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: Tang ASL, Wells GA, Talajic M, et al. Cardiac-resynchronization therapy for mild-to-moderate heart failure. N Engl J Med 2010;363: DOI: /NEJMoa

2 Resynchronization/Defibrillation for Ambulatory Heart Failure Trial (RAFT) Study Protocol Version July 1, 2007 Study Sponsor: European expansion Study Sponsor actively enrolling sites: Europe University of Ottawa Heart Institute Medtronic Principal Investigators: Bakken Research Center B.V Anthony Tang, MD, RCPC Director of Electrophysiology Director of Cardiology Research Endepolsdomein GW Maastricht Dr. George A. Wells, MSc, PhD Netherlands Director Cardiovascular Research Methods Centre U. of Ottawa Heart Institute 40 Ruskin Street Ottawa K1Y4W7 Canada Phone: Phone: (613)

3 Resynchronization/Defibrillation for Ambulatory Heart Failure Trial (RAFT) 1. SUMMARY BACKGROUND and RATIONALE Epidemiology of Congestive Heart Failure Therapy for CHF Pharmacological Therapy for CHF Device Therapy for CHF Summary of Rationale STUDY HYPOTHESIS OUTCOME EVENTS STUDY DESIGN Trial design Trial interventions Treatment Allocation Pre-randomization Pharmacological therapy Control group - ICD plus Optimal Medical Therapy Experimental group - CRT/ICD plus Optimal Medical Therapy Post-randomization pharmacological therapy STUDY POPULATION Inclusion Criteria: Exclusion Criteria: STUDY METHODOLOGY Pre-randomization procedure Randomization Protecting against sources of bias Duration of treatment period Frequency and duration of follow up Monitoring Regulations Investigator Records Sponsor Records: STATISTICAL CONSIDERATIONS Statistical Analysis/Sample size PARTICIPATING CENTRES STUDY ANALYSES Frequency of analyses Planned subgroup analyses STUDY ORGANIZATION Coordinating Centre Committees ETHICS REVIEW APPENDIX APPENDIX 2: Suggestions to manage patients with persistent NYHA Class III symptoms APPENDIX 3: Table APPENDIX 4: Table APPENDIX 5: Warranty Information APPENDIX 6: Informed Consent Template (Europe) APPENDIX 7: Labeling APPENDIX 8: European definitions: Page 2 of 44 Version July 1, 2007

4 1. SUMMARY Background: Cardiovascular mortality is decreasing in most industrial countries; however mortality for congestive heart failure is increasing. The most important predictors of mortality in advanced heart failure patients are depressed left ventricular function, severity of symptoms (NYHA class), and ventricular conduction abnormality manifested as wide QRS. Recent advances in pharmacological therapy including ACE inhibitors, beta-blocker and spironolactone have resulted in improvement of symptoms and reduction in mortality. Population epidemiological studies demonstrated that mortality and hospitalization rate for advanced congestive heart failure remains very high despite recent pharmacological therapeutic progress. Recent short-term clinical trials demonstrated that cardiac resynchronization therapy (CRT) is effective in improving symptoms of heart failure, functional capacity and quality of life in patients with heart failure and conduction abnormality optimally treated with drug therapy. However, the data for morbidity is conflicting and there is not data on mortality Objective: The objective of this trial is to determine if the addition of CRT to ICD and medical therapy will reduce total mortality and hospitalizations for congestive heart failure in patients with mild to moderate heart failure symptoms. Methods: This is a double-blinded randomized control trial. A total of 1800 patients with mild to moderate heart failure symptoms, LVEF 30%, and QRS 120 ms will be included in the study. Patients will be randomized to either ICD plus Optimal Medical Therapy (control) or CRT/ICD plus Optimal Medical Therapy (experimental) in a 1:1 randomization ratio. Patients in the control group will be implanted with a single or dual chamber ICD. Patients in the experimental group will receive a device with the capabilities of CRT and ICD. Optimal Medical Therapy will include ACE inhibitors and beta-blockers. Patients will be followed on a regular basis and will have clinical evaluation, quality of life assessment, and six minute walk tests performed. The primary outcome is a composite of total mortality and heart failure hospitalization. Secondary outcome measures will include total mortality, cardiovascular mortality, sudden arrhythmic death, health related quality of life and cost economics. The composite event rate of total mortality and CHF hospitalization is estimated to be 12.6% per year for patients receiving ICD-only. This estimate is based on the MADIT-CRT selected annual event rate of 16.7% for patients receiving ICD-only and a review of our RAFT data (see Section 8.1). In order to detect a 25% relative risk reduction in the primary endpoint under the experimental group (CRT/ICD) at alpha = 0.05 (two-sided) and 85% power, a sample size of 1800 patients will be required. We anticipate having a total of 21 Canadian sites participating, and an additional 20 sites in Australia and Europe. Patient accruement is scheduled for 4.5 years and a minimum follow of 18 months. 2. BACKGROUND and RATIONALE 2.1 Epidemiology of Congestive Heart Failure Cardiovascular mortality has decreased over the last three decades in most industrialized countries. The incidence and mortality rate for Congestive Heart Failure (CHF) is increasing. 1 Indeed, the rate of hospitalization for CHF has been rapidly increasing and now represents the most common discharge diagnosis for patients over the age of 65 in North America. 2 CHF is a major economic burden incurring. 3, 4 Many clinical and laboratory variables predict mortality in patients with advanced CHF. Severity of symptoms (NYHA class), ventricular function (LVEF), and etiology of disease (ischemic or non-ischemic) have been shown most consistently to have independent prognostic value. 5 Intraventricular conduction delay also has been shown to be an independent risk factor. 6-9 Aaronson demonstrated that QRS duration > 120 ms was associated with a hazard ratio of 1.84 (95% CI: 1.22, 2.76) for death or heart transplantation. A large multicentre CHF study demonstrated that mortality was three-fold higher in patients with QRS Page 3 of 44 Version July 1, 2007

5 duration > 150 ms compared to those with normal QRS. 10 A recently completed clinical trial, MADIT-II, also confirmed that QRS > 120 ms is an independent predictor of mortality. 11 This intraventricular conduction abnormality may be a result of dilatation and stretching of the left ventricle (LV). However, abnormal conduction also results in asynchronous contraction, thus potentially causing a vicious cycle of ventricular remodeling. It seems reasonable to hypothesize that a strategy to normalize ventricular conduction abnormality, that is resynchronize ventricular contraction by stimulation of both RV and LV, may reverse the remodeling process. This is known as cardiac resynchronization therapy (CRT). 2.2 Therapy for CHF Over the last 3 decades, great progress has been made in our understanding of the pathophysiology of CHF and in the development of improved therapy. Earlier approaches, aimed at improving cardiac performance directly with positive inotropic agents, have consistently been associated with adverse outcomes The most successful pharmacological approaches have been those aimed at modifying the progression of ventricular dysfunction in CHF involving angiotensin converting enzyme inhibition (ACEI) and beta-blockade (see section 2.2.1). Despite the advances and successes in pharmacological therapy of 16, 17 CHF, survival and symptom relief are still unacceptably poor. More recent pharmacological 18, 19 development has not been as successful. The addition of CRT to pharmacological therapy has been shown to be effective in reducing CHF symptoms. (See Section 2.2.1) There is a strong physiologic rationale that CRT, by improving LV performance, may reduce progressive CHF dead and by improving substrate for arrhythmogenesis, may reduce arrhythmia sudden death. Furthermore, the presence of chronotropic support will allow for more aggressive use of beta-blockade therapy, an approach that is often limited by the conduction disturbance. Implantable cardioverter defibrillator (ICD) is a very effective therapy for patients who have survived a near fatal ventricular arrhythmia or those at high risk for a cardiac arrest. Recent data cautioned that ICD while reduced mortality might increase morbidity of CHF hospitalization and increase CHF symptoms. (See Section 2.2.2) An implantable device with CRT and ICD capability may be the ideal treatment for CHF in conjunction to pharmacological treatment and is the object of this trial Pharmacological Therapy for CHF Diuretics and Digoxin: Until 15 years ago, the mainstay of CHF therapy included diuretics and digoxin. Therapy with diuretics was aimed at improving symptoms of congestion. Although the beneficial effect of diuretics on morbidity and mortality has been intuitively accepted by most clinicians, the RALES (Randomized Aldactone Evaluation Study) trial is the only data demonstrating a reduction of mortality with a diuretic. 20 Digoxin was also used empirically for decades in the therapy of CHF. It was not until the DIG trial, in which the impact of digoxin was examined in 7788 patients, that the role of digoxin was clarified that digoxin significantly reduced hospitalization, but not mortality. 21 Hemodynamic therapy Throughout the 1980's, the development of CHF therapy was characterized by efforts to improve the abnormal hemodynamics found in the CHF state. Initial efforts included the use of vasodilator therapy, leading to V-HeFT I, the first clinical trial to suggest a mortality benefit of a specific treatment for chronic CHF. 22 By the end of the 1980's, ACEI had been shown to improve survival in CHF 23 and the concept that some of this benefit was not mediated by their hemodynamic impact but rather by their ability to modify the neurohormonal dysregulation present in CHF, had begun to evolve. At the same time, efforts to improve outcomes in CHF with the use of positive inotropic therapy continued, with uniformly negative results. 15 This experience caused a shift from the traditional hemodynamic approach towards therapies designed at moderating neurohormonal activation and limiting disease progression. Page 4 of 44 Version July 1, 2007

6 Neurohormonal modulation and modification of disease progression: Further investigations confirmed the therapeutic importance of ACEI in patients with mild to moderate CHF (V-HeFT II and the SOLVD treatment trial 23, 24 ), asymptomatic patients with reduced EF (SOLVD prevention trial 25 ) and post MI patients with reduced EF with or without CHF (SAVE 26 and AIRE trials 27 ). The role of angiotensin receptor blocker (ARB) therapy remains controversial. Although the ELITE I study suggest a modest benefit of Losartan compared to ACEI therapy 28, the ELITE II study found no significant difference in mortality when Losartan was compared to captopril. 29 A recently completed Val-HeFT trial showed that the addition of valsartan to usual therapy incurred a 13.3% reduction in the composite endpoint of all-cause mortality and morbidity but did not affect mortality. 30 However, subgroup analysis showed a mortality benefit of valsartan in patients not on ACEI. 31 These data suggest that ARB is a reasonable substitute in patients not able to tolerate ACEI. Role of beta-blockers: Activation of the sympathetic nervous system is a prominent characteristic of the neurohormonal response in chronic CHF. The prognostic importance of sympathetic activation has been recognized for years and recent data from multiple clinical trials have confirmed that beta-blockers are highly effective in decreasing both morbidity and mortality in CHF The recently reported COPERNICUS study confirmed beneficial effects of carvedilol in patients with severe, symptomatic CHF. 39 To date, the only large-scale trial not demonstrating a clear benefit of beta-blockers in CHF was the BEST study, although it still showed a trend towards a beneficial effect. 40 In light of this, beta-blockade therapy has now become standard therapy for CHF. Other pharmacotherapy in CHF: Calcium channel blockers have generally been avoided in patients with advanced CHF because of the negative inotropic effect and studies suggesting increased mortality in patients with low EF. 41 Recent clinical trials suggest that amlodipine and felodipine can be given safely in this disorder although they do not have a beneficial effect on mortality. 42, 43 The role of antiarrhythmic therapy in CHF has also evolved dramatically. Amiodarone is an accepted therapy for the management of symptomatic atrial and ventricular arrhythmias in patients with CHF. 44 The prophylactic use of amiodarone in patients with CHF without significant rhythm disturbances remains controversial. Further information will be available upon the conclusion of the SCD-HeFT study Device Therapy for CHF The past decade has seen increasing use of device therapy in CHF patients. The best established of these is the implantable cardioverter defibrillator (ICD). ICD therapy has an established role in the management of patients with malignant ventricular arrhythmias. ICD Therapy ICD is the most effective therapy for patients who have survived a cardiac arrest, or VT (2 secondary prevention). Three randomized 2 prevention trials demonstrated a mortality reduction with ICD therapy compared with antiarrhythmic drugs (mostly amiodarone) When this data was combined, there was a highly significant mortality reduction with ICD of 28%. 48 Subsequent analysis of AVID and CIDS data identified that patients with poor LV function and CHF symptoms benefited the most from ICD therapy Three randomized 1 primary prevention trials were conducted to evaluate the efficacy of ICD therapy in high-risk patients They selected patients at high risk of ventricular arrhythmias based on LV dysfunction (EF 35-40%), and either non-sustained VT, inducible VT (in the MADIT and MUSTT trials) or abnormal signal average ECG (in the CABG-Patch trial). Overall the results suggested that ICD reduced mortality. The most recently published MADIT-II trial determined that ICD reduced mortality by 31% in a broader patient group, who have a previous MI and LVEF < 30%. However, the trial also showed that patients with Page 5 of 44 Version July 1, 2007

7 ICD had an increased rate of hospitalization for CHF compared to control despite optimal medical therapy for CHF 70% received an ACEI and 70% received a beta-blocker. One future ICD primary prevention trial is ongoing. Sudden Cardiac Death in Heart Failure Trial (SCD- HeFT) will determine whether prophylactic ICD is an effective therapy for CHF patients. It is a three-arm trial of optimal medical therapy, optimal medical therapy plus amiodarone, and optimal medical therapy plus ICD. The patients in SCD HeFT have NYHA class II-III symptoms and EF<35%. This trial has completed enrollment of its targeted 2500 patients and will continue to follow patients for a minimum of 2.5 years. SCD-HeFT will be conducting an economic analysis to determine the economic impact of such therapy. Cardiac Resynchronization Therapy (CRT) In patients with advanced CHF, 28-42% have 1st degree or 2nd degree AV block 55 and 23-53% have intraventricular conduction delay with QRS > 120 ms These patients have disadvantaged AV transport, paradoxical septal motion, interventricular and intraventricular asynchronous contraction, and concealed AV delay (even when PR interval is normal). Pacing both RV and LV simultaneously would correct many of these disadvantages and may improve ventricular function. Studies have reported acute hemodynamic benefits of CRT showing reduction of LV filling pressure, and mitral regurgitation; increase of cardiac index and EF. Initially, LV stimulation was accomplished with an epicardial electrode introduced by a thoracotomy. However, the procedure is cumbersome and has not met with clinical acceptance. A less invasive approach with total transvenous lead implantation is preferred. This was accomplished by advancing a pacing lead via the coronary sinus to a LV venous branch. 64 Such a pacing system has been successfully implanted in 103 patients participating in a non-randomized, uncontrolled InSync study. 65 Patients had CHF (68%- NYHA class III, 32%-NYHA class IV) on standard medical therapy, low EF of 22 ± 8%, QRS =180 ± 29 msec., and reduced functional capacity with six minutes walk of 290 ± 110 meters. After 12 months follow-up, there was a significant improvement of NYHA class, six-minute walk distance, and quality of life. 64, 66 There were no significant implant complication such as operative death, arrhythmia at implantation or infection. Four randomized control trials of CRT for the management of CHF have been completed. All these studies included patients with CHF despite optimal drug therapy for heart failure, wide QRS and EF 35%. The MUSTIC (Multi-site Stimulation in Cardiomyopathies) was a single blind randomized crossover study in which patients were randomized to a three-month period of CRT or back up pacing at a rate of 40 beats per minute. 67 Of 48 patients that completed the study, the mean 6-minute walk distance improved by 25%, the quality of life scores improved by 32% and the peak oxygen uptake increased by 8%. Hospitalization rate decreased significantly. The MIRACLE (Multi-Centre InSync Randomized Clinical Evaluation) was a randomized double blind controlled trial. 68 All patients received a CRT device, 189 patients randomized to the control arm had the device turned to a back-up pacing mode and CRT was turned on in the other 181 patients. There was a significant improvement of the six-minute walk distance, quality of life, and NYHA symptoms classification in the CRT group compared with control. Echocardiography demonstrated reduction of mitral regurgitation jet area and a reduction of LV end-diastolic dimension. In patients randomized to the CRT there was also a reduction of hospitalization due to CHF. CONTAK CD and MIRACLE-ICD both enrolled patients with CHF who also had an ICD indication. 69, 70 All patients received the device and were randomized to have CRT turned on or off for a period of 6 months. There was an improvement of peak VO 2, six-minute walk distance, and improvement of quality of life score. These four trials indicate that CRT improves heart failure symptoms, quality of life, and exercise performance in patients with LV systolic dysfunction and ventricular conduction abnormality. Device therapy promoting better optimization of pharmacological therapy Device therapy also allows better optimization of medical therapy for CHF. The two drugs that have shown mortality benefit in treating heart failure are ACEI and beta-blocker. They should be used in most heart failure patients in adequate dosages. However, in clinical trial and in clinical practice, a significant number of patients are not taking these drugs, mainly because of adverse effects of hypotension 71 and Page 6 of 44 Version July 1, 2007

8 bradycardia including heart block. 36 This is particularly a problem in patients with advanced heart failure and ventricular conduction abnormality so that less than optimal dosages of these drugs are used, if at all. It has been suggested that cardiac pacing may allow a greater use of these drugs. 72 However, chronic right ventricular pacing may induce ventricular dysfunction 73 and cause worsening of heart failure. Cardiac resynchronization may have the ability to provide chronotropic and inotropic support to allow more aggressive up-titration of these two drugs. 2.3 Summary of Rationale The evidence to date, summarized above, suggests that CRT improves CHF symptoms, exercise capacity, and quality of life in CHF patients with LV dysynchrony. This data is encouraging but inadequate and insufficient for the following reasons: 1) Lack of long term data The clinical trials data are of 6-months duration. The only longer-term reports are three non-randomized longitudinal follow-up showing sustained improvement of patients with CRT for 12 months ; 2) Inconsistent results of surrogate outcome measures While most of the data supporting CRT are of subjective nature, there are important objective evidence showing benefit of CRT. CRT caused a reduction of mitral regurgitation, and LV chamber size, an increase of stroke volume and LV-EF without increasing myocardial oxygen consumption 77, 78, suggesting a process of reverse ventricular remodeling. 79, 80 However, neurohormone analyses in the clinical trials have all been negative; 3) Inconsistent morbidity data All four randomized trials evaluated the impact of CRT on hospitalization. Two showed an improvement and two trials did not show any difference. This may be due to the short-term follow-up of these trials; 4) Lack of mortality data - There is insufficient data from these trials to describe the effect of CRT with or without ICD on survival, although each of these trials showed a trend of short-term mortality reduction with CRT of 25-30% even when compared with patients receiving ICD alone. There is a need for a well designed randomized controlled trial now. There are two randomized controlled trials underway to evaluate the efficacy of CRT and CRT/ICD on mortality and morbidity. A European trial, CARE-HF 81, is comparing in open-label fashion the effects of CRT on the combined endpoint of all-cause mortality and unplanned cardiovascular hospitalization in CHF patients with EF< 35% and wide QRS. The study will randomize 800 patients and has 80% power to detect 25% reduction in the primary endpoint, assuming 40% annual event rate in the control group. A US trial, COMPANION 82 is a three-arm (medical therapy, medical + CRT, medical + CRT + ICD) study of 2400 patients in NYHA class III or IV with EF 35% and a QRS duration 120 ms. The primary endpoint is a composite of all-cause mortality and all-cause hospitalization. The trial has 80% power to detect 25% reduction of composite endpoint comparing medical + CRT + ICD to medical at = 0.03 and comparing medical + CRT to medical at = 0.02 using the logrank test procedure, assuming 40% annual composite event rate and 25% annual mortality rate in the control group. While these two trials appear to be similar to the proposed RAFT study, there are important differences. 1) Differences of trial objective the objective of CARE-HF is to determine the value of CRT compared to medical treatment. The objectives of COMPANION are two: to determine the value of CRT compared to medical treatment, and also the value of CRT/ICD compared to medical treatment. RAFT s objective is to determine the value of CRT when added to patients receiving medical treatment and ICD. These are very different objectives in light of the results of recent trials leading to a general acceptance of ICD for primary prevention of patients at high risk of cardiac arrest. Therefore, many have questioned the clinical relevance of CARE-HF and COMPANION. Many of the patients included in CARE-HF and COMPANION would be eligible to ICD by today s standard of care. RAFT study design has taken the possible evolution of CHF treatment into consideration. Any new CHF therapy approved for clinical use will be incorporated in both treatment arms. RAFT will be the only trial that is assessing the value of CRT over all approved CHF management. The result of RAFT will have a major impact on the acceptance of CRT and will have a major influence on decision makers about this therapy. 2) Differences in trial design CARE-HF and COMPANION are open-label studies. The control group of these two trials will not be receiving a device. The patient or the assessor will not be blinded to the treatment allocation. RAFT is a double-blinded controlled trial. (See Page 7 of 44 Version July 1, 2007

9 Section 5) 3) Differences of statistical power - CARE-HF and COMPANION are underpowered for mortality. The mortality rate assumed in both trials is much higher than contemporary trial data While these two trials will be useful to determine the long-term effect of CRT on symptom relief, quality of life, and exercise capacity, RAFT will be the only trial properly designed and adequately powered to address the question of morbidity and mortality benefit of CRT in addition to current treatment of these patients. Contribution to informing clinical decision-making/improve understanding RAFT will be able to determine the contribution of CRT on mortality and morbidity in this patient group. The economic analysis will determine the cost-effectiveness of CRT when added to current therapy. The result of RAFT will be influential to the medical community to adopt this therapy or not. Currently the short-term data is supportive of CRT. For this reason the 2002 practice guideline for device therapy gave CRT a class II indication that means, There is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of the treatment. 86 RAFT will clarify this. NEW DATA: Two CRT trials, Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) 87 and Cardiac Resynchronization in Heart Failure study (CARE-HF) 88 were published. In particular, the CARE-HF study indicated that in patients with NYHA class III-IV heart failure and ventricular dyssynchrony, cardiac resynchronization (CRT pacing) improves symptoms and quality of life and reduces mortality. This has led to published guidelines (ACC/AHA;HFSA;Canadian Cardiovascular Society/ESC suggesting CRT pacing for NYHA Class III-IV patients with reduced ejection fraction, and wide QRS. There is still no information on the contribution of CRT to ICD and medical therapy. RAFT will be able to contribute to this information. 3. STUDY HYPOTHESIS The objective of this trial is to determine if the addition of CRT to optimal pharmacological therapy and ICD is effect in reducing mortality and morbidity in patients with poor LV function, wide QRS and heart failure symptoms. HYPOTHESIS: In patients with LV Dysfunction (EF 30%), QRS duration 120 ms, and mild to moderate CHF symptoms, the addition of CRT to ICD and optimal medical therapy reduces the combined end point of all-cause mortality and CHF hospitalization. 4. OUTCOME EVENTS 4.1 Primary Outcome Measures: The primary outcome is a composite of: total mortality and hospitalization for CHF. Total mortality includes any death. Hospitalization for CHF is defined as an admission to hospital with a diagnosis of worsening CHF for >24 hours. Why use composite endpoint of total mortality and CHF hospitalization? The two are not equal but both are important measures for the patient. It is important to be relatively certain that excess mortality is not being caused in the pursuit of fewer symptoms and fewer hospitalizations, as observed with inotropic agents. 15 Conversely, it is also important to ascertain if the pursuit of less mortality leads to an increase in symptoms and hospitalization, as is reported in ICD therapy for high-risk patients. 92 For these reasons, the composite of all-cause mortality and CHF hospitalization is a well-accepted primary endpoint in clinical trials of CHF therapy and is endorsed by DeMets and Califf. 93 An 85% power was selected for the composite endpoint. A RRR of 25% was selected. The selection of 25% was based on a consensus among the RAFT Investigators (See Section 8.1). Page 8 of 44 Version July 1, 2007

10 4.2 Secondary Outcome Measures: Total mortality, cardiovascular mortality, sudden arrhythmic death, progressive CHF death, all cause hospitalization rate, CHF hospitalization rate, health related quality of life and cost economics. 4.3 Other Outcome Measures: 6 minute walk distance, NYHA Class, development of new atrial fibrillation, and non-fatal ventricular tachycardia 5. STUDY DESIGN 5.1 Trial design This trial is a multi-centre randomized double-blinded controlled trial of two treatment groups. The patients, primary physicians and the heart failure caregivers will be blinded to the treatment allocation. The device follow-up caregivers will not be blinded. (See section 7.3 for allocation concealment) 5.2 Trial interventions This trial will have two treatment groups. Eligible and consenting patients will be randomized in a 1:1 proportion to ICD plus Optimal Medical Therapy (control) or CRT/ICD plus Optimal Medical Therapy (experimental). All devices used in the RAFT trial will be the most up-to-date Medtronic market release resynchronization/defibrillator model along with the most up-to-date market release lead model. The patient randomized to the control group will receive a single or dual chamber ICD (with RV ± RA leads) and optimal doses of 1) ACEI (if not tolerated then ARB or hydralazine and nitrates) and 2) betablocker.,. Diuretics, nitrates, and digoxin may also be used for adjunctive CHF therapy. Amiodarone may be used in patients with symptomatic atrial arrhythmias, symptomatic VT after randomization, or to reduce ICD discharges from atrial or ventricular arrhythmias. The patient randomized to the experimental group will receive a CRT/ICD (with RA, RV and LV leads) and optimal doses of medications as in the control group. 5.3 Treatment Allocation Pre-randomization Pharmacological therapy All randomized patients will receive optimal heart failure pharmacological therapy for six weeks prior to enrollment into the study. These therapies should include: ACEI: All patients should receive ACE inhibitor whenever possible, limited by symptomatic hypotension, renal dysfunction, cough, allergic reaction, or significant other side effect. A target dosage of enalapril mg bid (or equivalent ACEI and dosage) is recommended. For patients unable to tolerate ACEI, an ARB or a hydralazine/nitrate combination should be used. Beta-blocker: All patients should receive beta-blocker whenever possible, limited by symptomatic bradycardia, allergic reaction, or significant side effect. A target dosage of metoprolol 75 mg BID, carvedilol 25 mg BID, or bisoprolol 10 mg OD is recommended unless limited by symptomatic bradycardia or hypotension, pulmonary wheeze, allergic reaction, or significant other side effect. Digoxin: Digoxin may be used at the discretion of the treating physician. Nitrates: Any formulation of nitrates can be used for CHF symptom control. Diuretic: Diuretic may be added or reduced according to patient s symptoms. Amiodarone: Amiodarone may be used for the treatment of symptomatic atrial arrhythmias. Amiodarone should not be started for asymptomatic or minimally symptomatic PVC or non-sustained VT. Other anti-arrhythmics: Amiodarone should be the drug of choice if anti-arrhythmic drug is necessary. In the event that a patient requires an anti-arrhythmic drug and is intolerant to or has significant side effect from amiodarone then another anti-arrhythmic drug may be chosen at the discretion of the treating physician. Page 9 of 44 Version July 1, 2007

11 Anticoagulation: Anticoagulation will be prescribed as clinically indicated Control group - ICD plus Optimal Medical Therapy Patients randomized to the control group will receive an ICD device. Device implantation will be performed within 7 working days of randomization. The choice of using a single chamber or a dual chamber ICD will be at the discretion of the treating physician according to the guideline outlined in Appendix 1. The RV defibrillation lead should be placed at the RV apex if possible. If a dual chamber device is used, the RA lead should be placed at the RA appendage. Electrical testing and programming of the device will be standardized (Appendix 1) Experimental group - CRT/ICD plus Optimal Medical Therapy Patients randomized to CRT/ICD plus optimal medical therapy will receive an ICD device capable of delivering CRT. Device implantation will be performed within 7 working days of randomization The device will be implanted in a facility that has the capacity to perform coronary sinus venography at the time of implantation. The LV stimulation lead should be placed at one of the LV venous branches, preferably a lateral LV vein. The RV defibrillation lead should be placed at a RV site providing the widest possible physical and electrical separation from the LV lead, usually at the RV apex if the LV is at a lateral cardiac vein or at the RVOT if LV is at the middle cardiac vein. The RA lead should be placed at the RA appendage. Electrical testing and programming of the device will be standardized (Appendix 1). Defibrillation testing will be optional during implant for the Control group and the Experimental group. The options include: 1. RAFT sites may choose to participate in the RAFT Sub study titled: A Randomized Controlled Pilot Study to Determine the Safety of Intra-Operative Defibrillation Testing and to Estimate the Effect of Testing on the Success of Clinical Defibrillation and Mortality and adhere to testing as outlined in that protocol. 2. RAFT sites may choose to NOT participate in this RAFT Sub study. Defibrillation testing will then be done according to clinical indications. Testing results or no testing should be recorded on the RAFT implant CRF Post-randomization pharmacological therapy CHF medication may be adjusted during the study as indicated with the intention to provide optimal medical care for each patient. Up-titration of CHF medications especially beta-blocker and ACEI is encouraged as this trial is a test of optimal therapy including device support for drug dosing. It is understood that drug imbalance will emerge but the result of the trial will be more applicable to the reality of CHF patient care. Down-titration of CHF medication is discouraged. Amiodarone may be used for symptomatic ventricular arrhythmias developed after patient s enrolment into the study, or frequent ICD shocks due to atrial or ventricular arrhythmias. 6. STUDY POPULATION 6.1 Inclusion Criteria: NYHA Class II 1 LV EF 30% by MUGA/Catheterization OR LVEF 30% and LV end diastolic dimension 60 mm (by echocardiogram) within 6 months prior to randomization Intrinsic QRS Complex Width 120 ms OR Paced QRS measurement 200 ms ICD indication for primary or secondary prevention 94 1 NYHA Class II: Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue or dyspnea Page 10 of 44 Version July 1, 2007

12 Optimal heart failure pharmacological therapy (defined above section 5.3) Normal Sinus Rhythm OR Chronic persistent Atrial Tachyarrhythmia with resting Ventricular Heart Rate 60 bpm and 6 Minute Hall Walk Ventricular Heart Rate of 90 bpm OR Chronic persistent Atrial Tachyarrhythmia with resting Ventricular Heart Rate > 60 bpm and 6 Minute Hall Walk Ventricular Heart Rate of > 90 bpm and booked for Atrio-Ventricular Junction Ablation 6.2 Exclusion Criteria: Intra-venous inotropic agent in the last 4 days Patients with a life expectancy of less than one year from non-cardiac cause Expected to undergo cardiac transplantation within one year (status I) Patients with an acute coronary syndrome including MI 1 can be included if the patient has had a previous MI with LV dysfunction (LVEF 30% ) In hospital patients who have acute cardiac or non-cardiac illness that requires intensive care Uncorrected or uncorrectable primary valvular disease. Restrictive, hypertrophic or reversible form of cardiomyopathy Severe primary pulmonary disease such as cor pulmonale Tricuspid prosthetic valve Patients with an existing ICD 2 (Patients with an existing pacemaker may be included if the patients satisfies all other inclusion/exclusion criteria) Coronary revascularization (CABG 3 or PCI 4 ) < 1 month if previously determined LVEF > 30%. Patients with a more recent revascularization can be included if a previous determined LVEF was 30%. Patients included in other clinical trial that will affect the objectives of this study History of noncompliance of medical therapy Unable or unwilling to provide informed consent 7. STUDY METHODOLOGY Allocating participants to trial groups 7.1 Pre-randomization procedure After a qualified patient has consented for the study, a baseline physical exam, QOL assessment, 6-minute walk test, and baseline chemistry blood work will be performed. 7.2 Randomization Eligible and consenting patients will be equally randomized to control (ICD) or experimental (CRT/ICD) groups. Within each centre, the randomization will be stratified by chronic persistent AF (Yes or No) and by type of ICD patient indicated for pre randomization (Dual vs. single chamber AICD). The AF and type of ICD are stratified in the design since there is a significant difference in the mortality/hospitalization rates in these groups and we want to ensure balance on these critical factors. 1 Definition of MI (Myocardial Infarction)requires 2 of the 3 following criteria: (1)Symptoms of chest pain; (2) cardiac enzymes elevation TNT or TNI or CKMB > 1.5X; (3) ECG changes 2 ICD: Implantable Cardioverter Defibrillator 3 CABG: Coronary Artery Bypass Graft 4 PCI: Percutaneous Coronary Intervention Page 11 of 44 Version July 1, 2007

13 Central Randomization will occur from the Ottawa Heart Institute Coordinating Centre. A telephone number will be available for randomization and study concerns/queries. Once a call is received by the coordinating centre, appropriate questions for unique identification and appropriate stratification (Center number, date of birth year, gender, presence of AF, and ICD indication pre randomization [Dual vs Single]) will be requested. Responses will be verified and the pre-randomized information will be stored for downloading into the database. The caller will then be informed of the group allocation for that patient. 7.3 Protecting against sources of bias Prior to providing treatment allocation for a patient, the site study coordinator making the call will be informed that the allocation and pre-randomization information identifying the patient has been recorded, to avoid manipulation of group allocation. Blinding: The patient is blinded to the treatment allocation. In addition to obtaining consent to the trial prior to randomization, the patient will be required to consent to the device implantation, which will read ICD implantation with or without cardiac resynchronization therapy. The devices used in the two treatment arms are identical in size and shape. Although the number defibrillation/pacing leads used in the two treatment arms are different, the patient will have no way of knowing by touch or feel. Each center will be required to identify two teams of doctors and staff: 1) The blinded team will have no knowledge to the treatment allocation for the duration of the trial. They will be responsible for CHF follow-up, adjustment of medication, and assessment of the patients for outcome measures such as death, hospitalization, 6-minutes walk, NYHA class, QOL. This team is requested not to perform ECG or chest X-ray. If a chest X-ray is required for clinical reasons the result will be reported to the unblinded team member and the pertinent information regarding CHF will be conveyed to the CHF staff without disclosing the treatment allocation. The follow-up assessment schedule is the same for all patients. 2) The unblinded team will be responsible for device implantation and follow-up. By necessity the electrophysiologist/device implanter and the device clinic personnel will be aware of the treatment allocation. The implantation procedure and device follow-up of the two treatment groups although different are substantially similar. All patients will have an ICD implantation procedure. In the control group one or two leads will be inserted, and in the experimental group three leads will be inserted. On an average, procedure time will be longer for the patients randomized to the experimental group, but the variability is quite big so that it is difficult to guess the treatment allocation. In addition the patients are well sedated or under general anesthesia for the procedure. The device assessment follow-up is the same for both treatment groups. Every effort will be made to conceal treatment allocation from the patient, and the heart failure staff. 12 lead ECG and device interrogation record will not be reviewed to the patients or the heart failure personnel. Generalizability: We have taken a number of steps to minimize referral filter as well as understand its effect and the generalizability of study results. All ICD centres in the country are participating in the trial. Patients will be recruited from large and smaller community. Ascertainment Bias: An adjudication process will be instituted to minimize ascertainment bias in primary and in the more subjective outcome measures. The clinical and device adjudication committee will not have knowledge of the patient s treatment allocation. 7.4 Duration of treatment period Patients will be recruited over a 4 ½ year period and followed for a minimum of 18 months. The average follow-up will be years. (Appendix 4) Page 12 of 44 Version July 1, 2007

14 7.5 Frequency and duration of follow up All patients will be seen at clinic follow up visits at one and six month and then six-monthly intervals. To maintain the blinding process, each patient will have separate CHF clinic and Device clinic follow up visits. At each CHF Clinic Follow-up Visit, the following information will be collected: Mortality status; Health care utilization; Concurrent medication; A limited cardiac physical examination focusing on the presence of jugular venous distention, S3, murmur of mitral regurgitation, chest crackles, peripheral edema; Six minute walk test at baseline, 12 months and every 12 months thereafter; QOL assessment; Adverse events. At each Device Clinic Follow-up Visit, the following information will be collected: Device interrogation, ECG, and adverse events of the device. At each Telephone Follow-up Visit (performed by the blinded/chf study coordinator) at the 3 month interval between the 6 month Clinic Visits, the following information will be collected: Health care utilization, concurrent medication, and adverse events. In addition, at the 3 month follow up, a QOL assessment will be requested. Patients may be seen more frequently at the discretion of the treating physician and the local co-investigator. 7.6 Monitoring On-site monitoring visits are not planned for this study. Investigational sites are responsible for maintaining all source documentation in their hospital and clinic files. The coordinating center will collect source documentation from sites (hospital/clinic records) for the following study events: hospitalizations, patient deaths, patient exit due to transplant. 7.7 Regulations The RAFT study will be conducted in accordance with The Declaration of Helsinki concerning medical research and in accordance to the laws and regulations in the countries in which it is conducted. In Europe, ISO 14155, part 1 and 2 will be followed as guidance. 7.8 Records and Reports Investigator Records Investigators must maintain study records for a period of at least two years (or longer according to local requirements) after the date that the study is terminated or completed. These records include current protocol version, CVs, patient records, consent forms, research agreements, case report forms, study management forms, and correspondence with UOHI, the Ethics review board (ERB) /IRB/MEC, Medtronic and government regulatory agencies. The investigator must forward all information to UOHI in the event that the ERB/IRB/MEC takes any action relating to RAFT. The following reports are the investigator s responsibility: REPORT SUBMIT TO DESCRIPTION Withdrawal of MEC Approval (either Sponsor Report if required by local law. suspension or termination) Deviation from the Protocol Sponsor & IRB/MEC If the deviation may affect the rights, safety and welfare of the patients the deviation must be reported to UOHI and the reviewing MEC. A deviation that does not affect these issues ( rights, safety, etc.) will be captured and reported to UOHI and if required, reported to the site s MEC (i.e., protocol required visit out of window) Sponsor Records: The sponsor will maintain records relating to ERB/IRB/MEC approvals, study correspondence, investigator agreements and training documentation. Page 13 of 44 Version July 1, 2007

15 The sponsor will maintain study records for a period of at least two years after the date the study is terminated or completed. The following reports are the sponsor s responsibility: REPORT SUBMIT TO DESCRIPTION Premature termination or suspension of the clinical investigation Final Report/Protocol Amendments 8. STATISTICAL CONSIDERATIONS 8.1 Statistical Analysis/Sample size Investigators, /IRB/MECs/Competent authority All IRB/MECs, all Investigators, and competent authority (upon request) Medtronic will provide prompt notification of termination or suspension and reason(s). A final report will be submitted to the IRB/MECs within 6 months after completion or termination of the study The composite event rate of total mortality and CHF hospitalization is estimated to be 25% per year. This is based on a total mortality rate of 11% and an annual CHF hospitalization rate of % in the control arm. These estimates are based on an annual mortality rate of 11.2% in the MADIT II subgroup with QRS > 120 msec., and a 25-30% CHF hospitalization rate in the MIRACLE/ICD and CONTAK-CD trials. There will be some overlap of these two endpoints so that a conservative estimate of 25% per year primary endpoint event rate is made. It is generally accepted that for cardiovascular treatment 20% relative risk reduction is a clinically meaning difference. 95 In order to detect a 20% relative risk reduction (i.e. an absolute annual reduction of 5%) in the primary endpoint under the experimental group (CRT/ICD), at alpha = 0.05 (two-sided) and 90% power, a sample size of 1500 patients will be needed (750 in the control group and 750 in the experimental group). This calculation assumes an exponential survival with all patients followed to the primary endpoint or termination of the study, and allows for a 5% inability to implant the LV lead (this is based on the most recent data of 96% implant success rate in a world-wide registry), and 3% of crossover from control group (ICD) to experimental group (CRT/ICD). This treatment comparison is based on the log-rank test. This sample size will also be able to detect a 25% relative risk reduction of total mortality with the assumption of 11% annual mortality in the control group, at alpha of 0.05 (two-sided) and 80% power. A 25% relative risk reduction is realistic as recently completed CRT trials (MIRACLE, MIRACLE-ICD and CONTAK CD) showed an annual relative risk reduction of total mortality of 25-30%. NEW DATA: 1. Event rate: Control Arm (ICD-only) With the revised protocol to enroll only NYHA class II patients, the composite endpoint event rate was decreased. The MADIT-CRT selected an annual event rate of 16.7% (30% over two years) for patients receiving ICD-only, whereas a review of our RAFT data following procedures outlined by Wittes 96 and Betensky 97, indicated an event rate that was much lower. The conclusion was that the event rate selected for the sample size calculation for the MADIT-CRT trial was too high and the one implied from the RAFT analysis was too low because of the limited follow-up time. The consensus among the RAFT investigators was to select an event rate of 12.6 for the ICD-only study group. 2. Power The past CRT and ICD trials were reviewed for the selection of power, in particular for studies with a primary endpoint that included mortality and/or heart failure hospitalization (Appendix 3). The choice for power usually varied between 80% and 90%. An 85% power was selected. Page 14 of 44 Version July 1, 2007

16 3. Minimal Clinically Important Difference (MCID) The past CRT and ICD trials were reviewed for the selection of the relative risk reduction (RRR) for the MCID, in particular for studies with a primary endpoint that included mortality and/or heart failure hospitalization (Table 3). The choice for RRR usually varied between 25% and 40%. A RRR of 25% was selected, for the composite endpoint. The selection of 25% was based on a consensus of the RAFT investigators. 4. Event rates: CRT Arm (ICD/CRT) and Overall Based on the 25% RRR and the 12.6% event rate for ICD-only, the event rate for the ICD/CRT group is postulated to be 9.4%. The event rate for the Overall group is 11%. 8.2 Planned recruitment rate We anticipated a ramp up period from the beginning of the study before full-scale enrolment. The anticipated enrolment will be 500 in year one, 500 in year two and 500 year 3. This recruitment estimate is based on each individual center s estimate. We have observed, in the last year, an average enrollment of 27 patients per month (325 per year) with the current enrolling centers. We plan to add an additional centres in Europe and Turkey to increase the enrollment rate to 34 patients per month. The majority of the participating centres are referral centres. They have a well-established referral base. All the centres have participated in clinical trials including many device trials. The recent wide acceptance of ICD for 1º prevention will help recruitment. Many of these patients have CHF and wide QRS and will be eligible for this trial. All the participating centres have established CHF follow-up clinic. Screening patients in the heart failure clinic will also identify eligible patients. The investigators in this trial are all highly regarded specialists who regularly participate in continued medical education locally, and nationally. Through education recruitment will be enhanced. The participating centres cover most regions of the country. There are noticeable exceptions: northern Ontario, Saskatchewan, some Atlantic Provinces, and northern territories. There are no ICD implant centres in these areas. Their patients are referred to centres participating in this trial. If patient recruitment has not kept up to expectation, particularly if referrals from these non-icd centres are not as anticipated, then satellite centres will be formed in these regions so that appropriate screening can be carried out there. Several non-icd centres have expressed interest in this trial. If recruitment is still less than anticipated, recruitment can be extended to non-canadian sites. We have had experience of collaboration in clinical trials with centres from other countries. This will be explored if necessary. 8.3 Compliance Compliance of device therapy is near 100%, as the patients do not administer the therapy. Programming of the device will ensure near 100% CRT in the experimental group. The device clinic and the coordinating centre will monitor this. 8.4 Loss to follow up All ICD centres in the country are participating with the trial so geography migration should not be a hindrance to follow-up. However, the patient may refuse to participate with follow-up and wish to drop out. This is highly unlikely as observed in an ICD trial conducted in Canada, 0% loss-to-follow in the CIDS trial. 98 Patients may change their mind, or die between randomization and device implantation. This is estimated to be 2%. This is based on the data from CIDS, although ICD is gaining more acceptance from physicians and the general public. NEW DATA: The loss to follow-up rates were increased from 1% to 2% to reflect the experience to date in the RAFT study. A crossover rate of 5% from experimental (CRT/ICD) to control (ICD), due to inability to implant a LV lead, is estimated; this is based on the latest data of worldwide implant registry. All the participating centres are experienced with ICD and pacemaker implantation. In addition, centres are required to have performed a minimum of 10 CRT implants before entry into the trial. The crossover from control (ICD) to Page 15 of 44 Version July 1, 2007