Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints (Core and Extension Phases)

Study Overview
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Brief Summary
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The purpose of this study was to determine whether, in patients with type 2 diabetes and pre-existing disease of the heart and the circulatory system and/or the kidney, aliskiren at a target dose of 300 mg once daily (compared to placebo), on top of conventional treatment, reduces death and disease caused by the heart, the circulatory system and the kidney. AMENDMENT 4 RATIONALE (MARCH 2012) : Protocol amendment 4 served to address the data monitoring committee recommendation dated 14 Dec 2011 to discontinue study treatment in all participating patients. It also addressed the subsequent Health Authorities request to implement a 12 month safety follow-up period (actual duration was 9 months in average) post study drug discontinuation.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Determine Whether, in Patients With Type 2 Diabetes at High Risk for Cardiovascular and Renal Events, Aliskiren, on Top of Conventional Treatment, Reduces Cardiovascular and Renal Morbidity and Mortality

Conditions
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Type 2 Diabetes Mellitus, Cardiovascular Disease

Intervention / Treatment
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* Drug: Aliskiren
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 diabetes and at least one of the following: Macroalbuminuria and an eGFR ≥30 mL/min/1.73 m2 Microalbuminuria and a reduced kidney function (eGFR eGFR ≥30 and <60 mL/min/1.73 m2) A history of CV disease (previous MI, previous stroke, heart failure, coronary artery disease, history of percutaneous coronary intervention, angiography proven stenosis ≥50% in at least one coronary artery and a reduced kidney function (eGFR ≥30 and <60 mL/min/1.73 m2) Concomitant treatment should follow national guidelines and must include either an Angiotensin-converting-enzyme-inhibitor (ACEi) or an Angiotensin-receptor-blocker (ARB) but not both. Exclusion Criteria: Type 1 diabetes mellitus Cardiovascular event or procedure ≤ 3 months prior to Visit 1 Unstable serum creatinine Hypertension: Mean sitting systolic blood pressure (msSBP) ≥ 135 and < 170 mmHg or Mean sitting diastolic blood pressure (msDBP) ≥ 85 and < 110 mmHg unless treated with at least 3 anti-hypertensive medications Hypertension msSBP ≥ 170 or msDBP ≥ 110 mmHg Baseline Serum Potassium > 5.0 mmol/L Patients who are treated with two renin-angiotensin-aldosterone-system-blockers Patients with NYHA class III or IV heart failure Known renal artery stenosis Previous randomization into the AVOID trial (CSPP100C2201) EXCLUSION SPECIFIC TO THE SAFETY FOLLOW-UP PERIOD: - Aliskiren or aliskiren containing fixed combination products must not be used Other protocol-defined inclusion/exclusion criteria applied

Ages Eligible for Study
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Minimum Age: 35 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aliskiren<br>In Core (Double Blind) phase, Aliskiren 150 mg once daily (o.d.) for 4 weeks; then patient was uptitrated to 300 mg o.d. at Visit 5/Week 4 (or 150 mg o.d. if patient could not tolerate target dose of study drug). Visits took place at 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until end of core phase. With the recommendation of Data Monitoring Committee (DMC), after discontinuation of study drug, a follow up was added as Extension Phase (9 months in average) with no active treatment | Drug: Aliskiren<br>* Aliskiren 150 mg film-coated tablets<br>|
| Placebo Comparator: Placebo<br>In Core (Double Blind) phase, placebo to match aliskiren 150 mg once daily (o.d.) for 4 weeks; from Visit 5/Week 4 placebo to match aliskiren 300 mg o.d. (or placebo to match aliskiren 150 mg if patient could not tolerate target dose of study drug). Visits took place 1, 4 , 5, 8 and 12 weeks after randomization (Visit 3/Week 0). Subsequent visits were planned every three months until end of core phase. With the recommendation of Data Monitoring Committee (DMC), after discontinuation of study drug, a follow up was added as Extension Phase (9 months in average) with no active treatment. | Drug: Placebo<br>* Placebo to match aliskiren 150 mg film-coated tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Occurrence of Primary Composite Endpoint (Core : Active Treatment Phase) | Occurrence was defined as the first event of the following composite primary endpoint: Cardiovascular (CV) death Resuscitated sudden death Non-fatal myocardial infarction (MI) Non-fatal stroke Unplanned hospitalization for heart failure (HF) Onset of end-stage renal disease (ESRD) or death due to renal failure. Onset of ESRD was defined as initiation of dialysis, renal transplantation, or a serum creatinine concentration above 6.0 mg/dL (530 μmol/L), sustained for at least a month. Doubling of baseline serum creatinine concentration, sustained for at least one month. To fulfill the endpoint, the serum creatinine concentration had to be above the upper limit of normal for men and women according to the central laboratory. The upper limit of normal for men is 1.20 mg/dL and for women is 0.91 mg/dL. | Time from randomization to the first event (Maximum 50 months) | 
| Percentage of Participants With Cardiovascular (CV) Death (Core: Active Treatment Phase) |  | Time from randomization to the first event (Maximum 50 months) | 
| Percentage of Participants With Resuscitated Sudden Death (Core: Active Treatment Phase) | Resuscitated sudden death was adjudicated when a subject experiences sudden death or cardiac arrest and is successfully resuscitated by cardioversion, defibrillation or cardiopulmonary resuscitation with a meaningful recovery of consciousness. This definition excludes known transient losses of consciousness such as seizure or vasovagal episodes that do not reflect significant cardiac dysfunction. | Time from randomization to the first event (Maximum 50 Months) | 
| Percentage of Participants With Fatal/Non-fatal Myocardial Infarction (MI) (Core: Active Treatment Phase) |  | Time from randomization to the first event (Maximum 50 Months) | 
| Percentage of Participants With Fatal/Non-fatal Stroke (Core: Active Treatment Phase) |  | Time from randomization to the first event (Maximum 50 Months) | 
| Percentage of Participants With Onset of End-stage Renal Disease (ESRD) (Core: Active Treatment Phase) | ESRD is defined as initiation of dialysis, renal transplantation, or a serum creatinine concentration above 6.0 mg/dL (530 µmol per liter) or renal death | Time from randomization to the first event (Maximum 50 Months) | 
| Percentage of Participants With Doubling of Baseline Serum Creatinine Concentration, Sustained for at Least One Month (Core: Active Treatment Phase) | To fulfill the endpoint, the serum creatinine concentration had to be above the upper limit of normal for men and women according to the central laboratory. The upper limit of normal for men is 1.20 mg/dL and for women is 0.91 mg/dL. | Time from randomization to the first event (Maximum 50 Months) | 
| Percentage of Participants With Unplanned Hospitalization for Heart Failure (Core: Active Treatment Phase) |  | Time from randomization to the first event (Maximum 50 Months) | 
| Percentage of Participants With All Cause Mortality (Core: Active Treatment Phase) |  | Time from randomization to the first event (Maximum 50 months) | 
| Percentage of Participants With Occurrence of Primary Composite Endpoint (Extension Phase) | Occurrence was defined as the first event of the following composite primary endpoint: Cardiovascular (CV) death Resuscitated sudden death Non-fatal myocardial infarction (MI) Non-fatal stroke Unplanned hospitalization for heart failure (HF) Onset of end-stage renal disease (ESRD) or death due to renal failure. Onset of ESRD was defined as initiation of dialysis, renal transplantation, or a serum creatinine concentration above 6.0 mg/dL (530 μmol/L), sustained for at least a month. Doubling of baseline serum creatinine concentration, sustained for at least one month. To fulfill the endpoint, the serum creatinine concentration had to be above the upper limit of normal for men and women according to the central laboratory. The upper limit of normal for men is 1.20 mg/dL and for women is 0.91 mg/dL. | From cut-off date (20Dec2011/End of Treatment (EOT) ) to the first event after cut-off date (9 months in average) | 
| Percentage of Participants With Cardiovascular (CV) Death (Extension Phase) |  | from cut-off date (20Dec2011/End of Treatment (EOT) ) to the first event after cut-off date (9 months in average) | 
| Percentage of Participants With Resuscitated Sudden Death (Extension Phase) |  | From cut-off date (20Dec2011/End of Treatment (EOT) ) to the first event after cut-off date (9 months in average) | 
| Percentage of Participants Fatal/Non-fatal Myocardial Infarction (MI) (Extension Phase) |  | From cut-off date (20Dec2011/End of Treatment (EOT) ) to the first event after cut-off date (9 month in average) | 
| Percentage of Participants With Fatal/Non-fatal Stroke (Extension Phase) |  | From cut-off date (20Dec2011/End of Treatment (EOT) ) to the first event after cut-off date (9 months in average) | 
| Percentage of Participants With Onset of End-stage Renal Disease (ESRD) (Extension Phase) | ESRD is defined as initiation of dialysis, renal transplantation, or a serum creatinine concentration above 6.0 mg/dL (530 µmol per liter) or renal death | From cut-off date (20Dec2011/End of Treatment (EOT) ) to the first event after cut-off date (9 months in average) | 
| Percentage of Participants Doubling of Baseline Serum Creatinine Concentration, Sustained for at Least One Month (Extension Phase) | To fulfill the endpoint, the serum creatinine concentration had to be above the upper limit of normal for men and women according to the central laboratory. The upper limit of normal for men is 1.20 mg/dL and for women is 0.91 mg/dL. | From cut-off date (20Dec2011/End of Treatment (EOT) ) to the first event after cut-off date (9 months in average) | 
| Percentage of Participants With Unplanned Hospitalization for Heart Failure (Extension Phase) |  | From cut-off date (20Dec2011/End of Treatment (EOT) ) to the first event after cut-off date (9 months in average) | 
| Percentage of Participants With All Cause Mortality (Extension Phase) |  | from cut-off date (20Dec2011/End of Treatment (EOT) ) to the first event after cut-off date (9 months in average) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Occurrence of Secondary Cardiovascular Composite Endpoint (Core: Active Treatment Phase) | Occurrence was defined as the first event of the following secondary cardiovascular composite endpoint: Cardiovascular (CV) death Resuscitated sudden death Non-fatal myocardial infarction (MI) Non-fatal stroke Unplanned hospitalization for heart failure (HF) | Time from randomization to the first event (Maximum 50 months) | 
| Percentage of Participants With Occurrence of Secondary Renal Composite Endpoint (Core: Active Treatment Phase) | Occurrence was defined as the first event of the following secondary renal composite endpoint: Onset of end-stage renal disease (ESRD) or death due to renal failure. Onset of ESRD was defined as initiation of dialysis, renal transplantation, or a serum creatinine concentration above 6.0 mg/dL (530 μmol/L), sustained for at least a month. Doubling of baseline serum creatinine concentration, sustained for at least one month. To fulfill the endpoint, the serum creatinine concentration had to be above the upper limit of normal for men and women according to the central laboratory.The upper limit of normal for men is 1.20 mg/dL and for women is 0.91 mg/dL. | Time from randomization to the first event (Maximum 50 months) | 
| Percentage of Participants With Occurrence of Secondary Cardiovascular Composite Endpoint (Extension Phase) | Occurrence was defined as the first event of the following secondary cardiovascular composite endpoint: Cardiovascular (CV) death Resuscitated sudden death Non-fatal myocardial infarction (MI) Non-fatal stroke Unplanned hospitalization for heart failure (HF) | From cut-off date (20Dec2011/End of Treatment (EOT) ) to the first event after cut-off date (9 months in average) | 
| Percentage of Participants With Occurrence of Secondary Renal Composite Endpoint (Extension Phase) | Occurrence was defined as the first event of the following secondary renal composite endpoint: Onset of end-stage renal disease (ESRD) or death due to renal failure. Onset of ESRD was defined as initiation of dialysis, renal transplantation, or a serum creatinine concentration above 6.0 mg/dL (530 μmol/L), sustained for at least a month. Doubling of baseline serum creatinine concentration, sustained for at least one month. To fulfill the endpoint, the serum creatinine concentration had to be above the upper limit of normal for men and women according to the central laboratory. The upper limit of normal for men is 1.20 mg/dL and for women is 0.91 mg/dL. | From cut-off date (20Dec2011/End of Treatment (EOT) ) to the first event after cut-off date (9 months in average) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 diabetes mellitus, renal morbidity and mortality, cardiovascular disease, micro-albuminuria, macro-albuminuria, RAAS, renin inhibitor, Reduced estimated glomerular filtration rate