care * If HbA1c > 6.0% Adjustment of medical treatment Per Treatment Algorithm Guidelines Target euglycemia at 12 mos Primary Endpoint Percent of treatment group achieving HbA1c < 6% at 1 year * Diabetic teaching, diet and exercise education per current ADA guidelines CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

76 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August 2009 Introduction Background Type 2 Diabetes Mellitus Type 2 diabetes mellitus (T2DM) is a complex, chronic metabolic disease that results from defects in both insulin secretion and insulin action leading to hyperglycemia. Simply stated, marked increases in plasma insulin concentration due to pancreatic B-cell function are not sufficient to meet the demand of excessive glucose production by the liver. Also, muscle, liver and fat tissue becomes resistant to the action of insulin, due to defects in insulin transportation and insulin receptor signaling and function. As hyperglycemia ensues (over 140mg/dL) insulin secretion decreases progressively, and in patients with fasting plasma glucose levels of mg/dl, there is an absolute deficiency of insulin. The increased rate of basal hepatic glucose production and impaired postprandial disposal of glucose are clinically reflected by the hemoglobin A1c value (HbA1c). Effective medical therapy improves glycemic control in patients with T2DM and includes agents that: 1) reduce the elevated basal rate of hepatic glucose production; 2) improve insulin secretion; and 3) improve muscle insulin sensitivity. 48 Obesity Obesity is a major risk factor for the development of glucose intolerance and type 2 diabetes. This predisposition is driven by obesity-related insulin resistance and the transition to impaired glucose tolerance (IGT), and then to type 2 diabetes heralded by the progressive deterioration of pancreatic B-cell function. It is well established that weight loss, even relatively modest amounts, usually improves hyperglycemia in patients with IGT and type 2 DM. Advanced Medical Therapy Given the complexity of the pathophysiology of type 2 diabetes and obesity, advanced medical therapy should be based on effective weight reduction (diet and exercise education), coupled with drug therapy targeting insulin resistance (metformin, thiazolidinediones) and restoration of B cell function with thiazolidinediones and stimulation of insulintropic or incretin hormones (GLP-1 agonists, exenatide). It should be noted that caution needs to be exercised when reducing blood glucose levels in patients with type 2 diabetes to as close to normal as possible to avoid symptomatic hypoglycemia. Early institution of insulin therapy also reduces both glucotoxicity and lipotoxicity that result in tissue damage. In addition to glycemic control, medical therapy targeting optimal control of lipids, blood pressure and cardiovascular risk (aspirin therapy) has clearly been shown to be effective in reducing micro and macro-vascular complication in the diabetes population. Surgical Therapy Because medical programs have commonly failed to achieve a satisfactory long-term effect on weight loss in the obese population, a range of surgical procedures has been used over a period CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

77 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August of 50 years. The initial operation of jejunoileal bypass (JI Bypass) (Figure 1) achieved good weight reduction but was associated with unacceptable morbidity. Gastric restrictive procedures, utilized since the 1960s, have reported to have the capability of achieving and maintaining good weight reduction in the morbidly obese. Laparoscopic approaches to bariatric surgery, including sleeve gastrectomy and RYGBP, emerged in the early to mid-1990s. Advantages over open bariatric approaches included reduced perioperative morbidity (especially wound related) and shorter recovery. Two primary strategies of surgically induced weight loss have arisen over the past 50 years: gastric restriction and intestinal malabsorption. The restrictive procedures cause early satiety by creation of a small gastric pouch and prolong satiety by creation of a small outlet to that pouch. Significant dietary compliance is required with restrictive operations, because the intake of highcalorie liquids or soft foods is not inhibited by the narrow outlet and will result in failure to lose weight. Benefits include technical simplicity with no staples, anastomoses, or bypasses of any part of the intestinal tract. Protein calorie malabsorption and vitamin and mineral deficiencies are unlikely events after restrictive procedures. Relative disadvantages include less weight loss than with alternative procedures and more late failures due to pouch or anastomosic dilatation or maladaptive eating behavior. Malabsorptive procedures in use today involve some degree of gastric volume reduction, but primarily depend on bypass of various lengths of small intestine to cause malabsorption akin to a controlled short-gut syndrome. Benefits include greater sustained weight loss that is less dependent on dietary compliance than are the restrictive procedures. Disadvantages include increased risk of malnutrition and vitamin deficiencies, with a need for close physician follow-up to reduce these risks. The malabsorptive procedures are generally more technically complex than the restrictive operations, with two anastomoses, including partial gastric resection. Roux-en-Y gastric bypass (RYGBP; Figure 2), an intermediate operation, has historically been considered a restrictive operation, although many argue that there is a degree of malabsorption due to the foregut bypass. Although there are many variations, most surgeons create a 15- to 50- ml gastric pouch (isolated or stapled in continuity) with a 75- to 150-cm Roux-limb connected as an enteroenterostomy to the jejunum 30 to 50 cm from the ligament of Treitz. Because of the foregut bypass, associated vitamin and mineral deficiencies may occur with RYGBP, but protein calorie malnutrition rarely, if ever, occurs. Sleeve gastrectomy is another restrictive procedure that can be used either as a single-stage bariatric operation or as the first stage of a two-stage approach for super obese patients. For this study, sleeve gastrectomy will be performed laparoscopically (LSG) as a primary bariatric procedure, and involves resection of the greater curvature and body of the stomach from the antrum to the angle of His (Figure 3). The benefits of LSG include relative technical ease to perform, the lack of any anastomoses, and minimal risk of vitamin, mineral, or protein deficiencies. Though LSG is not reversible, it can be converted to a gastric bypass or duodenal switch operation for patients who fail to lose adequate weight. The disadvantages include a long staple line that can bleed or leak, less weight loss than gastric bypass, and, as with any restrictive operation, the potential for weight gain due to excessive intake of high calorie liquids. Despite CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

78 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August good clinical results, the effect of LSG on glucose metabolism and diabetes has not been thoroughly investigated. Resection of the gastric fundus decreases Ghrelin levels which may induce long-term appetite suppression and weight loss but there is no foregut bypass with this operation as there is with RYGBP. The effect of sleeve gastrectomy on the insulo-enteric axis and incretin production (GLP,GIP, PYY) is unknown. Surgical Intervention in Non-severely Obese Patients According to the widely adopted National Institute of Health (NIH) Consensus Development Panel report of 1991, eligibility for bariatric surgery is based on the severity of obesity using BMI as the primary measurement and presence or absence of significant comorbidity as a secondary measurement of severity. Adult patients with a body mass index (BMI, kg/m2) 35 with comorbidities such as diabetes, obstructive sleep apnea, or arthritis or with a BMI 40 without comorbidities are eligible for surgery. The lower thresholds (BMI 35, BMI 40) were somewhat arbitrary assignments, since there is no direct evidence that these thresholds accurately distinguish severe obesity from mild obesity. Most insurance carriers accept the NIH standards. Thus patients who are less obese (BMI < 35), regardless of comorbidity, are not eligible to receive benefit of surgery. We and others have shown that bariatric surgery in diabetic patients (requiring oral agents or insulin) with a BMI in the range results in a high-resolution rate ( 83%) and low mortality (0 mortality). 11,15,18 The vast majority of diabetics are overweight (BMI >25) or obese (BMI >30), but relatively few (estimated 10%) are severely obese (BMI >35). Although no studies have addressed outcomes of bariatric surgery in diabetic patients with BMI < 35, it is quite reasonable to suggest that diabetic patients with a BMI between 30 and 35 are likely to enjoy similar benefit of bariatric surgery as patients with BMI > Review of Prior Studies Type 2 Diabetes Currently, advanced medical management of T2DM in severely obese patients consists of conventional (low risk) weight loss strategies and advanced medical therapy to achieve a HbA1c of < 7%. Results of recent studies employing nonsurgical weight loss strategies in patients with a mean BMI of 35 kg/m2, show only minimal benefit Weight loss was modest, varying from 3 5 Kg or 2 3 BMI units, and sustained weight loss beyond 1 year was demonstrated in only 2 23, 25 of the 6 studies. Correspondingly, modest improvement in glycemic control was achieved, but the mean HbA1c remained above 7% despite fairly intense medical therapy. Minimal data are available regarding reduction in medication requirement with medical weight loss. In one study, oral agents were added over time as patients progressed from impaired fasting glucose (IFG) to T2DM despite modest weight loss. 23 In another study, oral agents were reduced slightly as the mean HbA1c decreased from 8.3% to 7.6%. 24 Tight glycemic control with medication (HbA1c less than 7%) has been shown to decrease the risk of microvascular complications (retinopathic, nephropathic, and neuropathic) associated 28, 29 with diabetes in 2 large randomized studies, both with 10 year follow-up. The Diabetes CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

79 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Control and Complications Trial (DCCT) monitored risk of developing microvascular complications in type 1 diabetes mellitus. Compared to patients receiving standard therapy, patients randomized to intensive therapy demonstrated greater improvement in HbA1c and a reduction in risk of developing or progressing retinopathy, nephropathy and neuropathy by 50% or greater. The United Kingdom Prospective Diabetes Study (UKPDS) provided definitive information on the relation between improved glycemic control and prevention of complications in type 2 diabetes. Patients with newly diagnosed type 2 diabetes were randomized to intensive therapy or conventional diet therapy. Patients receiving intensive therapy maintained lower HbA1c values (7.0% compared with 7.9%; P <0.001), which was associated with a significant 25% risk reduction (P= 0.009) in combined microvascular end points (eye, kidney, and nerve). There was a tendency toward fewer myocardial infarctions in the group assigned to intensive therapy. In a sub-group of overweight patients assigned to intensive treatment with metformin or conventional treatment, patients receiving intensive treatment maintained a 0.6% lower HbA1c, resulting in a 32% lower risk for any diabetes-related end point (P = 0.002) and a 36% lower risk for death from any cause (P = 0.021). These studies both showed that for every drop of 1% (i.e., from 9% to 8% HbA1c) there was a relative risk reduction of 25% to 45%. Glycemic control to achieve a HbA1c of 7% in some of these patients was only possible with insulin doses greater than 100 units per day and even then for only short periods of time. 29 It is believed that in community settings where 95% of diabetic patients are treated, HbA1c levels in T2DM patients typically vary from 8.5 to 9% suggesting that tight control with medication is difficult to achieve. Furthermore, advanced medical therapy required to achieve HbA1c of 7% has a corresponding 2%-4% yearly incidence of severe hypoglycemia. 29 Behavior modification programs seek to identify the social and psychological cues and habits that induce overeating or under activity and use cognitive restructuring, stress management and counseling to change these behaviors. Perri and co-workers have shown that, after an initial weight loss has been achieved, a maintenance program of behavioral therapy, combined with social support and exercise can maintain and even enhance the weight loss achieved during the initial period. 30 Surgical Therapy In a recent study, the authors followed 191 patients classified as both obese (BMI 35) and diabetic (T2DM or impaired fasting plasma glucose), for 5 years after performing laparoscopic Roux-en-Y gastric bypass (RYGBP). Significant improvements were noted in several critical health components. Mean values of interest were: weight loss (60% Excess Body Weight Loss), normalization of FPG (187 mg/dl to 100 mg/dl; P< 0.001), and normalization of HbA1c (8.2% to 5.5%, P < 0.001). The authors also noted a reduction in antidiabetic medication usage (oral agent usage 65% to 13%; insulin usage 27% to 6%, P<0.001). 18 The observed major morbidity and mortality rate of 13.6% and 0.5% respectively, appears reasonable for these relatively high risk patients. CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

80 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Laparoscopic Sleeve Gastrectomy (LSG) is a restrictive procedure that results in significant weight loss and improvement or resolution of diabetes. This procedure was originally used to achieve short-term excess weight loss of 30% to 40% in super-obese patients (BMI>50) as a staged procedure prior to duodenal switch or gastric bypass. 19,31 Recent experience as a standalone procedure, though, has demonstrated better excess weight loss (> 60%) in patients with lower BMI s (35 to 45). 20 In a study of patients with BMI s ranging from 30 to 56 (average 37), the average excess weight loss one year after surgery was 83%, and 100% of patients had resolution of their diabetes within six months after surgery. In this series of 130 patients, major morbidity occurred in 4.8% of patients and there were no mortalities Rationale and Risk/Benefits In the United States, the current estimate of diabetes prevalence among people between the ages of 20 and 60 are at least 8% or 20.6 million people. Each year, the incidence of new cases increases, with the Center of Disease Control and Prevention estimating 1.5 million new cases diagnosed in people aged 20 years or older in 2005 alone. It is well established that obesity is the critical etiologic factor in the development of T2DM. With no medical cure for T2DM, the natural course of the disease is characterized by progression to microvascular complications, leading to blindness, renal failure, amputation, and death due to cardiovascular disease. The medical, physical and social dilemmas generated by diabetes and obesity are great. Diabetes, is the number 2 cause of hospitalizations in adults aged 18 years or older in the United States accounting for about 11% of discharges. Morbidity and mortality related to diabetes and its related complications are represented in the table below. Table 1 Complications of Type 2 Diabetes Mellitus* Mortality 5-7 fold increased in men and 9-12 fold increased in women Disability 50% Metabolic Complications 5-8 per 1000 diabetic persons/yr Vision disorder 20% at diagnosis; 30-70% prevalence Neuropathy 30-70% Kidney disease 20-30% microalbuminuria; 20-30% macroalbuminuria; 35% ESRD Heart Disease 42% Peripheral Artery Disease 20-30% Foot Ulcers/Amputations 4-10% Stroke 2-13% Digestive Diseases 32% of hospital discharges Infections 9-15% Oral Complications 5-30% Psychosocial aspects/ Depression 14% * Reference: Diabetes in American 2 nd Edition NIDDK People with diabetes can reduce the occurrence of microvascular complications by controlling levels of blood glucose, blood pressure and blood lipids in a timely manner. With intensification CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

81 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August of medical therapy, increasing the number and dosage of medications required to reduce levels of HbA1c, can result in modest weight gain and increased risk of hypoglycemia. Table 2 lists major trials and risks related to achieving optimal glycemic control with insulin therapy. Weight gain and fear of hypoglycemia may limit patient s potential to reach a euglycemic biochemical status. With advances in therapy and increased self-management education for patients, these rates may change. Table 2 Risks of Tight Glycemic Control with Insulin in Patients with Type 2 Diabetes Study HbA1c Hypoglycemia Mean Weight Gain (year) Severe* Any UKPDS (1998) Kumamoto (Ohkubo 1995) VACSDM (Abraira 1997) 7.1% (115%)** 1.8% / yr 28% / yr 4 kg > control (10 yrs) 7.1% (111%) 0% 1.9% / yr BMI incr (6 yrs) 7.3% (120%) 3% / yr 41% / yr Same as control UGDP (Genuth 1996) FPG 6.7 mmol / l (120.6 mg / dl) 3.2 % N/A 0.2% / yr * Severe hypoglycemia is defined as an episode requiring third party assistance; ** HbA1c in the group randomized to initial therapy with insulin; Abbreviations: BMI, Body Mass Index; FPG, fasting plasma glucose Current options for obese, T2DM individuals are limited, and bariatric surgery is not currently considered a therapeutic option in the management algorithm for T2DM. Lifestyle modification including improved eating practices and increased physical activity, supplemented by pharmacotherapy, generally achieve modest and transient results. Tight glycemic control, necessitating continued monitoring of HbA1c and adjustment of therapy to achieve normal levels, remains a constant challenge for physicians and patients. Bariatric Surgery has evolved as an acceptable solution to achieve long-term effects on weight loss in the obese population. Recent studies have also reported surgical intervention achieved significant improvement or resolution of T2DM, both in the short and long-term, with reduction in disease related co-morbidities. Despite good clinical results, surgery is not without risk. Table 3a lists complications associated with laparoscopic gastric bypass, and Table 3b lists complications with laparoscopic sleeve gastrectomy. Table 4 lists complications specifically in adult patients under the age of 61 years with a BMI between 35 and 45 kg/m 2, undergoing RYGBP surgery at the Cleveland Clinic during the 2004 through July CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

82 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Table 3a.Complications in selected series of laparoscopic gastric bypass Study (year) n PE Leak Schauer (2000) Wittgrove (2000) Nguyen (2001) Higa (2001) Dresel (2002) DeMaria (2002) Papasavas (2002) Oliak (2002) Gould (2002) Bowel obstruction GI bleed Wound infections Stomal stenosis Ventral hernia Pneumonia Death 275 2/275 12/275 3/275 3/275 24/275 13/275 2/275 1/275 1/ NA 11/500 3/500 NA 28/500 8/500 0/500 NA 0/ /79 1/79 3/79 3/79 1/79 9/79 0/79 NA 0/ / / /1500 NA 2/ /1500 4/1500 1/1500 3/ /100 3/100 5/100 3/100 2/100 3/100 1/100 NA 0/ /281 14/281 5/281 NA 3/281 18/281 5/281 NA 0/ /116 3/116 12/116 2/116 NA 4/116 NA NA 1/ /300 4/300 5/300 NA 20/300 6/300 NA 1/300 3/ NA 4/223 4/223 NA 17/223 12/223 2/223 NA 0/223 Total n / / / /570 97/ / /2958 3/2075 8/3374 Total % 0.4% 2.0% 2.7% 1.9% 3.0% 4.3% 0.5% 0.1% 0.2% Data from Podnos Y, Jimenez J, Wilson S. complications after laparoscopic gastric bypass: a review of 3464 cases. Arch Surg 2003;138: Table 3b Complications in selected series of laparoscopic sleeve gastrectomy Wound Study n Leak Bleed Hernia infection Pulmonary 1 Cardiac 2 Stricture Moon Han (2005) Organ system dysfunction 3 Splenic injury 130 1/130 1/ / /130 4 Cottam 126 2/ / /126 4/ (2006) 1/126 Langer (2006) Baltasar / /31 (2005) Milone / (2005) Mognol (2005) Almogy /21 1/21 2/ / (2004) Regan / /7 --- (2003) Total n Total % 0.8% 0.8% 0.2% 0.5% 1.1% 0.5% 1.3% 1.3% 0.2% 0.8% Death 1 Includes pulmonary embolus, pneumonia and atelectasis. 2 Includes Hypotension, Myocardial Infarction and Congestive Heart Failure. 3 Includes Acute Renal Insufficiency and Hepatic Insufficiency. 4 Mortality from Pulmonary Embolus. CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

83 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Table 4 Complications of RYGBP in 112 select patients at The Cleveland Clinic between January 2004 and July 2006 * LOS > 7 days Readmit Re-Op PE Leak Stricture Transfusion Wound infections Other** Death Total n Total % 4.5% 8.9% 4.5% 0.0% 0.9% 9.8% 8.9% 5.4% 1.8% 0.0% * Age > 20 and < 60 years; Body Mass Index (BMI) > 35 and < 45 kg/m2. ** Includes acute renal failure, drain hemorrhage, bowel perforation, constipation, omental necrosis, and rhabdo Abbreviations: RYGBP, Roux-en-Y Gastric Bypass Procedure; LOS, length of stay; n, number; PE, pulmonary embolism. Several studies have evaluated whether gastric bypass surgery for obesity benefit type 2 diabetes. The most striking long-term results are from Poires et al, from the East Carolina University group. 37, 38 The effects of gastric bypass were assessed in 165 patients with type 2 DM and 165 with impaired glucose tolerance (IGT). After mean follow-up of 7 6 years, 83% of diabetic patients were off pharmacological treatment and 99% of those with IGT were euglycemic. In another report the same investigators compared 154 diabetic patients who had surgery with 78 who did not. 38 The percentage requiring oral medications or insulin rose from 56% to 88% in the control group, but fell from 32% to 9% in the treatment group. The Swedish Obese Subjects (SOS) study followed patients following gastric bypass surgery and with respect to effects on type 2 DM and reported that mean weight loss of 28 kg at 2 years led to improved glycemic control in 118 diabetic patients. 39 This weight loss led to withdrawal of oral hypoglycemic drugs or insulin in many patients, whereas the need for drugs increased in the 77 non-surgically treated patients. The proportion treated by diet alone rose from 59% to 73% in the surgical group, but in the non-surgical group it declined from 55% to 34%. Surgery resulted in a 30-fold reduction in risk of progression from impaired glucose tolerance to diabetes in the Greenville study and the frequency of diabetes was reduced 30-fold at 2 years and five-fold at 8 years after surgery in the 40, 41 SOS study. In a series of 2241 patients, biliopancreatic diversion (BPD) resulted in a mean permanent reduction of 75% of the initial excess weight, with an operative mortality of 0 5%. 42 In this study, Scopinaro et al. showed that BPD achieved durable normalization of plasma glucose, plasma insulin, and glycosylated hemoglobin in % of severely obese diabetic patients Given the findings of a powerful effect upon clinical status of type 2 DM and IGT, additional metabolic studies have documented the potent effect of bariatric procedures on improving all aspects of pathogenesis of type 2 diabetes. Numerous studies have documented the insulinotropic ( incretin ) effects that restore pancreatic B cell function and potent insulin sensitizing effect of these procedures. Three hypotheses have been generated as to mechanisms for diabetes reversal following surgery. The first is negative energy balance. The second is amelioration of lipotoxicity, a process related to dysregulated fatty acid flux, lipid metabolites in tissues, and to direct and indirect endocrinological effects of hormones and cytokines secreted by adipocytes. The third postulate may be related to gut hormones. It is possible that the surgical alterations to the anatomy of the small intestine secondary to the Roux-en-Y gastric bypass CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

84 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August surgery results in altered sites, or at least altered relative distribution, of carbohydrate and fat absorption, which may trigger altered gut hormone responses to meal ingestion. Studies by Rubino et al. have documented these findings prior to weight loss, suggesting that the benefit of bariatric surgery for remission of diabetes may be independent of weight loss. 46 Therefore, we propose bariatric surgery as a novel primary treatment modality for resolution of type 2 diabetes in patients with mild to moderate obesity. We also propose metabolic substudies to document mechanisms of reversal of diabetes in this population. These substudies are mechanistic in nature and will asses these procedures with respect to changes in pancreatic B cell function, insulin sensitivity as a function of changes in gut hormones, adipocytokines and body composition. Recently, in a randomized controlled trial, O Brien et al compared bariatric surgery (laparoscopic adjustable gastric banding) to aggressive diet and exercise in patients with a BMI between during 2 year follow-up. 36 Bariatric surgery resulted in superior weight loss (87% EWL vs. 21.8% EWL, P<0.001) and resolution of the metabolic syndrome (14/15 patients vs 7/15 patients, P < 0.002) The remarkable weight loss and resolution of metabolic syndrome achieved by surgical intervention in patients with only moderate obesity (BMI 30-35) suggests that type 2 diabetics would likely have similar profound benefits. We have a dilemma in advising our mildly obese patients with diabetes. On the one hand we have the traditional programs of diet and exercise, which can achieve a modest weight loss, sufficient for those who are overweight (BMI 25 30) but probably not for the obese (BMI > 30). On the other hand, traditional surgical procedures have generally been reserved for those with a BMI > 35 if co-morbidity is present and BMI > 40 for the remainder. However, use of bariatric operations in mildly obese diabetics has not been extensively evaluated to date. Our study intends to evaluate the efficacy of bariatric operations specific to type 2 diabetics with BMI This is the central question of this study in which we propose randomly allocating those in this weight range to a medical path or a surgical path and following the outcomes for at least five years. It is hoped that this study will define what can be achieved by the best of the current options. 2 Study Objectives Diabetes and obesity are two of the most common and most intractable health problems. The common perception is that medical and dietary management does not work and that surgical procedures can be effective but are too invasive and dangerous. In recent years there has been major refinement of both the medical options and the surgical options. The proposed study enables us to document carefully the efficacy of each treatment modality and their relative efficacy in a prospective controlled fashion. The aim of the study is to compare the relative clinical outcomes between bariatric surgery (RYGBP and LSG) and advanced medical therapy for diabetes in patients with mild to moderate obesity. Specifically, the study will examine the short and long term effects of each intervention on biochemical resolution of diabetes, diabetic complications and end-organ damage. Each program will occur in the setting of dietary and exercise advice and support. CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

85 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Study Design General Design This is a randomized controlled trial assessing advanced medical therapy to advanced medical therapy plus bariatric surgery for the resolution of type 2 diabetes. Following 2 screening visits, including nutritional and psychological assessment and appropriateness of subjects for surgical consideration, subjects will be randomly assigned to be in the advanced medical vs. the advanced medical + surgical treatment arm. The advanced medical arm will consist of timely application of diabetes nutrition and exercise counseling, frequent home glucose monitoring, and aggressive pharmacologic intervention with insulin sensitizers, incretin mimetics, and early intervention with insulin therapy. The advanced medical plus surgical arm will deliver these therapies plus one of two bariatric procedures following randomization. 3.2 Primary Study Endpoints The primary study endpoint is the success rate of biochemical resolution of diabetes at 12 months as measured by HbA1c < 6%. 3.3 Secondary Study Endpoints The following parameters will be analyzed as secondary endpoints. Methods of analysis will be fully described in the Statistical Analysis Plan (SAP). Long Term Diabetes Control 1. Time to first occurrence of HbA1c < 6%. 2. Mean and change from baseline in HbA1c. 3. Mean and change from baseline in fasting plasma glucose levels. 4. Number of medications (number of insulin injections) required for targeting euglycemia End Organ Damage 1. Renal Assessment a. Development of nephropathy defined as meeting one of the following criteria: i. Doubling of serum creatinine or a 20 ml/min/1.73m 2 decrease in estimated GFR as estimated by the MDRD equation. ii. Development of macroalbuminuria (albumin/creatinine ratio > 300mg albumin per gram creatinine in random urine sample) iii. Development of renal failure as defined by renal transplantation or initiation of dialysis or a rise in serum creatinine >3.3 mg/dl in the absence of an acute reversible cause. b. Development of microalbuminuria (albumin/creatinine ratio > 30 mg albumin per gram creatinine in random urine sample). 2. Ophthalmologic Assessment a. New development or worsening of existing retinopathy at 2 and 5 years. CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

86 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Cardiovascular Assessment a. Change in carotid intimal medial thickness (measure of atherosclerotic burden) b. Change in brachial artery reactivity in response to hyperemia (as measured by strain gauge plethysmography in substudy patients) c. Incidence of any of the following: i. Myocardial infarction ii. Stroke iii. Diagnosis of congestive heart failure Comorbidity Reduction 1. Percentage of patients with hypertension and/or requiring antihypertensive therapy. 2. Percentage of patients with dyslipidemia and/or requiring cholesterol lowering medications. Body Composition 1. Change from baseline in neck, hip and waist measurements. 2. Percent weight loss from baseline. 3. Truncal and peripheral fat as measured by DEXA scan (in sub study patients). Quality of Life (QOL)/Health Economics 1. Change from baseline in score for SF-36 and diabetes QOL questionnaires. 2. Cost effectiveness analysis. 3.4 Safety Endpoints Complications specifically related to diabetes disease and treatment, as well as complications of bariatric surgery will be evaluated. Complications of Diabetes Disease and Treatment 1. Death from any cause 2. Episodes of severe hypoglycemia requiring third party assistance. 3. Weight gain from baseline Complications of Bariatric Surgery 1. Gastrointestinal leaks 2. Pulmonary embolus 3. Deep vein thrombosis (DVT) 4. Fascial dehiscence 5. Hernia formation 6. Stricture 7. Wound infection CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

87 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Marginal ulceration 9. Gastrointestinal fistula 10. Bowel obstruction 11. Respiratory complications that extend hospital stay 12. Gallbladder disease 13. GI bleed leading to transfusion 14. Stomal stenosis 15. Length of Stay >7 day post-operative 3.5 Exploratory Endpoints Contingent upon IRB approval/favorable opinion and acquisition of additional research funding, the following tests may be performed on frozen stored samples at a later date: 1. Cardiovascular biomarkers such as CRP, PAI-I, Fibrinogen, Homocysteine, Apo-A, Apo- B, Uric acid and Lpa. 2. Gut hormones such as Gherlin, PYY, GLP-1, GIP, SRBP4 3. Research Repository for Adipokines such as resistin, adiponectin, leptin, SRBP, TNFalpha, IL-6 4. Genomic analysis 3.6 Other Assessments Tissue samples - will be collected on all surgery patients at baseline only a. Liver Biopsy for measures of fatty liver disease and steatohepatitis 3.7 Sub Studies Cardio-metabolic Assessment The first 20 patients per arm who are able to complete the procedures, for a total of 60 patients, will have the following tests performed at baseline, 1 and 2 years. a. Mixed Meal Tolerance Test (MMTT) to assess measures of B cell function and insulin resistance as a function of changes in expression of gut hormones and adipokines. b. Dexa Scan to assess truncal and peripheral fat. c. Strain gauge venous occlusion plethysmography as a measure of brachial artery reactivity. Objectives: This sub-study is designed to investigate rates and mechanisms of reversal and improvement of type 2 diabetes mellitus following the two bariatric surgery interventions and advanced medical therapy. We propose a prospective systematic evaluation at baseline and at one and two years following the respective therapy to assess glucose metabolism; insulin resistance, insulin secretion (pancreatic B cell recovery) and gut hormones profile in type 2 diabetic subjects. Since diabetes is a risk equivalent for cardiovascular disease, measures of CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

88 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August endothelial function will also be assessed. Specific aim of the sub-study will concern the rate of improvement of pancreatic B cell function (measurement of insulin secretion in response to mixed meal), gut hormone secretion, and overall glucose metabolism following bariatric surgery. Hypothesis: We anticipate marked improvement of B cell function with surgical therapy and no change or decline with medical therapy alone. Specifically, with the bariatric interventions, we anticipate a decrease of lipotoxicity leading to improvement of insulin resistance and perhaps more importantly, a marked improvement in insulin secretion due not only to alleviation of insulin resistance, but also by specific effects of Roux-en-Y procedure on the entero-insular axis of gut hormones and subsequent effects on ß-cell function. Design/Methods: The first twenty subjects from each arm of the study will be enrolled. A mixed meal tolerance test will be administered following a twelve hour overnight fast. Antidiabetic medications will be held for 24 hours prior to study. However, short acting insulin may be taken for glucose control as indicated by the research staff. Prior to initiation of baseline blood draw for mixed meal tolerance test, subjects will undergo strain gauge venous occlusion plethysmography. Rate of change in vessel size (brachial artery reactivity) will be determined in response to hyperemia and nitroglycerine administration. Urine for microalbumin will also be measured prior to meal administration. Body composition assessment of total body and regional fat mass, as well as bone mineral mass and density will be measured using total body dual energy x-ray absorptometry (DEXA). Descriptions of these procedures are listed in the Appendix Randomization Patients will be randomized in a 1:1:1 ratio into one of the 3 treatment options. The randomization scheme will be developed by a statistician at the Cleveland Clinic Coordinating Center for Clinical Research (C5Research). A blocking sequence will be used and subjects will be stratified according to diabetes severity, defined as insulin-requiring at the time of screening. Sealed and sequentially numbered envelopes containing the treatment assignment will be provided to the nurse coordinator responsible for patient enrollment. Once eligibility is confirmed, the nurse will select and open the next sealed envelope in sequence to reveal the treatment assignment. Envelopes must be selected in sequence and not to be opened prior randomization. The date and time of randomization (envelope opened) will be recorded on the Case Report Form. 3.9 Blinding Patients and study personnel will not be blinded to treatment assignment. The treatment assignment will remain unknown until the patient is randomized after meeting all eligibility requirements. 4 Subject Selection 4.1 Inclusion Criteria Entry into the study would require that the patient: CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

89 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Is a candidate for general anesthesia. 2. Is > 20 and < 61 years old. 3. Have a body mass index > 27 and < 43 kg/m2. 4. Have biochemical evidence of type 2 diabetes confirmed by the following diagnostic criteria: a. If treated HbA1c > 7.1% b. If untreated - fasting 2-hour plasma glucose level of > 200mg/dL during an oral glucose tolerance tests and a HbA1c of > 7.1%. 5. Have the ability and willingness to participate in the study and agree to any of the arms involved in the study. 6. Able to understand the options and to comply with the requirements of each program. 7. Have a negative urine pregnancy test at screening and baseline visits (prior to surgery) for women of childbearing potential. A woman of childbearing potential is one who is biologically capable of becoming pregnant. This includes women who are using contraceptives or whose sexual partners are either sterile or using contraceptives. 8. Female patients must agree to use reliable method of contraception for 2 years. 4.2 Exclusion Criteria Patients who meet the following criteria will be excluded from the study: 1. Prior bariatric surgery of any kind. 2. Prior complex foregut surgery including splenectomy, upper GI, Nissen, trauma. 3. Abdominal, thoracic, pelvic and/or obstetric-gynecologic surgery within 3 months or at the discretion of the surgeon. 4. Any other surgery requiring general anesthesia within 6 weeks prior to signing the ICF. 5. Cardiovascular conditions including significant known coronary artery disease (CAD), dysrhythmia, known peripheral vascular disease (large vessel disease), uncompensated congestive heart failure, history of stroke, or uncontrolled hypertension (defined as medically treated with the mean of 3 separate measurements SBP > 180 mm Hg or DBP > 110 mm Hg). Subjects with CAD that have been successfully treated with coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI), or are 1 year after implantation of drug eluting stent, and have no evidence of active ischemia are eligible. 6. Kidney disease including renovascular hypertension, renal artery stenosis, or chronic renal insufficiency with a creatinine level > 1.8 mg/dl. 7. Known history of chronic liver disease (except for NAFLD/NASH), hepatitis, positive serologic test result for hepatitis B surface antigen and/or hepatitis C antibody, alpha-1- antitrypsin deficiency. 8. Gastrointestinal disorders including a known history of celiac disease and/or any other malabsorptive disorders or inflammatory bowel disease (Crohn s disease or ulcerative colitis). 9. Psychiatric disorders including dementia, active psychosis, severe depression requiring > 2 medications, history of suicide attempts, alcohol or drug abuse within the previous 12 months. 10. Pregnancy. 11. Malignancy within five years (except squamous cell and basal cell cancer of the skin). Subjects diagnosed with early / stage 1 cancer that have been successfully treated are eligible per Investigator discretion. CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

90 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Anemia defined as hemoglobin less than 9 in females and 11 in males. 13. Any medical condition requiring anticoagulation therapy that cannot be temporarily discontinued for surgical procedure. 14. Known history of clotting disorders, including pulmonary embolus and deep vein thrombosis. 15. Use of any medications (prescription or OTC), including herbal or other supplements for treatment of obesity, or liver conditions at the time of consent. 16. Any condition or major illness that, in the investigator s judgment, places the subject at undue risk by participating in the study. 17. Unable to understand the risks, realistic benefits and compliance requirements of each program. 18. Use of investigational therapy or participation in any other clinical trial within 12 weeks prior to signing the ICF. 19. Severe pulmonary disease defined as FEV1 < 50% of predicted value. 20. ASA class IV or higher. 21. Non-English speaking. 22. Plans to move outside the Greater Cleveland area within the next 2 years. 4.3 Subject Recruitment and Screening Initial recruitment into the study would be achieved by a general awareness campaign, which will emphasize a study of methods of diabetes management, and may include identification of subjects through internet associated contacts and media lists. A research nurse, familiar with the trial, will initially pre-screen patients for inclusion and exclusion criteria. Detailed information regarding the problems of diabetes, obesity and of the randomization arms of the study would be provided by at least two discussion periods and the provision of a Patient Information Booklet. Evaluation of the inclusion and exclusion criteria will occur both at the initial screening visit and the baseline visit prior to randomization. Patients who no longer meet the criteria at baseline will not be randomized and will be considered a screen failure. Subjects who previously screen failed may be considered for re-consenting when clinically appropriate, and will have screening / baseline procedures repeated at the discretion of the Principal Investigator. Subjects who have screen failed based on HbA1c and/or BMI and are re-screened within 6 months, will only have the baseline HbA1c and BMI repeated. 4.4 Early Withdrawal of Subjects Patients may withdraw from the study at any time without prejudice. All subjects will be followed until the conclusion of the study unless the subject requests withdrawal of consent Data Collection and Follow-up for Withdrawn Subjects If a patient discontinues or withdraws prior to study completion, all applicable activities scheduled for the final study visit should be performed at the time of discontinuation. Any adverse experiences that are present at the time of discontinuation/withdrawal should be recorded. CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

91 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Study Treatments Description Individuals with type 2 diabetes and BMI > 27 and < 43 kg/m2 who meet the eligibility criteria (Section 4.1 and 4.2) and initial screening evaluation and baseline labs, will be randomized to one of three treatments: advanced medical therapy, advanced medical therapy plus Roux-en-Y Gastric Bypass, or advanced medical therapy plus Laparoscopic Sleeve Gastrectomy. The advanced medical management program will consist of current therapies designed to achieve intensive glycemic control with lifestyle and drug therapy (insulin sensitizers, GLP agonists, insulin), weight reduction with lifestyle modification and exercise and diet as per the current ADA guidelines. During the one to three months period prior to randomization, all patients who have completed the screening labs will receive standard medical therapy to control HbA1c, hypertension and lipids according to current ADA guidelines Glycemic Target In this trial, all subjects will receive intensive medical treatment based on the targeted level of glycemic control. The target and Action Required for HbA1c and self-monitoring of blood glucose (SMBG) are listed in Table 5. This target will be achieved by using a combination of currently approved pharmacologic therapy, self-management education and lifestyle interventions. Table 5. Glycemic Targets and Thresholds for Action No Action Required Action Required Threshold HbA1c < 6.0% > 6.0% SMBG If half of the measurements, over a 4 day period Are recorded as Fasting / ac < 100 mg/dl and 2 hr pc < 140 mg/dl Ac: antecibal; pc: postcibal; SMBG: self monitoring of blood glucose. Fasting / ac > 100 mg/dl or 2 hr pc > 140 mg/dl Self Management Education The goal of self-management education is to empower patients to take responsibility for making daily changes in their therapy to maintain the targeted level of glycemic control. Proficiency in self-monitoring of blood glucose (SMBG) using a home glucose monitor, is a key component of self-management, and will be stressed to all patients. Patients will be provided information and instructions of how to use SMBG data to alter therapy to achieve the target glycemic level. CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

92 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Patients will be asked to perform self-monitoring of blood glucose (SMBG) according to type of therapy (diet, oral treatment or insulin), blood glucose value and frequency of hypoglycemic episodes. Patients will be provided with algorithms to allow them to self-titrate their therapy according to their SMBG results and to avoid hypoglycemia or hyperglycemia. Patients requiring insulin will be taught how to vary their dose according to the carbohydrate content of their meals and variations in exercise. Less frequent testing may be acceptable if patients have safely achieved the glycemic target Dietary and Lifestyle Interventions All patients will have diabetes nutrition and education at baseline. Following randomization, patients will receive dietary and lifestyle recommendations, as recommended by the American Diabetes Association, to optimize glucose control. A designated certified diabetes educator will provide patient education and nutrition guidelines. These include: a) teaching dietary principles including carbohydrate counting; advice to engage in regular aerobic exercise (if medically fit to do so according to the physician who provides their medical care); teaching the technical and interpretative skills of blood glucose monitoring; and education of participants regarding management of hypoglycemia Visit Frequency and Inter-Visit Contacts Table 6 describes the activities to be performed at each post-randomization visit. Participants will have study visits every three months for the first two years of the trial, then every six months for the duration of trial. If glycemic target is not achieved, patients will be seen more frequently for aggressive clinical management of their diabetes. Changes in therapy will be documented in the medical record and captured in CRF at the time of regularly scheduled study visits. Inter visit contact (via , FAX or phone) will be in place between visits to monitor therapy, assess hypoglycemic episodes and detect any significant clinical changes. Patients will be instructed to contact the research staff if any of the following events occur: any major illness or hospitalization, any new diagnosis or drug prescription, any episode of hypoglycemia requiring assistance, or any concerns regarding their therapy. Supplemental visits will be arranged when ever required. Subjects on insulin therapy will undergo carbohydrate counting instruction per certified diabetes education. 5.2 Advanced Medical Management The advanced medical therapy for type 2 diabetes in this trial will consist of several strategies that utilize diet/lifestyle recommendations and aggressive combination pharmacotherapy targeting both hyperglycemia and weight loss that will begin at the time of randomization. The advanced medical arm will utilize the latest currently available glucose lowering therapies (biguandies, thiazolidinediones, exenatide, and hypoglycemic agents such as sulfonylureas and human insulin preparations). Prandial glucose lowering therapy such as pramilitide will also be utilized when appropriate in selected subjects. Advancement to combination therapy will be done swiftly for these patients and self management education will be provided to promote self CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

93 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August titration. All subjects will undergo a baseline education/self monitoring class with Certified Diabetes Educator and will undergo follow up visits with Educator as instructed by Endocrinologists. All subjects in this arm will be directly under the care by a board certified Endocrinologist from the Department of Endocrinology, Diabetes and Metabolism at Cleveland Clinic. Visits with the nurse or Physician will be scheduled more frequently if glycemic target is not achieved to ensure optimal glycemic management. Research nurse visits will occur at a minimum of every three months during the first 2 years if glycemic target is achieved, and every 6 months for the remaining 60 months follow-up period. Several approaches will be used to achieve and maintain near normal glycemia in all patients. These include aggressive early use and titration of several different acting oral agents targeting glycemia and weight loss, early use of GLP-1 agonist drug exenatide, frequent visits with the nurse or Endocrinologists, telephone contact, point-of care HbA1c testing, targeting postprandial and pre-prandial glucose levels, and emphasis on combination of agents. The exact time at which insulin will be started in individuals not taking insulin at randomization will be left to the discretion of the endocrinologist. Glycemic targets have been set at HbA1c of 6.0% and fasting plasma glucose of less than 126 mg/dl. To achieve these glycemic targets, subjects will require self management education and dietary and lifestyle interventions. Participation in diabetes education classes will include dietary guidance (carbohydrate counting) and self titration/management instructions. These approaches reflect intensive management strategies employed by certified Endocrinologist/Diabetologist in a teriatry referral center and those currently utilized by the multi-center NIH sponsored ACCORD trial. The following approaches, which are considered to be advanced when compared to current community practice for treatment of type 2 diabetes, will be implemented in the current trial. 1. Baseline diabetes education classes and exercise/nutrition guideline per the most current ADA clinical practice statement. 2. Initiate antihyperglycemic therapy for all patients (metformin 500 mg bid titrated to 850 mg bid over 2-3 months). Subjects who experience extreme adverse reaction to metformin (severe GI intolerance) or have a baseline A1c of 8% or greater will receive Actos 30mg q day titrated to 45 mg q day over 3 months. 3. In addition to biguanide and actos initiation, exenatide will be initiated at 5 mcg sub cut bid for one month, followed by dose titration to 10 mcg sub cut bid. If subjects are previously on maximal biguanide and actos therapy, exenatide will be initiated at initial post-randomization visit. 4. Following 3 months of biguanide, actos and exentide injection therapy, if target HbA1c remains above 6%, sulfonylureas will be initiated and titrated over 3 months period. Repaglinide, an insulin secretagogue may be substituted for sulfonylurea therapy in those individuals with erratic meal schedules or with hypoglycemia or sustained postprandial hyperglycemia. 5. Insulin will be administered for those with HbA1c of 6.0% or greater after the above agents have been utilized within 6 months of randomization. Insulin will be initiated at bedtime and titrated per algorithm. Specific algorithms, listing current ADA guidelines, and sequence of glycemic therapy to follow pending results of HbA1c and /or SMBG are included in the Appendices. CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

94 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Glycemia Medications currently available within STAMPEDE The following classes of antihyperglycemic drugs are currently available within STAMPEDE. Please refer to Appendix 4 for complete details: a. Biguanides (eg. Metformin) b. Thiazolidinediones (eg. Pioglitazone) c. Exenatide (eg. Byetta) d. Secretagogues (eg. Sulfonylureas such as glimepiride and meglitinides such as repaglinide) e. Insulins (e.g., NPH, glargine, aspart, regular, apidra) As new medications are approved for therapy, they will be added to the list and treatment algorithm. Antihyperglycemic therapy will not be reduced for any patients whose HbA1c is greater than 6.0%, unless required due to adverse effects or severe hypoglycemia. Anti hyperglycemic therapy will be reduced if any of the following occur: 1. Any severe hypoglycemia. 2. > 1 episode of hypoglycemia per week. 3. Adverse effects of antihyperglycemia medications. 4. > 50% of SMBG levels < 90 ml/dl (5 mmol/l). 5. HbA1c < 5.5% on one occasion or 5.6% 5.99% on two consecutive occasions Hypertension Management It is recommended that blood pressure intervention begin at the first visit at the same time glycemia therapy is initiated. Blood pressure will be measured at every routine visit. Patients found to have systolic blood pressure > 130 mmhg or diastolic blood pressure > 80 mmhg, confirmed on a separate day, will be treated and monitored according to the current ADA guidelines and outlined in Appendix Lipid Management Testing for lipid disorders will be performed on all patients at least on an annual basis, and more often if needed to achieve goals. The primary goal is an LDL < 100 mg/dl (2.6 mmol/l) and triglycerides < 150 mg/dl (1.7 mmol/l). Treatment recommendations and goals will be followed according to the current ADA guidelines with specific attention given to patients over the age of 40 years. 5.3 Advanced Medical Therapy Plus Surgical Management Patients randomized to RYGBP or LSG will have the procedure performed by standard technique as soon as possible after randomization. LSG normally requires approximately 60 minutes of operating time and a one to three day length of hospital stay. A barium meal will be performed on the first day postoperatively to document sleeve patency and the absence of leaks. CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

95 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August The Roux-en-Y gastric bypass procedure requires 1-2 hours of operating time and two to three day length of hospital stay. For both operations, there will be a transition from initial liquid food intake through to solid food only intake over an eight-week period. Glucose will be monitored in the hospital post-operatively. Due to limited oral intake and negative energy balance during the first week after surgery, no oral agent or insulin will be prescribed at the time of discharge. Patients will be instructed to monitor their blood glucose at home with fasting and post prandial checks in the morning and evening for the first week after discharge and call the bariatric surgery clinic if glucose levels are above 200 mg/dl. At the time of the one-week follow-up appointment, fasting glucose will be measured and, if elevated, Metformin will be initiated. Further antidiabetic medication will be added / titrated / reduced in these patients as defined in Section 5.2 Advanced Medical Management and outlined in Appendix 4, 5 and 6. 6 Study Procedures In addition to laboratory testing to monitor diabetic control, labs and clinical studies will be performed to evaluate end-organ damage and metabolic changes in the medical and surgical groups during the follow-up period: 6.1 Labs and Clinical Studies Laboratory Studies Table 6 shows the schedule of laboratory procedures drawn during screening and baseline to determine eligibility status. After randomization, laboratory tests will be drawn at regular intervals during the 60 month follow-up. HbA1c levels will be used to determine titration of hypoglycemic therapy, for safety purposes and for later analysis. Blood samples for gut hormones, cardiovascular markers and a research repository including a urine specimen (Center for Cardiovascular Diagnostics Biobank) will be drawn and frozen for later analysis. Patients will also be consented to participate in a one time blood sample that will be stored for future DNA extraction for genetic analysis. Refusal to participate in the genetic analysis will not effect participation or treatment in the main study. Body Composition Measurements Anthropometry measurements will occur at screening, baseline, and at every 6 months after medical or surgical intervention, for 60 months. Measurements include body weight, and neck, hip and waist measurements. For a subgroup of patients enrolled in the study, total body and regional fat mass, as well as bone mineral mass and density will be measured using total body dual energy x-ray absorptometry (DEXA). A total body radiation exposure of < 1 usievert will be given over 20 minutes. The CV of this test is < 1 % for bone and 2% for soft tissue. This subgroup of patients will consist of 20 medical and 20 surgical patients from both surgical treatments (total of 60 patients). Testing in this subgroup will occur at randomization and 12 and 24 months during follow-up. CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

96 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Assessment of End-Organ Damage Renal Urine Microalbumin and urine creatinine will be measured by a morning urine sample collected at baseline and 6, 12, 18, 24, 36, 48, and 60 months. In addition to performing a standard urinalysis, the urine sample will be tested for albumin and creatinine. The urine albumin to creatinine ratio provides an accurate screening test for renal parenchymal (structural) damage. Cardiovascular Carotid intima-media thickness (CIMT) is a measurement of the thickness of the two inner layers of the carotid artery. It represents a window through which the risk of developing coronary or cerebral atherosclerotic disease can be estimated, as well as assessing responsiveness to interventions. A standardized protocol will be utilized using duplex ultrasound to obtain the mean and maximum CIMT values of the common carotid arteries. All scans will be performed by experienced ultrasound technologists and measured by a technician trained specifically for measuring CIMT, there will a second reviewer and physician reader. Baseline measurements will be taken of all patients in each of three arms of the study and follow up scans will be performed at 2 years. Strain gauge venous occlusion plethysmography provides a measure of endothelial function of brachial artery in response to hyperemia, and will be performed in sub study patients only (20 per group). It involves baseline measurements of the brachial artery followed by occlusion of the brachial artery with a blood pressure cuff for five minutes. After the cuff is released, measurements of the brachial artery are repeated. Oral nitroglycerin is then given and the measurements are repeated. This test provides information regarding the stiffness of the brachial artery which closely correlates with coronary atherosclerotic disease. This non-invasive test takes approximately 30 minutes to complete and will be performed at baseline and 24 months after medical or surgical intervention begins. Eye Ophthalmologic examination will be performed by a qualified ophthalmologist in all patients enrolled in the study. All Patients entering the study will undergo baseline ophthalmologic examination and re-examination at year 2 and year 5 of the study. If treatments are required during the course of the study, those treatments will be noted on the data sheets. Snellen acuity will be measured and diabetic retinopathy and macular edema will be graded on a severity scale (Appendix 12). Questionnaires The Rand 36-Item Health Survey (SF-36) a multi-purpose survey of general health and outcomes. It uses patient responses to measure each of eight health concepts, and can be scored as an 8-scale profile of summary physical and mental health outcomes. It also includes a selfevaluation of outcomes, which have been shown to capture changes in health during the past year. CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

97 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Diabetes Questionnaire two questions, scored in the same manner as the standard SF-36 form, to evaluate the impact of diabetes interventions on health status and health-related quality of life. Patient Utility Questionnaire and Healthcare Utilization Form - developed to collect both the cost and effectiveness data for persons in the trial from the societal perspective. 6.2 Screening / Visit 1 (up to 3 months) Prior to study entry the following screening procedures will be performed: Obtain written informed consent prior to conducting any study related procedures Review inclusion and exclusion criteria to establish eligibility Medical history and full physical exam Sitting BP Demographic details including height, weight, smoking history, alcohol consumption Psychiatric evaluation Nutrition counseling Resting 12-lead electrocardiogram Central Laboratory tests Blood collection to perform the following assessments: Hemoglobin A1c Fasting Plasma Glucose Chem 12 CBC Lipids TSH Record medication treatments All patients will be treated for diabetes with standard therapy Schedule next visit within the next 4 weeks Between the screening and baseline visit, patients will be scheduled for diabetic education. This will include standard diabetic teaching in the Endocrinology department and will include the initiation of a diet and exercise program. Additionally, patients will attend a workshop that specifically addresses the treatments offered in this study. This will be a small group format and will take place in the Bariatric and Metabolic Institute. These workshops will be presented by the investigators and appropriate nursing staff and the study coordinator and will consist of a formal presentation of the medical and surgical treatments involved in the study and the risks and potential benefits of each arm will be presented again to the patients. The formal presentation will be followed by a question and answer session with the patients. 6.3 Baseline and Randomization / Visit 2 (within 1 month of Day 0) The following Baseline procedures will be performed at Visit 2 or Visit 3, prior to randomization Review inclusion and exclusion criteria to establish eligibility Medical history and full physical exam Sitting BP Weight Body composition measurements including neck, hip and waist circumference CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

98 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Medical clearance for surgery will be based on Health Quest. Patients will be evaluated by the Impact Center at the discretion of the surgical team. Central Laboratory tests Blood collection to perform the following assessments: Hemoglobin A1c Fasting Plasma Glucose C Peptide Insulin Chem 12 CBC Lipids Urinalysis (microalbumin and creatinine) Urine Pregnancy test Gut Hormones (refer to Section 3.5) Cardiovascular Markers (refer to Section 3.5) Research Repository (refer to Section 3.5) Retinal Exam Carotid IMT SF-36 Diabetes Questionnaire Patient Utility Questionnaire Review medication treatments and record any changes Randomize subject into study via the coordinating center Patient education for diabetes Medical clearance will be based on Health Quest. Patients will be evaluated by the Impact Center at the discretion of the surgical team. 6.4 Post Randomization / Visit 3 (+ 1 month) Sub Study The first 20 patients randomized per study arm that are able to complete the procedures, for a total of 60 patients, will have the following assessments prior to any intervention: MMTT Dexa Scan Strain gauge plethysmography Advanced Medical Treatment Adjust diabetic therapy according to baseline labs. Surgery patients randomized to RYGBP or LSG Surgery will be scheduled as soon as possible after randomization. If subjects are unable to have surgery within 2 months of randomization date, follow-up visits will be based on surgery date, and central labs (HbA1c, fasting plasma glucose, others) may be redrawn prior to surgery for baseline values, at the discretion of the Principal Investigator. Pre-op clinic visit Adjust diabetic treatment according to baseline labs Preoperative education CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

99 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Initiate liquid diet 2 days pre-op Day of surgery Liver biopsy tissue sample obtained at time of surgery Post-op Day 1 - Barium Meal Introduction to solid food diet instruction Adjust diabetic medication as needed Day 5 to 7 - nurse visit for surgical drain removal One month post-op Physician evaluation Psychological and nutritional follow-up as needed 6.5 Follow-up Visits If a subject does not return for a scheduled visit, every effort should be made to contact the subject. In any circumstance, every effort should be made to document subject outcome, if possible. If subjects randomized to surgery are unable to have surgery within 2 months of randomization date, follow-up visits will be based on surgery date. Advanced Medical Management Fasting labs and HbA1c will be monitored in all patients. If HbA1c or fasting glucose is in the action required range (Table 5), therapy will be adjusted accordingly Weight Loss and Reducing Antihyperglycemic Agents If weight loss is achieved and fewer agents are required for diabetic control later in the follow-up period, agent will be discontinued in the reverse order that they were instituted and evaluation will continue to maintain the patient s HbA1c < 6% and fasting glucose < 126 mg/dl Visit 4 / Month 3 (+ 2 weeks) Medical history and full physical exam Sitting BP Weight Central Laboratory tests Blood collection to perform the following assessments: Hemoglobin A1c Fasting Plasma Glucose Patient Utility Questionnaire and Healthcare Utilization Form Nutrition Counseling Diabetes Education Adjustment of medical treatment as needed Schedule next visit Visit 5 / Month 6 (+ 2 weeks) Medical history and full physical exam Sitting BP CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

100 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Weight Body composition measurements including neck, hip and waist circumference Central Laboratory tests Blood collection to perform the following assessments: Hemoglobin A1c Fasting Plasma Glucose Urinalysis (microalbumin and creatinine) Cardiovascular Markers (refer to Section 3.5) Patient Utility Questionnaire and Healthcare Utilization Form Nutrition Counseling Diabetes Education Adjustment of medical treatment as needed Schedule next visit Visit 6 / Month 9 (+ 2 weeks) Medical history and full physical exam Sitting BP Weight Central Laboratory tests Blood collection to perform the following assessments: Hemoglobin A1c Fasting Plasma Glucose Patient Utility Questionnaire and Healthcare Utilization Form Nutrition Counseling Diabetes Education Adjustment of medical treatment as needed Schedule next visit Visit 7 / Month 12 (+ 2 weeks) Sub Study -patients randomized will also have the following assessments: MMTT Dexa Scan Strain gauge plethysmography Medical history and full physical exam Sitting BP Weight Body composition measurements including neck, hip and waist circumference Central Laboratory tests Blood collection to perform the following assessments: Hemoglobin A1c Fasting Plasma Glucose Insulin Chem 12 CBC Lipids Urinalysis (microalbumin and creatinine) CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

101 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Gut Hormones (refer to Section 3.5) Cardiovascular Markers (refer to Section 3.5) Research Repository (refer to Section 3.5) SF-36 Diabetes Questionnaire Patient Utility Questionnaire and Healthcare Utilization Form Nutrition Counseling Diabetes Education Adjustment of medical treatment as needed Schedule next visit Visit 8 / Month 15 (+ 2 weeks) Medical history and full physical exam Sitting BP Weight Central Laboratory tests Blood collection to perform the following assessments: Hemoglobin A1C Fasting Plasma Glucose Patient Utility Questionnaire and Healthcare Utilization Form Nutrition Counseling Diabetes Education Adjustment of medical treatment as needed Schedule next visit Visit 9 / Month 18 (+ 2 weeks) Medical history and full physical exam Sitting BP Weight Body composition measurements including neck, hip and waist circumference Central Laboratory tests Blood collection to perform the following assessments: Hemoglobin A1c Fasting Plasma Glucose Urinalysis (microalbumin and creatinine) Patient Utility Questionnaire and Healthcare Utilization Form Nutrition Counseling Diabetes Education Adjustment of medical treatment as needed Schedule next visit Visit 10 / Month 21 (+ 2 weeks) Medical history and full physical exam Sitting BP Weight CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

102 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Central Laboratory tests Blood collection to perform the following assessments: Hemoglobin A1c Fasting Plasma Glucose Patient Utility Questionnaire and Healthcare Utilization Form Nutrition Counseling Diabetes Education Adjustment of medical treatment as needed Schedule next visit Visit 11 / Month 24 (+ 4 weeks) Sub Study -patients randomized will also have the following assessments: MMTT Dexa Scan Strain gauge plethysmography Medical history and full physical exam Sitting BP Weight Body composition measurements including neck, hip and waist circumference Central Laboratory tests Blood collection to perform the following assessments: Hemoglobin A1c Fasting Plasma Glucose Insulin Chem 12 CBC Lipids Urinalysis (microalbumin and creatinine) Gut Hormones (refer to Section 3.5) Cardiovascular Markers (refer to Section 3.5) Research Repository (refer to Section 3.5) Retinal Exam Carotid IMT SF-36 Diabetes Questionnaire Patient Utility Questionnaire and Healthcare Utilization Form Nutrition Counseling Diabetes Education Adjustment of medical treatment as needed Schedule next visit At month 27, mail Economic/Cost Utilization Questionnaire Visit 12 / Month 30 (+ 4 weeks) Medical history and full physical exam Sitting BP CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

103 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Weight Central Laboratory tests Blood collection to perform the following assessments: Hemoglobin A1C Fasting Plasma Glucose Patient Utility Questionnaire and Healthcare Utilization Form Nutrition Counseling Diabetes Education Adjustment of medical treatment as needed Schedule next visit At month 33, mail Economic/Cost Utilization Questionnaire Visit 13 / Month 36 (+ 4 weeks) Medical history and full physical exam Sitting BP Weight Body composition measurements including neck, hip and waist circumference Central Laboratory tests Blood collection to perform the following assessments: Hemoglobin A1c Fasting Plasma Glucose Insulin Chem 12 CBC Lipids Urinalysis (microalbumin and creatinine) SF-36 Diabetes Questionnaire Patient Utility Questionnaire and Healthcare Utilization Form Nutrition Counseling Diabetes Education Adjustment of medical treatment as needed Schedule next visit At month 39, mail Economic/Cost Utilization Questionnaire Visit 14 / Month 42 (+ 4 weeks) Medical history and full physical exam Sitting BP Weight Central Laboratory tests Blood collection to perform the following assessments: Hemoglobin A1c Fasting Plasma Glucose Patient Utility Questionnaire and Healthcare Utilization Form Nutrition Counseling Diabetes Education Adjustment of medical treatment as needed CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

104 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Schedule next visit At month 45, mail Economic/Cost Utilization Questionnaire Visit 15 / Month 48 (+ 4 weeks) Medical history and full physical exam Sitting BP Weight Body composition measurements including neck, hip and waist circumference Central Laboratory tests Blood collection to perform the following assessments: Hemoglobin A1c Fasting Plasma Glucose Insulin Chem 12 CBC Lipids Urinalysis (microalbumin and creatinine) SF-36 Diabetes Questionnaire Patient Utility Questionnaire and Healthcare Utilization Form Nutrition Counseling Diabetes Education Adjustment of medical treatment as needed Schedule next visit At month 51, mail Economic/Cost Utilization Questionnaire Visit 16 / Month 54 (+4 weeks) Medical history and full physical exam Sitting BP Weight Central Laboratory tests Blood collection to perform the following assessments: Hemoglobin A1c Fasting Plasma Glucose Patient Utility Questionnaire and Healthcare Utilization Form Nutrition Counseling Diabetes Education Adjustment of medical treatment as needed Schedule next visit At month 57, mail Economic/Cost Utilization Questionnaire End of Study - Visit 17 / Month 60 (+ 4 weeks) An End of Study Visit must be performed for all randomized subjects when the study is completed. The study will be considered complete when all subjects have had the opportunity CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

105 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August for 60 months of follow-up. The estimated study duration is months based on projected enrollment. Medical history and full physical exam Sitting BP Weight Body composition measurements including neck, hip and waist circumference Central Laboratory tests Blood collection to perform the following assessments: Hemoglobin A1c Fasting Plasma Glucose Insulin Chem 12 CBC Lipids Urinalysis (microalbumin and creatinine) Gut Hormones (refer to Section 3.5) Cardiovascular Markers (refer to Section 3.5) Research Repository (refer to Section 3.5) Retinal Exam EKG SF-36 Diabetes Questionnaire Patient Utility Questionnaire and Healthcare Utilization Form Adjustment of medical treatment as needed. 7 Statistical Considerations 7.1 Sample Size Determination The primary end point of the study is defined as biochemical resolution of diabetes at 12 months after entry into the study. Assuming rates of diabetes resolution at 12 months to be 83%, 50% and 20% in the gastric bypass, laparoscopic sleeve gastrectomy and advanced medical therapy arms, respectively, 50 patients will be enrolled into each arm in order to meet the objectives of the study. The expected lost to follow-up rate is 20% patients, leaving approximately 40 evaluable patients per arm. This will provide >99% power to detect differences among any of the 3 groups and 80% power to detect a difference between the 2 surgical arms, using a 2-sided alpha of The primary analysis will not be adjusted for multiple comparisons since the probability of diabetes resolution in one group is independent of the probability of diabetes resolution in either of the other two groups; therefore, the comparisons are assumed to be independent. 7.2 Analysis Populations Modified Intention-to-treat The modified intention-to-treat (ITT) population consists of all randomized patients that initiate treatment (surgery for those randomized to surgery and medical treatment for those randomized CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

106 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August to medical treatment). All analyses will be conducted in the modified ITT population and patients will be analyzed according to their original randomized treatment assignment. Per Protocol The protocol population consists of all randomized patients adhering to the treatment group to which they were assigned at randomization. Patients randomized to the medical therapy arm who then elect to have bariatric surgery will not be included in the per protocol population. The primary analysis will also be conducted in the per protocol population as a sensitivity analysis. 7.3 Statistical Methods Data will be analyzed according to the program into which the patients were randomized at baseline (modified intention-to-treat analysis). Data will be summarized using descriptive statistics. Categorical data will be described using frequencies and percentages and the chisquare statistic or fisher s exact test will be used, as appropriate, to compare treatment groups. Continuous variables will be summarized using means, medians, interquartile ranges and minimum and maximum values. For comparison of treatment groups, ANOVA will be used for data that are normally distributed. For non-normal data, the Kruskal-Wallis will be used. Further details will be provided in the Statistical Analysis Plan (SAP). 7.4 Interim Safety Analyses A Data Safety Monitoring Board (DSMB) will be assembled to review safety information. The first session will occur after the first 30 patients have completed the 3 month visit or at the end of the first year of enrollment, which ever comes first. The second session will occur after 90 patients have completed the 3 month visit. The purpose of this review will be to monitor the patient safety through a thorough review of adverse events and complications. No formal efficacy analysis will be conducted. Further details are described in the DSMB Charter. 7.5 Cost Effectiveness analysis The cost-effectiveness analysis will be conducted from the U.S. societal perspective as recommended by the U.S. panel for cost effectiveness in health and medicine 32. Sub-analysis may be conducted differently from the perspectives of patients, physicians, hospitals, and thirdparty insurance payers if necessary. The initial time horizon of the analysis is the 5-year study period, but will also be extended to 10 and 20 years using Markov modeling approach to measure the long-term cost-effectiveness difference between advanced medical therapy alone and advanced medical therapy combined with bariatric surgery. When data are collected after each visit, the intermediate analysis will be conducted to analyze the short-term costeffectiveness outcomes. The results from the intermediate study could be used to guide the concurrent treatment in clinical settings. Two categories of data are collected for the cost-effectiveness analysis: cost data and effectiveness data. The cost data will include both direct cost and indirect cost for patients with either advanced medical therapy alone and advanced medical therapy combined with bariatric surgery (Appendix 2). The direct cost will include three components: First, costs of inpatient care and emergency-room visits; second, costs of outpatient care, physician visits, and laboratory CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

107 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August tests; third, costs of prescription medications. In addition to the study-related cost itself, the direct cost that will be collected also include those costs for any medical reasons of the enrolled patients within the 5-year follow-up. All cost data in the study will be inflated to a common year using the medical care inflation indices from the Bureau of Labor Statistics (http// For patients with advanced medical therapy alone, costs of inpatient and/or emergency room visits should include any costs of this kind after the randomization, for example, the adverse event due to medications. For patients with advanced medical therapy combined with bariatric surgery, the additional inpatient cost will include the cost of LSG or RYGBP surgery procedure, post-surgery hospital stays, and any other inpatient visits. While data collection, if a patient is hospitalized after randomization, the primary reason and length of stay will be determined. Diagnosis categories will be coded on the Healthcare Utilization Case Report Form. This will be converted to a DRG code and mean Medicare charges for that DRG and length of stay will be used to derive a charge for this hospitalization ( The hospitalization costs will be estimated by adjusting charges using cost-to-charge ratios ( if charge value is the only available data. This component of the cost data should be collected with the best accuracy because it is presumably a large proportion of the overall costs. Table 7 Cost Data Advanced medical therapy Direct Cost 1. Medication prescription costs: Both medications for the study and any other medications (diabetes and/or obesity related). 2. Any inpatient and/or emergency room service costs: e.g., adverse events due to medicines. 3. Any kind of outpatient care and physician visit costs: Regular clinical visits and other kinds of visits Diagnostic and/or surveillance Laboratory tests Indirect Cost 1. Loss of work in hours due to the treatment or any diseaserelated kinds 2. Time of self-management education CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

108 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Bariatric Surgery 1. Any inpatient or emergency room costs: Surgery of LSG or RYGBP, other hospitalizations. 2. Any kind of outpatient care and physician visit costs: Regular clinical visits and other kinds of visits Care for short-term and long-term surgical complications Diagnostic and/or surveillance Laboratory tests 3. Medication prescription costs: Any diabetes and/or obesity related medications: e.g., used for treating surgical complications. 1. Loss of work in hours due to the treatment or any diseaserelated kinds 2. Time of self-management education Regarding the second component of the direct cost, patients with advanced medical therapy alone will have regular clinical visits for diabetes or obesity, diagnostic (to assess disease activity and disease extent) and/or surveillance, and laboratory tests. Patients with advanced medical therapy combined with bariatric surgery will have additional regular clinical visits for diabetes and obesity before, during, and after LSG or RYGBP, care for short-term surgical complications, care for long-term complications, diagnostic and/or surveillance, and laboratory tests. Information of clinical visits and lab tests for other medical reasons need to be collected as well. Based on the patient healthcare utilization case report form (CRF), these healthcare utilizations will be collected during each follow-up visit from the medical records and EPIC database. The costs will be priced using the Medicare reimbursement CPT and physician fee schedules ( The cost of prescription medications is another important component that needs to be collected after randomization because everyone starts with the advanced medical therapy. For patients with advanced medical therapy combined with bariatric surgery, the cost of medications for treating diabetes and/or obesity-related symptoms and surgery complications will be particularly of interest. Basically, every prescription the patient takes during the study period needs to be recorded. In order to calculate the prescription cost, information of prescription name, dosing amount, and days of supply are needed. National drug code (NDC) is helpful if it is available to collect but not required. The drug costs will be estimated based on the average wholesale price (AWP) reported in the Drug Topics Red Book. The indirect cost comes from the loss of work or loss of productivity due to the treatment. From the society perspective, such costs associated with both patients and their family members or caregivers who take care of the patients will be collected. During each follow-up visit, number of diabetes and/or obesity-related loss of hours (or work-days) from the last visit to this visit will be collected from the patients including the time for hospitalizations, clinical visits, traveling to the clinic, and waiting in the clinic. Time of self-management education should be included for all patients. The loss of productivity and time-related costs will be calculated as a product of days (hours) lost by their salary or salary range determined as part of the patients demography data at CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

109 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August baseline. Since the study investigators consent that our study patients will need minimal care from family caregivers, the indirect cost from family caregivers will not be collected. EQ-5D and paper standard gamble questionnaire 33 will be used to collect patients overall health related quality of life data both at the study baseline and each follow-up visits. These data will be used to derive the utility outcome (effectiveness) of the cost-effectiveness analysis. In its most typical form, the standard gamble involves the question of offering the patient a hypothetical magic pill. If the patient takes the pill, there is some chance he will immediately achieve perfect health, but there is 1 minus this chance that the patient will die immediately. Thus, with standard gamble, we are asking how much risk the patient is willing to take for a chance of perfect health. Because it involves uncertainty, standard gamble is the only true utility measure. Originally, a facilitator used props during a face-to-face encounter with the patient. This method is expensive, because it requires the facilitator s time. For ease-of-administration reasons, the paper-base tool (paper standard gamble) was designed and good results have been achieved 34. Using TreeAge Data pro suite, a cost utility model will be designed to investigate the costeffectiveness of the patients receiving the advanced medical therapy combined with bariatric surgery compared to the cohort of patients with advanced medical therapy alone. The cost of all healthcare utilization as calculated above will be included in the model. The health related quality of life (utility) results of the paper standard gamble will be applied so that results may be expressed as cost per quality adjusted life years (QALYs). Discount rates of 3% per year will be used for both costs and outcomes in this cost-utility model for multiple year adjustment. The incremental cost effectiveness ratio (ICERs) will be calculated for the base-case analysis, which is calculated by dividing the overall cost difference between advanced medical therapy alone and advanced medical therapy combined with bariatric surgery by the utility difference between therapies for the patients. Bootstrap simulation with replacement will be utilized to derive mean costs and utilities and associated ICERs with 95% confidence intervals. Net benefits will be constructed to determine the probability of the one therapy being cost-effective over the other under certain cost-effectiveness thresholds. Conventionally, ICERs of less than $50,000 per QALY are considered very cost-effective whilst those with an ICER of between $50,000 and $100,000 per QALY are considered moderately cost-effective 35. Similarly, cost-effectiveness analysis can be conducted using either the HbA1c level or the fasting plasma glucose level as the effectiveness outcomes of interest. The calculated ICERs will be costs per HbA1c percentage point reduction or costs per mg/dl glucose reduction. Although these outcomes are not as generic as QALYs, they can still be used to compare with related thresholds or guidelines in diabetes literature to decide whether the treatments are cost-effective. The Markov decision tree model will be used to derive the long-term cost-effectiveness differences between advanced medical therapy alone and advanced medical therapy combined with bariatric surgery for 10 and 20 years. The transition cycle of the Markov model will be 3 months. The transitional probabilities between different disease states (diabetic and non-diabetic status combined with obesity, overweight, or normal weight status) will be calculated from the collected incidence of the study, which is the number of incidence from a certain disease stage A to stage B in 3 months divided by the number of total patients. The cost and utility data of the Markov model will share the data from the 5-year study period after discounting of 3% as a base- CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

110 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August case. Similarly, ICERs will be calculated and bootstrap simulation will be used to derive the 95% confidence intervals of the ICER. Sensitivity analysis will be performed by varying costs and utilities by their 95% confidence intervals established in our study. The impact of varying the probabilities of the detection of preclinical disease and incidental findings will also be investigated in sensitivity analysis. Subgroup analysis will be used to investigate the patient characteristics that could contribute to the different cost-effective outcomes, including age, gender, race, and other risk factors. 8 Adverse Events Any adverse event as defined in Section 8.1 will be reported to the IRB following their reporting requirements. Patient safety will be protected according to standard clinical practice. 8.1 Definitions Adverse Event An adverse event (AE) is any new untoward medical occurrence or worsening of a preexisting medical condition in a subject which does not necessarily have a causal relationship with either surgery or medical management of diabetes. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of surgery or a medicinal product, whether or not related. This definition thus excludes those expected and normal responses to surgery, (including but not limited to post-operative pain normal to the procedure, nausea with vomiting not requiring treatment, lassitude, fatigue, sleeplessness, depression) and/or changes in diabetes medications (including but not limited to hyper and/or hypoglycemia not requiring medical intervention such as administration of insulin, glucose or hospital admission). Refer to Section 3.4 for a list of safety endpoints. Serious Adverse Event Adverse events are classified as serious or non-serious. A serious adverse event is defined as any adverse experience occurring that results in any of the following outcomes: death a life-threatening experience inpatient hospitalization or prolongation of existing hospitalization a persistent or significant disability or incapacity a congenital anomaly or birth defect Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. All adverse events that do not meet any of the criteria for serious should be regarded as non-serious adverse events. CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

111 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Recording of Adverse Events At each evaluation, subjects will be interviewed in a non-direct manner to elicit potential adverse reactions. The occurrence of an adverse event will be based on changes in the subject s physical examination, laboratory results, and/or signs and symptoms. All adverse events (except Grade 1 or 2 laboratory abnormalities that do not require an intervention), regardless of causal relationship, are to be recorded in the case report form (CRF) and source documentation. All adverse events occurring after study randomization will be recorded on the case report form. The clinical course of each event should be followed until resolution, stabilization, or until it has been determined that the study treatment or participation is not the cause. Serious adverse events that are still ongoing at the end of the study period must be followed up to determine the final outcome. Any serious adverse event that occurs after the study period and is considered to be possibly related to the study treatment or study participation should be recorded and reported immediately to the Principal Investigator. 9 Data Safety Monitoring Board A DSMB will be appointed for this study. Members of the DSMB will be independent of the study Investigators and will be responsible for the ongoing review of efficacy and safety data as well as the conduct and quality of the study. Members will be selected, a chairman will be appointed and a formal charter will be developed. DSMB members will meet at least two times during the course of the trial and safety data will be evaluated. The first meeting will occur either after 30 patients have reached their 3 month visit or in one year after enrollment begins, whichever comes first. The second meeting will occur after 90 patients have reached their 3 month visit. 10 Data Handling and Record Keeping 10.1 Confidentiality Information about study subjects will be kept confidential and managed according to the requirements of the Health Insurance Portability and Accountability Act (HIPAA). Those regulations require a signed subject authorization informing the subject of the following: What protected health information (PHI) will be collected from subjects in this study Who will have access to that information and why Who will use or disclose that information The rights of a research subject to revoke their authorization for use of their PHI. In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains the ability to use all information collected prior to the revocation of subject authorization. For subjects that have revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study period. CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

112 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Source Documents Source data is all information, original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents Case Report Forms As used in this protocol, the term case report form (CRF) should be understood to refer to either a paper form or an electronic data record or both, depending on the data collection method used in this trial. A CRF is required and should be completed for each consented subject. The completed original CRFs are the sole property of The Cleveland Clinic and should not be made available in any form to third parties, except for appropriate regulatory authorities. It is the investigator's responsibility to review, ensure completion and approve all CRFs. CRFs must be signed by the investigator or by an authorized staff member. These signatures serve to attest that the information contained on the CRFs is true. At all times, the investigator has final personal responsibility for the accuracy and authenticity of all clinical and laboratory data entered on the CRFs. Subject source documents are the physician's subject records maintained at the trial site. In most cases, the source documents will be the hospital's or the physician's chart. In cases where the source documents are the hospital or the physician's chart, the information collected on the CRFs must match those charts Records Retention The Investigator must maintain confidential all study documentation, and take measures to prevent accidental or premature destruction of these documents. It is recommended that the Investigator retain the study documents at least two (2) years after the completion or discontinuation of the Clinical Trial. However, applicable regulatory requirements should be taken into account in the event that a longer period is required. 11 Study Timeline The estimated study duration is 78 months. All patients will be followed from randomization until the study end date, which will occur when the last patient has been followed for 60 months, based on an 18-month recruitment period. 12 Publication Plan It is the policy of the Principal Investigators to encourage the presentation and/or publication of the results of their studies. At least thirty (30) days in advance of proposed submission, the primary author should forward a copy of the manuscript or abstract for review by the Sponsor. All study participants (Co-Investigators and Committee members) give full authority to the Principal Investigators for primary presentation and/or primary publication of the results in the CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

113 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August name of wholehearted collaborators. No other publication is allowed before the primary publication. Any subsequent presentation or publication by a study participant (including for sub studies) must be approved by the Principal Investigators and make reference to the study and the primary publication. The final decision to publish articles and their content will be made by the Principal Investigators after prior notice to the Sponsor, allowing their review and comments on all manuscripts (at least thirty days in advance of submission, unless a mutual agreement allows a shorter notice). 13 Protocol Signatures After reading the protocol, each Principal Investigator will sign the protocol signature page and send a copy of the signed page to C5Research. 14 References 1. Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and trends in obesity among US adults, Jama 2002;288(14): Flegal KM, Carroll MD, Kuczmarski RJ, Johnson CL. Overweight and obesity in the United States: prevalence and trends, Int J Obes Relat Metab Disord 1998;22(1): Harris MI, Flegal KM, Cowie CC, et al. Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults. The Third National Health and Nutrition Examination Survey, Diabetes Care 1998;21(4): Overweight, obesity, and health risk. National Task Force on the Prevention and Treatment of Obesity. Arch Intern Med 2000;160(7): Nathan DM. Clinical practice. Initial management of glycemia in type 2 diabetes mellitus. N Engl J Med 2002;347(17): Panzram G. Mortality and survival in type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 1987;30(3): Hogan P, Dall T, Nikolov P; American Diabetes Association. Economic cost of diabetes mellitus in the US in Diabetes Care 2003;26: Pories WJ, Swanson MS, MacDonald KG, et al. Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus. Ann Surg 1995;222(3): ; discussion DeMaria EJ, Sugerman HJ, Kellum JM, et al. Results of 281 consecutive total laparoscopic Roux-en-Y gastric bypasses to treat morbid obesity. Ann Surg 2002;235(5): ; discussion Schauer PR, Ikramuddin S, Gourash W, et al. Outcomes after laparoscopic Roux-en-Y gastric bypass for morbid obesity. Ann Surg 2000;232(4): Wittgrove AC, Clark GW. Laparoscopic gastric bypass, Roux-en-Y- 500 patients: technique and results, with 3-60 month follow-up. Obes Surg 2000;10(3): Pontiroli AE, Pizzocri P, Librenti MC, et al. Laparoscopic adjustable gastric banding for the treatment of morbid (grade 3) obesity and its metabolic complications: a three-year study. J Clin Endocrinol Metab 2002;87(8): Marceau P, Kaufman D, Biron S, et al. Outcome of pregnancies after biliopancreatic diversion. Obes Surg 2004;14(3): Scopinaro N, Gianetta E, Adami GF, et al. Biliopancreatic diversion for obesity at eighteen years. Surgery 1996;119(3): Dixon JB, O'Brien PE. Health outcomes of severely obese type 2 diabetic subjects 1 year after laparoscopic adjustable gastric banding. Diabetes Care 2002;25(2): Sjostrom L, Lindroos AK, Peltonen M, et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med 2004;351(26): CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

114 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Karason K, Lindroos AK, Stenlof K, Sjostrom L. Relief of cardiorespiratory symptoms and increased physical activity after surgically induced weight loss: results from the Swedish Obese Subjects study. Arch Intern Med 2000;160(12): Schauer PR, Burguera B, Ikramuddin S, et al. Effect of laparoscopic Roux-en Y gastric bypass on type 2 diabetes mellitus. Ann Surg 2003;238(4): ; discussion Almogy G, Crookes PF, Anthone GJ. Longitudinal gastrectomy as a treatment for the high-risk super-obese patient. Obes Surg 2004;14(4): Baltasar A, Serra C, Perez N, et al. Laparoscopic sleeve gastrectomy: a multi-purpose bariatric operation. Obes Surg 2005;15(8): Moon Han S, Kim WW, Oh JH. Results of laparoscopic sleeve gastrectomy (LSG) at 1 year in morbidly obese Korean patients. Obes Surg 2005;15(10): Uusitupa MI. Early lifestyle intervention in patients with non-insulin-dependent diabetes mellitus and impaired glucose tolerance. Ann Med 1996;28(5): Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care 1997;20(4): Redmon JB, Raatz SK, Kwong CA, et al. Pharmacologic induction of weight loss to treat type 2 diabetes. Diabetes Care 1999;22(6): Paisey RB, Frost J, Harvey P, et al. Five year results of a prospective very low calorie diet or conventional weight loss programme in type 2 diabetes. J Hum Nutr Diet 2002;15(2): Metz JA, Stern JS, Kris-Etherton P, et al. A randomized trial of improved weight loss with a prepared meal plan in overweight and obese patients: impact on cardiovascular risk reduction. Arch Intern Med 2000;160(14): Agurs-Collins TD, Kumanyika SK, Ten Have TR, Adams-Campbell LL. A randomized controlled trial of weight reduction and exercise for diabetes management in older African-American subjects. Diabetes Care 1997;20(10): The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the diabetes control and complications trial. Diabetes 1995;44(8): Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352(9131): Perri MG, McAllister DA, Gange JJ, et al. Effects of four maintenance programs on the long-term management of obesity. J Consult Clin Psychol 1988;56(4): Cottam D, Mattar SG, Sharma S, et al. Laparoscopic sleeve gastrectomy as an initial weight loss procedure for high risk patients with morbid obesity. Surg Endosc 2006;20: Gold MR, Siegel JE, Russell LB, Weinstein MC. Cost Effectiveness in Health and Medicine. In: Press OU, ed. New York, Kattan MW. Comparing treatment outcomes using utility assessment for health-related quality of life. Oncology 2003;17: Ross PL, Littenberg B, Fearn P, et al. Paper standard gamble: A paper-based measure of standard gamble utility for current health. Int J Technol Assess Health Care 2003;19: Tengs T and Wallace A. One thousand health related quality of life estimates. Medical Care 2000;38: O Brien PE, Dixon JB, Laurie C, et al. Treatment of mild to moderate obesity with laparoscopic adjustable gastric banding or an intensive medical program. Ann Intern Med 2006;144: Pories WJ, MacDonald KG, Flickinger EG, Dohm GL, Sinha MK, Barakat HA, May HJ, Khazanie P, Swanson MS, Morgan E, Caro JF. Is type II diabetes mellitus (NIDDM) a surgical disease? Ann Surg 1992;215: Pories WJ, Swanson MS, MacDonald KG, Long SB, Morris PG, Brown BM, Barakat HA, deramon RA, Israel G, Dolezal JM, et al. Who would have thought it? An operation proves to be the most effective therapy for adult onset diabetes? Ann Surg 1995;222: Sjostrom CD, Lissner L, Wedel H, Sjostrom L.Reduction in incidence of diabetes, hypertension and lipid disturbances after intentional weight loss induced by bariatric surgery: the SOS Intervention Study. Obes Res 1999;7: Long SD, O'Brien K, MacDonald KG Jr, Leggett-Frazier N, Swanson MS, Pories WJ, Caro JF.Weight loss in severely obese subjects prevents the progression of impaired glucose tolerance to type II diabetes. A longitudinal interventional study. Diabetes Care 1994;17: CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

115 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Sjöström L. Surgical intervention as a strategy for treatment of obesity. Endocrine 2000;13: Scopinaro N, Adami GF, Marinari GM, Gianetta E, Traverso E, Friedman D, Camerini G, Baschieri G, Simonelli A. Biliopancreatic diversion. World J Surg 1998;22: Scopinaro N, Gianetta E, Civalleri D, Bonalumi U, Bachi V: Biliopancreatic bypass for obesity. II. Initial experience in man. Br J Surg 1979;66: Mingrone G, De Gaetano A, Greco AV: Reversibility of insulin resistance in obese diabetic patients: role of plasma lipids. Diabetologia 1997;40: Caro JF, Dohm LG, Pories WJ, Sinha MK.Cellular alterations in liver, skeletal muscle, and adipose tissue responsible for insulin resistance in obesity and type II diabetes. Diabetes Metab Rev 1989;5: Rubino F, Gagner M. Potential of surgery for curing type 2 diabetes mellitus. Ann Surg 2002;236: Podnos Y, Jimenez J, Wilson S. complications after laparoscopic gastric bypass: a review of 3464 cases. Arch Surg 2003;138: DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 1999;131: CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

116 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Attachments TABLE 6 Patient Visit Schedule Test/Procedure Screening Period Baseline/ Randomization Treatment / Follow-Up Period Months from Randomization - 3 to Clinic Visit Visit 1 Visit 2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 V15 V16 V17 Inclusion/Exclusion Criteria X X Signed Informed Consent X History and Physical X X X X X X X X X X X X X X X X Blood pressure X X X X X X X X X X X X X X X X Height X Weight X X X X X X X X X X X X X X X X Neck, Hip, Waist Measurements X X X X X X X X X X X Psychiatric Evaluation X Medical Clearance for Surgery 5 X Nutrition Counseling X Ongoing Nutrition Counseling as per "Advanced medical Management" Patient Education for Diabetes X Ongoing Diabetes Education as per " Advanced medical Management" 10, 11, 11c Randomization X Other Clinical Exams Retinal Exam X 7 X X Carotid IMT X 7 X EKG X 4 X Questionnaires SF-36 X 6 X X X X X Diabetes QOL X 6 X X X X X Patient Utility Questionnaire X 6 X X X X X X X X X X X X X X Sub Studies 60 pts (20 per arm) MMTT X 7 X X Dexa Scan X 7 X X Strain gauge plethysmography X 7 X X Tissue Sample (surgery patients only) Liver Biopsy X

117 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August TABLE 6 (continued) Patient Visit Schedule Test/Procedure Screening Period Baseline/ Randomization Treatment / Follow-Up Period Months from Randomization - 3 to Lab Tests Visit 1 Visit 2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 V15 V16 V17 HbA1c X 13 X 8, 9 X X X X X X X X X X X X X X Fasting Plasma Glucose X 1 X 8 X X X X X X X X X X X X X X C Peptide X 8 Insulin X 8 X X X X X Chem 12 X 1 X 8 X X X X X CBC X 1 X 8 X X X X X Lipids X 1 X 8 X X X X X Urinalysis X 8 X X X X X X X (microalbumin and creatinine) TSH X 2 Urine pregnancy test X 8 DNA 12 X Research Repository 3 X X X X Gut Hormones 3 - Ghrelin, PYY, GLP-1, GIP, SRBP4 X 8 X X X Cardiovascular Markers 3 - CRP, PAI-1,, homocysteine, Apo-A, Apo-B,Uric Acid, Lpa,Fibrinogen X 8 X X X X CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

118 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August 2009 Notes for Table 6: 1. Screening lab value may be up to 6 months prior to the time of consent. 2. Screening TSH lab value may be up to 6 months prior to the time of consent. 3. Venipuncture, processing/storage (freeze) for later analysis. 4. Initial screening EKG may be up to 3 months prior to time of consent. 5. Medical clearance will be based on Health Quest. Patients will be evaluated by the Impact center at the discretion of the surgical team. 6. Must be completed prior to participant knowing randomization assignment. 7. May be performed up to 1 week prior to or 2 weeks after randomization but must be completed prior to surgery if randomized to surgical arm. 8. May be performed up to 1 week prior to randomization. 9. Result must be known prior to randomization. 10. Randomization will occur after all baseline procedures, not otherwise designated, are complete and results known. 11. V3 / post randomization (0-2 months) is inclusive of the initial treatment period: a. Patients randomized to advanced medical treatment, will have medications adjusted, according to current treatment algorithms, within 2 weeks. b. Patients randomized to advanced medical therapy plus bariatric surgery will have preoperative education, surgery, and post-op surgery care as outlined in Sections 5.3 and 6.4. c. If subjects randomized to surgery are unable to have surgery within 2 months of randomization date, follow- up visits will be based on surgery date, and central labs (HbA1c, fasting plasma glucose, others) may be redrawn prior to surgery for baseline values, at the discretion of the Principal Investigator. 12. Must have signed DNA consent to participate. Obtained any one time after randomization. 13. HbA1c must be drawn within 4 weeks prior to time of consent.

119 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August FIGURES Bariatric Surgery Figure 1. Jejunoileal Bypass Figure 2. Roux-en-Y Gastric Bypass Figure 3. Sleeve Gastrectomy

120 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August APPENDICES Appendix 1: Diabetes Quality of Life Questionnaire Items are scored in the same manner as the standard SF-36 form. The higher the score, the more positive the answer. Responses are given the following discrete scores: very much a problem (0), somewhat of a problem (33), a little bit of a problem (66), not a problem (100), and not applicable. 1. During the past months how much did your diabetes cause a problem with each of the following? * Doing things on the spur-of-the-moment * The amount of time or inconvenience involved in treating your diabetes * Maintaining a diet and preparing food * Having a large appetite for food * Feeling embarrassed in public while managing your diabetes * Taking a trip or going on vacation * Pain or discomfort involved in taking care of your diabetes * Doing things socially with friends/relatives * Planning meals or eating out with others * Your family life, getting along with others * Having to plan things differently to take care of your diabetes * Lack of interest in sex or enjoyment of sex 2. Overall, how much of a problem is it to live a normal life and take care of your diabetes? Copyright 2005 American Diabetes Association From Diabetes Care, Vol. 28, 2005; Reprinted with permission from the American Diabetes Association CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

121 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Appendix 2: Cost-Effectiveness Analyses Data Collection Patient Utility Questionnaire By placing a check mark in one box in each group below, please indicate which statements best describe your own health state today. CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

122 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August We are always looking for new ways to ask you how you feel about your health. The following question may seem strange, but it will ask you to think about your health and the risk you would be willing to take to change it, and the only correct answer is your opinion. Imagine a new (make-believe) pill is now available for all your health problems. Your doctor advises you that if you take the pill today and it works, it cures every health problem you currently have for the rest of your life. However, if you take the pill today and it does not work, it will cause sudden and painless death in your sleep tonight. Your doctor has no way of predicting which patients will be cured by this new (make-believe) pill, and will support whatever decision you make. Given everything you know about your current health, how it may change in the future, and your treatment options, we want to know what you think about this pill. Would you take this pill right now if you knew (Please circle Yes or No for every question.) it had a 100% chance of cure and a 0% risk of causing death in your sleep tonight? Yes No it had a 99% chance of cure and a 1% risk of causing death in your sleep tonight? Yes No it had a 97% chance of cure and a 3% risk of causing death in your sleep tonight? Yes No it had a 95% chance of cure and a 5% risk of causing death in your sleep tonight? Yes No it had a 93% chance of cure and a 7% risk of causing death in your sleep tonight? Yes No it had a 91% chance of cure and a 9% risk of causing death in your sleep tonight? Yes No it had a 90% chance of cure and a 10% risk of causing death in your sleep tonight? Yes No it had a 85% chance of cure and a 15% risk of causing death in your sleep tonight? Yes No it had a 80% chance of cure and a 20% risk of causing death in your sleep tonight? Yes No it had a 75% chance of cure and a 25% risk of causing death in your sleep tonight? Yes No it had a 70% chance of cure and a 30% risk of causing death in your sleep tonight? Yes No it had a 65% chance of cure and a 35% risk of causing death in your sleep tonight? Yes No it had a 60% chance of cure and a 40% risk of causing death in your sleep tonight? Yes No it had a 50% chance of cure and a 50% risk of causing death in your sleep tonight? Yes No it had a 40% chance of cure and a 60% risk of causing death in your sleep tonight? Yes No it had a 30% chance of cure and a 70% risk of causing death in your sleep tonight? Yes No it had a 20% chance of cure and a 80% risk of causing death in your sleep tonight? Yes No it had a 10% chance of cure and a 90% risk of causing death in your sleep tonight? Yes No CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

123 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Appendix 3: Medical Management / Pharmacotherapy for Glycemic control Metformin Antihyperglycemic agent in the biguinide class has been available in US since Its mechanisms of actions include reducing hepatic glucose production, and increasing muscle glucose. Its clinical efficacy in glucose/lipid lowering and cardiovascular benefits has been demonstrated in the UKPDS (reviewed above). Metformin has also been documented in delaying progression to diabetes in the Diabetes Prevention Trial where it reduced incidence of type 2 diabetes in high risk subjects by 33% (ref). Side effects are predominantly gastrointestinal (nausea and in some vomiting/diarrhea). Medication is not to be used in the presence of CHF, renal insufficiency (creatinine of greater than 1.5 mg/dl in men and 1.4 mg/dl in women). Thiazolidinediones TZDs are antihyperglycemic agents that have been available since The two currently available TZDs are pioglitazone (Actos) and rosiglitazone (Avandia) have been available since TZDs are PPAR gamma agonists that increase insulin sensitivity at the level of the muscle and liver, decrease hepatic glucose production and favorably effect adipocyte secretory products (decrease TNFalpha) and increase adiponectin. In addition to insulin sensitizing effects, TZDs have been implicated in restoring B cell function in the TRIPOD study and delaying progression to type 2 diabetes in women with history of gestational diabetes. Pioglitazone was shown to decrease cardiovascular mortality (16% vs. placebo, P < 0.02) in the PROACTIVE (Prospective Pioglitazone Clinical Trial in Macrovascular Events) study. Side effects include fluid retention, and weight gain. Exenatide Exenatide is an incretin mimetic which was FDA approved in 2005 as an antihyperglycemic agent for treatment of type 2 diabetes. Incretins are hormones produced from the gastrointestinal track that act to enhance the normal release of insulin after the oral ingestion of carbohydrates. They also slow gastric absorption of nutrients and act to promote a feeling of satiety that can lead to weight loss in overweight individuals. Therefore, these agents work to lower glucose levels in a glucose-dependent fashion without causing hypoglycemia, but with a gradual weight loss due to a decrease in caloric intake. Although exenatide can work as monotherapy, the first indication for their use has been in combination with a sulfonylurea agent, metformin or the combination o the two. Data from the registry trials demonstrated that patients in all 3 groups had a decrease in HbA1c levels of approximately 0.9% with a corresponding weight loss of 1.9 kg. The greatest weight loss was seen in patients who were on metformin monotherapy when exenatide was started. The most common side effect was nausea, and rarely vomiting. Nausea was noted in 44% of subjects on the high dose of exenatide (10mcg twice daily), but decreased and mostly disappeared over time. Only 3% of patients discontinued the drug. Another effect was an increased rate of hypoglycemia when used in patients on a sulfonylurea agent. Exenatide, on its own, will not cause hypoglycemia, and did not when used in combination with metformin alone. Insulin Many formulations of human insulin are now available. Clinical efficacy demonstrated in both DCCT and UKPDS trials as reviewed above. Side effects include hypoglycemia, weight gain. CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

124 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Appendix 4: Medical Treatment Algorithms for Glycemic Therapy Because hypoglycemia is believed to play an important role in the pathogenesis of microvascular and potentially macrovascular complications, the ADA has established 7.0% as a targeted HbA1c for treatment. However, because both the UKPDS and DCCT showed that treatment of diabetic patient with HbA1c values in the range of 6% to 7% is associated with a significant reduction in microvascular complications, and the present ACCORD trial (in progress) targeting normalization of glucose (HbA1c of 6%), we will target therapy in this trial to a HbA1c of 6.0% with a fasting plasma glucose less than or equal to 126 mg/dl. A separate reference binder / manual of operations will provide the basic treatment algorithms and provide guidance for patients entering the study on common combinations of oral agents or insulin. These algorithms will be adhered to as strictly as possible with the understanding that clinical situations may arise that may require deviation from the algorithms (adverse reaction to medication, hypoglycemia, and earlier initiation of insulin for patients with extremely high glucose levels). Any deviation from the algorithm will be recorded and reviewed by an endocrinology staff investigator. Continuation in the study after a large deviation in the treatment algorithm will be determined by the Endocrinology staff investigator. Notes for Appendix 4: Treatment Algorithm for Glycemic Therapy * Glycemic target = HbA1c < 6.0% ** Threshold for action required if: 1) HbA1c > 6.0%, or 2) > 50% of SMBG results / 4 days = fasting/ac > 100 mg/dl or 2 hr pc > 140 mg/dl. Antihyperglycemic therapy will be advanced if action required criteria met at any patient visit. If glycemic target achieved, continue current Rx and follow-up schedule. If action required later, titrate/add medications according to sequence. Bedtime glargine may be initiated earlier if HbA1c is greater than or equal to 8.5% since subjects may not respond to oral agents including sulfonylurea agents CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

125 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August 2009 Advanced Medical Management Guidelines (based on current ADA guidelines) Treatment Algorithm for Glycemic Therapy * Agent at entry Step 1 (post randomization) Step 2 Step 3 Step 4 Step 5 Step 6 HbA1c / SMBG ** Based on SMGB** HbA1c / SMBG** HbA1c / SMBG** HbA1c / SMBG** HbA1c / SMBG** Results of HbA1c and/or SMGB - Action Required? No - continue current Rx Yes titrate / add medications according to sequence No oral agent Initiate Metformin 500 mg bid Sulfonylurea - - titrate Sulfonylurea - Initiate Metformin 500 mg bid Metformin Titrate Metformin based on initial labs Sulfonylurea Metformin TZD Metformin TZD Sulfonylurea TZD - - titrate Sulfonylurea - Titrate Metformin based on initial labs Titrate TZD based on initial labs Titrate Metformin based on initial labs - titrate Sulfonylurea - Titrate TZD based on initial labs Titrate Metformin to mg/day Titrate Metformin to mg/day Titrate Metformin to mg/day Titrate Metformin to mg/day -initiate TZD and titrate -initiate metformin and Titrate over 3 months Titrate Metformin to mg/day Titrate TZD to max dose - if max Metformin dose - Initiate TZD and titrate to max dose - if max Metformin dose - Initiate TZD and titrate to max dose - if max Metformin dose - Initiate TZD and titrate to max dose - if max Metformin dose - Initiate Exenatide 5 mcg subq Initiate exenatide 5 mcg Sub q bid Initiate Exenatide 5 mcg subq bid - if max TZD dose - Initiate Exenatide 5 mcg subq Initiate Exenatide 5 mcg subq bid Initiate Exenatide 5 mcg subq bid Initiate Exenatide 5 mcg subq bid Increase Exenatide to 10 mcg subq bid Increase Exenatide to 10 mcg subq bid Increase Exenatide to 10 mcg subq bid Increase Exenatide to 10 mcg subq bid Increase Exenatide to 10 mcg subq bid Increase Exenatide to 10 mcg subq bid Increase Exenatide to 10 mcg subq bid Initiate insulin Initiate sulfonylurea or repaglinide Initiate insulin Initiate and titrate sulfonylurea Increase insulin Initiate sulfonylurea or Initiate insulin repaglinide if indicated. Initiate sulfonylurea or Increase insulin repaglinide Initiate insulin Increase insulin

126 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August 2009 Appendix 4 con t Treatment Algorithm for Glycemic Therapy`* Agent(s) at entry Step 1 (post randomization) Step 2 Step 3 Step 4 Step 5 Step 6 HbA1c / SMBG ** Based on SMGB** HbA1c / SMBG** HbA1c / SMBG** HbA1c / SMBG** HbA1c / SMBG** 54 Results of HbA1c and/or SMGB - Action Required? No - continue current Rx Yes titrate / add medications according to sequence Sulfonylurea Insulin Metformin Insulin TZD Insulin Sulfonylurea Metformin Insulin Sulfonylurea TZD Insulin Sulfonylurea TZD Metformin Insulin - D/C Sulfonylurea - Initiate Metformin 500 mg bid - Titrate Metformin based on initial labs -initiate exenatide and titrate - Titrate TZD based on initial labs - D/C Sulfonylurea - Titrate Metformin based on initial labs - D/C Sulfonylurea - Titrate TZD based on initial labs - D/C Sulfonylurea - Titrate TZD and Metformin based on initial labs - Titrate Metformin to mg/day -Initiate exenatide - Titrate Metformin to mg/day -initiate TZD - if max Metformin dose - Initiate TZD - titrate exenatide to max dose - if max Metformin dose - Titrate TZD to max dose - initiate sulfonylurea Titrate TZD to max dose - initiate/titrate Metformin to max dose Titrate Metformin to mg/day Titrate TZD to max dose Titrate TZD and Metformin to max dose - if max Metformin dose - Initiate TZD and titrate to max dose - initiate/titrate Metformin to max dose - if max Metformin and TZD dose - Initiate Exenatide 5 mcg subq bid -Titrate TZD - Initiate insulin for HbA1c > 8.5% - Initiate Exenatide 5 mcg subq bid - if max Metformin and TZD dose -initiate sulfonylurea -if HbA1c >8.5;start insulin + sulfonylurea - Initiate Exenatide 5 mcg subq bid - if max Metformin and TZD dose - Initiate Exenatide 5 mcg subq bid - if max Metformin and TZD dose - Initiate Exenatide 5 mcg subq bid - if max Metformin and TZD dose - Initiate Exenatide 5 mcg subq bid Increase Exenatide to 10 mcg subq bid -Follow insulin titration protocol; initiate prandi coverage - Increase Exenatide to 10 mcg subq bid -Follow insulin titration protocol; initiate prandi coverage - Increase Exenatide to 10 mcg subq bid Increase Exenatide to 10 mcg subq bid Increase Exenatide to 10 mcg subq bid Increase Exenatide to 10 mcg subq bid Titrate insulin per insulin protocol Titrate insulin per insulin protocol Titrate insulin per insulin protocol Titrate insulin per insulin protocol Titrate insulin per insulin protocol Titrate insulin per insulin protocol Increase Insulin CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

127 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August 2009 Appendix 5 Use of Insulin for Participants on Maximum Oral Agents and Exenatide Therapy Add Evening Glargine Start at 10 U or 0.2 U/kg/day Titrate dose NO YES Doing well? YES HbA1c > 6.0%? YES On insulin > 0.5 U/kg/day? YES Add / titrate Aspart/Lispro or (R) Before 1, 2, or 3 meals As needed Doing well? HbA1c > 6.0? NO NO NO Adjust pills or insulin as needed No Change Adjust pills or insulin as needed Titrate Aspart/Lispro or (R) Before meals as needed * Doing well: no severe hypoglycemic or adverse event or no reason to reduce therapy

128 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August 2009 Appendix 6 56 Algorithm for Post-Operative Patients Requiring Medical Therapy Post-op week one SMBG Metformin 500 mg bid/if action required 1 month HbA1c and SMBG/If action required, Titrate Metformin up to mg/day based on SMBG YES NO Continue current RX 3 months HbA1c and SMBG Action Required? and follow-up schedule, If action required later, titrate / add medications at left in sequence. If at max Metfrmin dose Initiate TZD Titrate TZD to maz dose YES 6 months HbA1c and SMBG Action Required? Initiate Exenatide / 5 mcg subq bid NO Continue current RX and follow-up schedule, If action required later, titrate / add medications at left in sequence. 9 months HbA1c and fasting labs If Action Required, Increase Exenatide to 10 mcg subq bid YES 12 months HbA1c and fasting labs Action Required? NO Initate insulin Action Required? Continue current Rx CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

129 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August 2009 Appendix 7: Treatment Algorithm for Blood Pressure (per current ADA guidelines) Goal: SBP < 140 mm Hg Start Here Is SBP < 130 mm Hg at this visit? Monitor as designated through follow-up NO YES Is SBP < 135 mm Hg on 2 consecutive visits? YES Step-down NO Is SBP > 160 mm HG at this visit Or > 140 mm HG On 2 consecutive visits? NO YES Titrate or Add Therapy Not Already in Use *** (ACEI*, thiazide, beta-blocker, CCB, reserpine, or alpha-blocker) Continue Therapy** * ARB can be considered as a substitute for participants who do not ACEI therapy ** Unless side effects warrant change in therapy *** Consult with Endocrinologist before adding a fifth antihypertensive medication

130 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Appendix 8: Mixed Meal Tolerance Test (MMTT) After a hour overnight fast 2 blood samples will be taken at 5-10 minute intervals through a venous catheter. At time zero subjects will be asked to drink a meal replacement drink over approximately 5 minutes and upon completion of ingestion, blood samples will be drawn approximately every 30 minutes for 2 hours for the determination of plasma glucose, free fatty acid (FFA), insulin, and C peptide concentrations. At baseline and 60 minutes a gut hormone profile will be drawn. Glucagon will also be drawn at baseline and 120 minutes. Blood for rna isolation will also be obtained to determine gene expression of adipokines and other inflammatory cytokines Insulin sensitivity will be determined by determining the area under the curve for glucose and insulin as well as the Matsuda index (8): (10,000/square root of [fasting glucose x fasting insulin] x [mean glucose x mean insulin during MMTT]). Insulin secretion will be determined as follows from the MMTT data: AUC insulin/ AUC glucose. Following MMTT, patients will be discharged. C-peptide deconvolution will also be performed as per Polansky method. The MMTT will be performed within 2-4 weeks prior to surgery and 2 weeks, 2 months and 6 months following surgery. Our experience has shown that oral intake is severely limited for the first few days following surgery; therefore MMTT will not be performed at 2 days following surgery. Baseline blood draws Prandial blood draws CBC Blood RNA X X Gut Hormones X X Adipokines X Glucose X X X X X X Insulin/C-pep X X X X X X FFA X X X Glucagon X X Urine (prior to MMTT) Total blood per visit approximately 80 cc Gut hormones: ghrelin, GLP-1, GIP, PYY, Glucagon Adipokines: Adiponectin, leptin, resistin Random spot urine for microalbumin/creatnine ratio at each MMTT MMTT at randomization, 1 and 2 years post randomization CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

131 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Appendix 9: Strain Gauge Plethysmography Brachial artery reactivity testing is a non-invasive vascular test that uses strain gauge phethysmography to measure endothial function. This test uses flow-mediated vasodilatation to evaluate vascular endothelial function of the brachial artery. Blood pressure cuff occlusion of the brachial artery and subsequent shear stress produced by hyperemia upon cuff release provides a stimulus for release of nitric oxide from the endothelium that produces vasodilatation. A normal vasodilatation and a close relationship between endothelial dysfunction in the coronary and brachial arteries has been established. Impaired relaxation of the artery suggests sub clinical atherosclerotic diseases. Brachial artery reactivity studies have shown impaired vasodilatory response in patients with coronary risk factors such as hypercholesterolemia, hypertension, smoking, diabetes mellitus and established coronary heart disease. Patients are asked to fast the morning of the procedure and avoid caffeine and they are asked to lie down in a quiet examination room. Blood pressure and pulses are taken prior to the examination and EKG leads are applied for continuous cardiac monitoring. A rubber strain gauge is placed around the forearm. The gauge, which is made up of silastic, is first calibrated by stretching it a set distance and measure the output on a chart recorder. An arterial occlusion cuff is then placed around the wrist and a venous cuff is placed on the upper arm. Thirty seconds prior to flow measurements, the occlusion cuff is inflated to 30 mm Hg above the patient s systolic pressure on the wrist to remove hand circulation from measurement of forearm flow. During flow measurements, the upper arm cuff placed approximately 4 cm above the elbow is inflated rapidly for 5 seconds. During this period the change in arm size transduced by the Strain Gauge to an electrical output and displayed on a chart recorder. After 5 seconds, a vacuum pump rapidly deflates the cuff for a period of 7 10 seconds and strain gauge readings recorded. Following 5 minutes of recovery time, the patient is given 0.4 mg sublingual nitroglycerin and final measurements performed. Patients are informed that they may experience numbness or tingling in the forearm and, a temporary headache and flushing after the nitroglycerin is given. The procedure takes approximately 30 minutes to perform. CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

132 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Appendix 10: Carotid Intima-Medial Thickness (CIMT) Carotid intima-media thickness (CIMT) is a measurement of the thickness of the two inner layers of the carotid artery. It represents a window through which the risk of developing coronary or cerebral atherosclerotic disease can be estimated, as well as assessing responsiveness to interventions. A standardized protocol will be utilized using duplex ultrasound to obtain the mean and maximum CIMT values of the common carotid arteries. Baseline measurements will be taken of all patients in each of three arms of the study and follow up scans will be performed at 2 years. All scans will be performed by experienced ultrasound technologists with additional training specific for performing CIMT measurements. All scans will be measured by a technician trained specifically for measuring CIMT, there will a second reviewer and physician reader. Summary of protocol Patients are placed in a supine position. 3 EKG leads are applied. Data is entered into the Philips IU22 ultrasound system. The Meijer s Arc is placed to assist with maintaining appropriate angle and to maximize reproducibility. Images are obtained of both the right and left common carotid arteries at the optimal angle of interrogation (OAI) and 45 degrees (anterior and posterior to the OAI, or two angles anterior or two angles posterior to the OAI) using a linear 8-4 MHz probe. Images should be obtained during the R wave of the EKG. Images are stored digitally and transferred to a secure server for measuring in the CIMT core lab. One of three specially trained technicians will measure the common CIMT at the far wall. Sonka tools auto-edge detection software will be used to perform the measurements which are recorded and entered into a database. An exam will be performed at baseline and at two years follow-up. To minimize loss of data with regard to drop out patients, an attempt to obtain a scan should be made on all patients who drop out prematurely. Scans will be performed using the same Philips ultrasound unit for every patient and nearly all studies and measurements will be performed by one of 3 trained technicians and one over reading physician. Measurements will be obtained primarily using autoedge detection (Sonka tools) or this may be overridden in cases of less clear images. All studies will be co-reviewed by a second technician. These steps are intended to minimize error introduced due to equipment and technician differences. All studies will be stored in an electronic database and reviewed in a single onsite core lab. Studies will be read as they arrive in the core lab in a random fashion (as opposed to batch reading) and the reader will be blinded to the assigned treatment. CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

133 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Appendix 11: Dual Energy X-ray Absorptometry (DEXA). Body composition assessing total body and regional fat mass, as well as bone mineral mass and density will be measured using total body dual energy x-ray absorptometry (DEXA). A total body radiation exposure of < 1 usievert will be given over 10 minutes. The CV of this test is < 1 % for bone and 2% for soft tissue. Patients are asked to wear comfortable clothing, and will be instructed to remove any metal objects (belts, buttons, etc) to avoid the absorption of photons, and the possibility of attenuation. The patient will be positioned in the center of the scanner table and will be instructed to lie flat on their back, with arms alongside the patient s body. Velcro straps will be used to secure the patient s knees and feet to prevent movement during the measurement. A scanner arm will pass over the patient from head to toe, taking approximately 6 minutes to acquire data. CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

134 Medical vs Surgical Management of T2DM Protocol EES Grant No Final Protocol, 23 October 2006 Amendment 7, 18 August Appendix 12: Severity Scale for Diabetic Retinopathy and Macular Edema Scale for retinopathy (adapted from the Diabetic Retinopathy Study): 1. None - No diabetic retinopathy anywhere 2. Background diabetic retinopathy (BDR) Mild a. At least one dot hemorrhage or microaneurysm with or without hard exudates 3. BDR - Moderate a. Any one of the following: i. Four or more blot hemorrhages per quadrant in one to three quadrants ii. Venous beading in one quadrant only 4. BDR Severe a. Any one of the following: i. Four or more blot hemorrhages per quadrant in four quadrants ii. Venous beading in two or more quadrants iii. Intraretinal microvascular abnormalities (IRMA) in one quadrant 5. Proliferative diabetic retinopathy (PDR) a. Any one of the following features: i. New vessels on optic disc (NVD) ii. New vessels elsewhere (NVE) iii. Pre-retinal or vitreous hemorrhage iv. Pre-retinal fibrosis ± tractional retinal detachment 6. PDR - High risk a. Any 3 out of the following four: i. NV Anywhere (ON or Retina) ii. NVD iii. Preretinal or vitreous hemorrhage iv. NVD greater than 1/3 disc area and NVE greater than ½ disc area Scale for macular edema (adapted from the Early Treatment in Diabetic Retinopathy Study): 1. Not present - no evidence present 2. Non macular edema - i.e. not meeting clinically significant criteria 3. Clinically significant macular edema a. Thickening of 500 microns within 500 microns of the central fovea b. Exudates of 500 microns in size within 500 microns of the central fovea if the adjacent fovea is thickened c. Thickening 1 Disc area in size within 1 Disc area of the fovea. CONFIDENTIAL This material is the property of the Cleveland Clinic, and may not be reproduced without written permission.

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158 Medical vs Surgical Management of T2DM STAMPEDE IRB # Protocol Amendment 6, 24 September 2008 Summary of Changes STAMPEDE Amendment 6 September 24, 2008 IRB # PI: Philip Schauer, MD Title of Project: A prospective Randomized Controlled Trial Comparing Advanced Practice Medical Management Versus Advanced Practice Medical Management Plus Bariatric Surgery In The Treatment Of Type 2 Diabetes Mellitus. Summary of requested changes: Section 4.1 Inclusion Criteria 3. Have a body mass index > 30 and < 40 kg/m 2. The protocol will amend to read (revision to criteria): 3. Have a body mass index > 27 and < 43 kg/m 2 Section 4.2 Exclusion Criteria skin). 11. Malignancy within five years (except squamous cell and basal cell cancer of the The protocol will amend to read (definition and clarification): 11. Malignancy within five years (except squamous cell and basal cell cancer of the skin). Subjects diagnosed with early / stage 1 cancer that have been successfully treated are eligible per Investigator discretion. Page 1 of 1

159 Medical vs Surgical Management of T2DM STAMPEDE IRB # Protocol Amendment 7, 18 August 2009 Summary of Changes STAMPEDE Amendment 7 September 21, 2009 IRB # PI: Philip Schauer, MD Title of Project: A prospective Randomized Controlled Trial Comparing Advanced Practice Medical Management Versus Advanced Practice Medical Management Plus Bariatric Surgery In The Treatment Of Type 2 Diabetes Mellitus. Summary of requested changes: Section Study Summary Rationale, last 2 paragraphs The purpose of this study is to evaluate whether advanced medical therapy alone, or advanced medical therapy combined with surgical intervention, is more effective in improving HbA1c and outcome measures in patients with T2DM and a BMI during 5 years follow-up. The hypothesis of the study is that surgical therapy is more effective than advanced medical therapy for the resolution of type 2 diabetes mellitus in patients with a BMI between 30 and 40 kg/m2. The protocol will amend to read (revision to criteria): The purpose of this study is to evaluate whether advanced medical therapy alone, or advanced medical therapy combined with surgical intervention, is more effective in improving HbA1c and outcome measures in patients with T2DM and a BMI during 5 years follow-up. The hypothesis of the study is that surgical therapy is more effective than advanced medical therapy for the resolution of type 2 diabetes mellitus in patients with a BMI between 27 and 43 kg/m2. Section Study Summary Objectives / Primary To assess the effects of advanced medical therapy alone or advanced medical therapy combined with either Roux-en-Y gastric bypass (RYGBP) or laparoscopic sleeve gastrectomy on the success rate of biochemical resolution of diabetes at 1 year as measured by HbA1c < 6% in subjects with Type 2 Diabetes Mellitus and BMI between kg/m 2. The protocol will amend to read (revision to criteria): To assess the effects of advanced medical therapy alone or advanced medical therapy combined with either Roux-en-Y gastric bypass (RYGBP) or laparoscopic sleeve gastrectomy on the success rate of biochemical resolution of diabetes at 1 year as measured by HbA1c < 6% in subjects with Type 2 Diabetes Mellitus and BMI between kg/m 2. Section Study Summary Trial Design Page 1 of 4

160 Medical vs Surgical Management of T2DM STAMPEDE IRB # Protocol Amendment 7, 18 August 2009 Summary of Changes This is a 3-arm randomized, controlled, single center study. Male and female subjects between the ages of 20 to 60 years old with clinical diagnosis of Type 2 diabetes mellitus and BMI between kg/m 2, will be included in this study. The protocol will amend to read (revision to criteria): This is a 3-arm randomized, controlled, single center study. Male and female subjects between the ages of 20 to 60 years old with clinical diagnosis of Type 2 diabetes mellitus and BMI between kg/m 2, will be included in this study. Sec 1.3 Risks and Benefits, last paragraph Our study intends to evaluate the efficacy of bariatric operations specific to type 2 diabetics with BMI This is the central question of this study in which we propose randomly allocating those in this weight range to a medical path or a surgical path and following the outcomes for at least five years. It is hoped that this study will define what can be achieved by the best of the current options. The protocol will amend to read (revision to criteria): Our study intends to evaluate the efficacy of bariatric operations specific to type 2 diabetics with BMI This is the central question of this study in which we propose randomly allocating those in this weight range to a medical path or a surgical path and following the outcomes for at least five years. It is hoped that this study will define what can be achieved by the best of the current options. Section 4.2 Inclusion Criteria 4. Have biochemical evidence of type 2 diabetes confirmed by the following diagnostic criteria: a. If treated HbA1c > 7.5% b. If untreated - fasting 2-hour plasma glucose level of > 200mg/dL during an oral glucose tolerance tests and a HbA1c of > 7.5%. The protocol will amend to read (revision to criteria): 4. Have biochemical evidence of type 2 diabetes confirmed by the following diagnostic criteria: a. If treated HbA1c > 7.1% b. If untreated - fasting 2-hour plasma glucose level of > 200mg/dL during an oral glucose tolerance tests and a HbA1c of > 7.1%. Section 4.2 Exclusion Criteria 3. Abdominal, thoracic, pelvic and/or obstetric-gynecologic surgery within 6 months Page 2 of 4

161 Medical vs Surgical Management of T2DM STAMPEDE IRB # Protocol Amendment 7, 18 August 2009 Summary of Changes The protocol will amend to read (revision to criteria): 3. Abdominal, thoracic, pelvic and/or obstetric-gynecologic surgery within 3 months or at the discretion of the surgeon. Section 5.1 Study Treatments Description Individuals with type 2 diabetes and BMI > 30 and < 40 kg/m2 who meet the eligibility criteria (Section 4.1 and 4.2) and initial screening evaluation and baseline labs, will be randomized to one of three treatments: advanced medical therapy, advanced medical therapy plus Roux-en-Y Gastric Bypass, or advanced medical therapy plus Laparoscopic Sleeve Gastrectomy. The protocol will amend to read (revision to criteria): Individuals with type 2 diabetes and BMI > 27 and < 43 kg/m2 who meet the eligibility criteria (Section 4.1 and 4.2) and initial screening evaluation and baseline labs, will be randomized to one of three treatments: advanced medical therapy, advanced medical therapy plus Roux-en-Y Gastric Bypass, or advanced medical therapy plus Laparoscopic Sleeve Gastrectomy. Section 6.4 Post Randomization / Visit 3(+ 1 month) Surgery patient randomized to RYGBP or LSG Surgery will be scheduled as soon as possible after randomization. The protocol will amend to read (definition and clarification): Surgery will be scheduled as soon as possible after randomization. If subjects are unable to have surgery within 2 months of randomization date, follow-up visits will be based on surgery date, and central labs (HbA1c, fasting plasma glucose, others) may be redrawn prior to surgery for baseline values, at the discretion of the Principal Investigator. Section 6.5 Follow-up Visits If a subject does not return for a scheduled visit, every effort should be made to contact the subject. In any circumstance, every effort should be made to document subject outcome, if possible. The protocol will amend to read (definition and clarification): If a subject does not return for a scheduled visit, every effort should be made to contact the subject. In any circumstance, every effort should be made to document subject outcome, if possible. If subjects randomized to surgery are unable to have surgery within 2 months of randomization date, follow-up visits will be based on surgery date. Page 3 of 4

162 Medical vs Surgical Management of T2DM STAMPEDE IRB # Protocol Amendment 7, 18 August 2009 Summary of Changes Section 15 Attachments Table 6 Patient Visit Schedule Test / Procedure 10, 11 Randomization X 10. Randomization will occur after all baseline procedures, not otherwise designated, are complete and results known. 11. V3 / post randomization (0-2 months) is inclusive of the initial treatment period: a. Patients randomized to advanced medical treatment, will have medications adjusted, according to current treatment algorithms, within 2 weeks. b. Patients randomized to advanced medical therapy plus bariatric surgery will have preoperative education, surgery, and post-op surgery care as outlined in Sections 5.3 and 6.4. The protocol will amend to read (definition and clarification): 10, 11 Randomization X 10. Randomization will occur after all baseline procedures, not otherwise designated, are complete and results known. 11. V3 / post randomization (0-2 months) is inclusive of the initial treatment period: a. Patients randomized to advanced medical treatment, will have medications adjusted, according to current treatment algorithms, within 2 weeks. b. Patients randomized to advanced medical therapy plus bariatric surgery will have preoperative education, surgery, and post-op surgery care as outlined in Sections 5.3 and 6.4. c. If subjects are unable to have surgery within 2 months of randomization date, follow-up visits will be based on surgery date, and central labs (HbA1c, fasting plasma glucose, others) may be redrawn prior to surgery for baseline values, at the discretion of the Principal Investigator. Page 4 of 4

163 STATISTICAL ANALYSIS PLAN A Prospective Randomized Controlled Trial Comparing Advanced Practice Medical Management Versus Advanced Practice Medical Management Plus Bariatric Surgery In the Treatment of Type 2 Diabetes Mellitus Surgical Therapy and Medications Potentially Eradicate Diabetes Efficiently (STAMPEDE) Study Biostatistician: Kathy Wolski, MPH Version: Final Date: December 6th,