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1 Clinical Trial Details (PDF Generation Date :- Mon, 18 Mar :19:00 GMT) CTRI Number Last Modified On 21/08/2013 Post Graduate Thesis Type of Trial Type of Study Study Design Public Title of Study Scientific Title of Study CTRI/2011/10/ [Registered on: 11/10/2011] - Trial Registered Retrospectively No Interventional Biological Randomized, Parallel Group, Active Controlled Trial Immunogenicity and Safety study of Wockhardts Human Insulin(Wosulin R, Wosulin N and Wosulin 70/30)} with the Novo Nordisks yeast based Human Insulin marketed in United States (Novolin R, Novolin N and Novolin 70/30) in Type 1 Diabetics. An Open Label, Randomized, comparison of the Immunogenicity and Safety of Wockhardts Human Insulin Basal Bolus Regimen {Intensified Conventional Insulin Therapy with Soluble Insulin and Isophane Insulin (Wosulin R, Wosulin N and Wosulin 70/30)} with the Novo Nordisk?s yeast based Human Insulin Basal Bolus Regimens, marketed in United States (Novolin R, Novolin N and Novolin 70/30) in Type 1 Diabetics. Secondary IDs if Any Secondary ID Identifier Details of Principal Investigator or overall Trial Coordinator (multi-center study) Details Contact Person (Scientific Query) Details Contact Person (Public Query) P3-WOS-IMS-01 Name Designation Affiliation Protocol Number Details of Principal Investigator Dr Deven Parmar Vice President - Global Clinical Research, Wockhardt Limited Wockhardt Limited Address Wockhardt Towers Bandra Kurla Complex, Bandra - E, Mumbai Wockhardt Towers Bandra Kurla Complex, Bandra - E, Mumbai Mumbai MAHARASHTRA India Phone Fax Name Designation Affiliation devenp@wockhardt.com Details Contact Person (Scientific Query) Dr Deven Parmar Vice President - Global Clinical Research, Wockhardt Limited Wockhardt Limited Address Wockhardt Towers Bandra Kurla Complex, Bandra - E, Mumbai Wockhardt Towers Bandra Kurla Complex, Bandra - E, Mumbai Mumbai MAHARASHTRA India Phone Fax Name Designation Affiliation devenp@wockhardt.com Details Contact Person (Public Query) Dr Rasendrakumar Jha Senior Vice President - Global Clinical Research, Wockhardt Limited Wockhardt Limited Address Wockhardt Towers Bandra Kurla Complex, Bandra - E, Mumbai 400 page 1 / 10

2 Source of Monetary or Material Support Primary Sponsor Details of Secondary Sponsor Countries of Recruitment Sites of Study Phone Fax Wockhardt Towers Bandra Kurla Complex, Bandra - E, Mumbai Mumbai MAHARASHTRA India rjha@wockhardt.com Source of Monetary or Material Support > Wockhardt Limited Wockhardt Towers Bandra Kurla Complennnx Bandra (East), Mumbai , India Name Address Type of Sponsor Name NIL List of Countries India United States of America Name of Principal Investigator Dr Mala Dharmalingam Dr KM Prasanna Kumar CEO Consultant Dr Neeta Deshpande Primary Sponsor Details Wockhardt Limited Wockhardt Towers, Bandra Kurla Complex, Bandra (East),Mumbai , India Pharmaceutical industry-indian Address NIL Name of Site Site Address Phone/Fax/ Bangalore Endocrinology & Diabetes Research Centre Banglore Diabetes Hospital Belgaum Diabetic Centre No. 35, 5th Cross Malleshwaram Circle, Banglaore Bangalore KARNATAKA 16/M, Miller Tank Bed Area, Thimmaiah road, Vasanthnagar, Banglore , India, Bangalore KARNATAKA Ground floor,beside mahila Vastu Bhander, Maruti Gali, Belgaum Belgaum KARNATAKA Dr Sudhir Bhandari Bhandari Clinic D-126 A, Krishna Marg, University Road, Bapu Nagar, Jaipur, Rajasthan Jaipur RAJASTHAN Dr Sanjay Kalra Bharti Research Institute of Diabetes & Endocrinology (BRIDE) Bharti Hospital, Wazir Chand Colony, Kunjpura, Karnal, Haryana Karnal HARYANA drmala@bedrc.com dr.kmpk@gmail.com neetarohit@gmail.com drs_bhandari@yahoo.c om brideknl@gmail.com page 2 / 10

3 Details of Ethics Committee Dr Banshi D Saboo Dia Care Research 1&2, Gandhi Park, Nr Nehrunagar Cross Roads, Ambawadi, Ahmedabad Ahmadabad GUJARAT Dr Sharad Pendsey Dr SK Sharma Dr Arvind Sosale Dr Mathew John Diabetes Clinic & Research Centre. Home for Diabetes Diabetes, Thyroid and Endocrine Centre Diacon Hospital, Diabetes Care and Research Centre Health & Research Centre Shree Nivas, Opposite Dhantoli Park, Nagpur Nagpur MAHARASHTRA 11, Shivaji Nagar, Civil Lines, Jaipur Jaipur RAJASTHAN , 19th Main, Ist Block,Rajajinagar,Bang alore Bangalore KARNATAKA Health & Research Centre,1st floor- Devi Scan Building, Kumarapuram Trivandrum, Kerala Thiruvananthapuram KERALA Dr K Kannan Madurai City Hospital Anna Nagar, Madurai, Madurai TAMIL NADU Dr Rakesh Sahay Osmania General Hospital Dept. of Endocrinology, 2nd Floor, Golden Jubilee Block, Afzalgunj, Hyderabad Hyderabad ANDHRA PRADESH banshisaboo@hotmail.c om sharad_ngp@sancharn et.in sksharma7@gmail.com diacon90@hotmail.com drmathewjohn@yahoo. com mide_2643@yahoo.co m sahayrk@gmail.com Name of Committee Approval Status Date of Approval Is Independent Ethics Committee? Bangalore Diabetes Hospital Ethics Committee, Dr Prasanna Kumar Bangalore Endocrinology & Diabetes Research Centre Ethics Committee on Human Research, Bangalore, Dr Mala Dharamlingam Bharti Research Institute of Diabetes & Endocrinology Institutional Ethics Committee, Dr Sanjay Kalra Approved 13/09/2011 No Approved 29/09/2011 No Approved 25/11/2011 No page 3 / 10

4 Regulatory Clearance Status from DCGI Health Condition / Problems Studied Intervention / Comparator Agent Inclusion Criteria Dia Care Ethics Committee, Dr Banshi Saboo Human Welfare Ethical Committee for Human Sciences and Research, Dr SK Sharma Institutional Ethics Committee of Diabetes Clinic & Research Centre, Shreeniwas, Opp. Dhantoli Park, Nagpur , Dr Sharad Pendsey Approved 03/09/2011 No Approved 12/09/2011 No Approved 17/09/2011 No Osmania Medical College Ethics Committee, Hyderabad, Dr Rakesh Kumar Sahay Approved 02/03/2012 No Swasthya Kalyan Ethics Committee, Jaipur, Dr Sudhir Bhandari Status Approved 12/10/2011 Yes Date Approved/Obtained 22/03/2011 Health Type Patients Condition Type 1 Diabetic Type Name Details Intervention Comparator Agent Age From Age To Gender Details Wosulin R, Wosulin N and Wosulin 70/30 Novolin R, Novolin N and Novolin 70/ Year(s) Year(s) Both Inclusion Criteria Subcutaneous injection in the dose calculated as per basal bolus metabolic requirement and BMI. Subcutaneous injection in the dose calculated as per basal bolus metabolic requirement and BMI. Patients must meet all of the following criteria: 1.Patients who understand the nature of the study and provide written informed consent. 2.Patients who have been diagnosed as cases of type-1 diabetes (Fasting C-peptide 0.5 nmol/l) and have been on an insulin regimen for at least 12 months prior to inclusion in the trial. 3.Patients who have been on a stable regimen of insulin for at least 3 months prior to randomization. A stable regimen is defined as the dose staying within +/- 10%. 4.Male or Female Patients 18 and 45 years of age 5.Patients with body mass index (BMI) 18.0 to 35.0 kg/m2 6.Patients with glycosylated hemoglobin (HbA1c) levels between 7.0 and 9.5% 7.Patients who are cooperative, reliable, and agree to have regular injections of insulin and are willing to comply with protocol page 4 / 10

5 Exclusion Criteria Method of Generating Random Sequence Method of Details Computer generated randomization Centralized procedures. 8.Female patients (non-pregnant and non-lactating with adequate protection from conception). Females of childbearing potential must agree to use an acceptable method of birth control (including barriermethod contraceptives or intrauterine device). Women with history of bilateral tubal ligation, women who have undergone total hysterectomy or women who are two years post-menopausal are also eligible (if within 18 and 45 years age limits). 9.Ability to use the self glucose-monitoring device and self inject insulin. Exclusion Criteria Patients who meet ANY of the following exclusion criteria at screening or baseline will NOT be eligible for enrolment: 1.Patient who is pregnant (as confirmed by a positive HCG test/ serum CG) or is currently breast-feeding. 2.Patient with compromised hepatic or renal function, as shown by but not limited to baseline AST or ALT 3 times the upper limit of normal range, serum creatinine 2.0 mg/dl and/or BUN 30 mg/dl, respectively. Abnormal findings should be discussed with the medical monitor prior to the patients entry. 3. Patient who is an employee of the Investigator or the Institution, or a patient who has direct involvement with the trial or other trials under the direction of the Investigator. 4.Patient who has been treated with other investigational agent or devices within the previous 30 days, has planned use of investigational drugs or devices, or has been previously randomized in this trial. 5.Patient with history or evidence of allergy to insulin preparations. 6.Patient with history or evidence of recurrent severe hypoglycemia 7.Patient whose requirement for total daily dose of insulin is 1.4 units/kg 8.Patient who has received Wockhardts (Wosulin) or Novo Nordisks Insulin (Novolin R, Novolin N, Novolin 70/30, for the previous one year 9.Patients with serum AIA level above 20 microu/ml. 10.Patient who has received any insulin of animal origin during the last 3 years. 11.Patients who are currently receiving or have received within the last year any immunomodulators medications, including corticosteroids that would possibly modify antibody generation either at the enrollment or during the course of the study. Topical/ ophthalmic/intra-articular/nasal spray corticosteroids will be allowed. 12.Patients who are Hepatitis B or C or HIV positive. 13.Patients who received an oral hypoglycaemic agent within 4 weeks prior to signing consent form. 14.Patients who have undergone pancreatectomy or pancreas/islet cell transplant 15.Patients unlikely to comply with the study protocol e.g. unable to return periodically for subsequent visits. 16.Patient with history or evidence of active severe proliferative retinopathy, nephropathy and/or neuropathy significant cardiovascular disease, anemia or hemoglobinopathy, hypothyroidism, alcohol or drug abuse or any other medical condition that in the opinion of Investigator can interfere with the study. 17.Patients who are judged by the investigator as inappropriate to participate in the study for any reason other than those mentioned above. page 5 / 10

6 Concealment Blinding/Masking Open Label Primary Outcome Outcome Timepoints Absolute change in HbAlc from baseline to 6 months of treatment between Wosulin and Novolin USA (as surrogate indicator of change in insulin antibodies titers between the two treatment arms) 6 months from baseline and 12 months from baseline Secondary Outcome Outcome Timepoints Target Sample Size Phase of Trial Phase 3 Date of First Enrollment (India) Date of First Enrollment (Global) Estimated Duration of Trial Recruitment Status of Trial (Global) Recruitment Status of Trial (India) Publication Details Brief Summary Correlation between the percent change in HbA1c from baseline to 6 months of treatment and percent change in anti insulin and neutralizing antibodies (AIA and INA) with absolute change in total insulin dose as covariate. Total Sample Size=242 Sample Size from India=100 18/07/ /03/2011 Years=1 Months=6 Days=0 Other (Terminated) Completed 6 months from baseline and 12 months from baseline. Title of Study An Open Label, Randomized, comparison of the Immunogenicity and Safety of Wockhardt s Human Insulin Basal Bolus Regimen {Intensified Conventional Insulin Therapy with Soluble Insulin and Isophane Insulin (Wosulin R, Wosulin N and Wosulin 70/30)} with the Novo Nordisk s yeast based Human Insulin Basal Bolus Regimens, marketed in United States (Novolin R, Novolin N and Novolin 70/30) in Type 1 Diabetics. Indication Type 1 Diabetes Study Objectives To evaluate and compare the Immunogenicity and Safety of Wockhardt s Human Insulin i.e. Wosulin (Wosulin R, Wosulin N and Wosulin 70/30) with the Novo Nordisk insulin i.e. Novolin (Novolin R, Novolin N and Novolin 70/30) in United States on the basis of the effects of the anti insulin antibodies generated following administration of these insulins on their efficacy and safety in Type I Diabetics. page 6 / 10

7 Primary Objective: Change in HbAlc from baseline to 6 months of treatment between Wosulin and Novolin USA (as surrogate indicator of change in insulin antibodies titers between the two treatment arms). Secondary Objective: Correlation between change in HbA1c from baseline to 6 and 12 months of treatment and change in anti insulin and neutralizing antibodies with insulin dose as covariate. In both the groups, the correlation of the immunogenicity (measured as percentage change in serum AIA & INA) with hypoglycemia, local allergic reactions and systemic allergic reactions will be evaluated. Patient safety will be assessed through the monitoring and reporting of any adverse events including laboratory change(s) that occur during the study Study Phase Phase III Study Population 242 eligible male and female Type I Diabetic patients Study Sites Approximately 40 sites across United States and India Study Design Phase 1 - Prospective, randomized, comparative, non- inferiority open-labeled, parallel group study for the first 6 months Phase 2- Single arm of Wosulin for 6 months (non comparative) page 7 / 10

8 Study Procedure Type 1 diabetics who have been on basal bolus insulin regime for at least a year will be enrolled. During the screening period patients will be evaluated for HbA1c, serum AIA, INA, 8- point blood glucose profile {(the first 2 readings i.e. fasting and postprandial plasma glucose levels (FPG & PPPG) will be analyzed at central lab as well as by Glucometers with the same blood sample and the remaining 6 samples will be performed only by Glucometers)}, liver and renal function tests (LFT & RFT), electrocardiogram (ECG), hematological & urine profile. Patients who meet all the eligibility criteria will be enrolled in the study and randomized at Visit 2 to either the Wosulin arm (for 12 months) or the comparator arm (for 6 months). All the patients randomized into the Wosulin treatment arm will receive Wosulin R & Wosulin N or Wosulin R & Wosulin 70/30. Those in the Novolin arm will receive Novolin R & Novolin N or Novolin R & Novolin 70/30. At least 2 doses of Wosulin NPH /or 70/30 or comparator NPH /or 70/30 insulins will be administered everyday as the basal / basal bolus insulins with suitable additional bolus regimens (of soluble insulins) as needed. There will be a 2-week dose titration phase during which attempts will be made to titrate the dosing so as to achieve fair glycemic control using blood glucose estimation and the investigator modifying the dose post discussion with the patient (the insulin doses shall be adjusted so as to achieve the HbA1c goal of <7% without increasing the risk of clinically significant hypoglycemia.). Patients will be instructed on Self Monitoring of Blood Glucose (SMBG), diet and exercise regimens. All patients will receive similar kind of instructions regarding SMBG, diet and exercise. All patients will evaluated for vitals and physical examination on all protocol visits and Haematological, Liver and Renal function Tests, urine profile and pregnancy test on Visits 1, 5, 7, 9, 11, 13 page 8 / 10

9 and 15. All patients will be evaluated for HbA1c and serum AIA, at the Month 3 (Visit 6), and month 6 (Visit 9) visits. The Wosulin arm will continue and be evaluated at the following additional time points, Month 9 (Visit 12) and Month 12 (Visit 15) visits. The tests will include FPG, 8-point blood glucose profile (including the PPPG) and HbA1c. Serum AIA for patients on Wosulin arm will be measured in Month 12 (visit 15). The serum INA will be estimated at baseline, Month 6 (visit 9) for all patients and Month 12 (Visit 15) for the Wosulin arm patients. The Investigator will continue to adjust the dosage and time of administration of the basal bolus regimen in accordance with the metabolic needs of the patient during the study period. Arm 1*: (Wosulin arm) a. Wosulin N & Wosulin R or b. Wosulin R & Wosulin 70/30 page 9 / 10

10 Powered by TCPDF ( Arm 2*: (Novolin arm) a. Novolin N & Novolin R or b. Novolin R & Novolin 70/30 *Allotment of treatment (a or b) will be based on what basal-bolus combination each patient was receiving before enrollment in the study. Study Drug See above (arm 1) Comparator Therapy See above (arm 2 ) Study Period Enrollment period 3 months Treatment period 12 months Proposed Start Date November 2010 page 10 / 10