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

Phase 3

Terminated

Conditions: Cardiovascular Disease
Type 2 Diabetes Mellitus

Interventions: Drug: Placebo
Drug: Aliskiren

Registration Number: NCT00549757

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 8606

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	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.
Aliskiren	Aliskiren	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

Primary Outcome Measures

Name	Time	Method
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 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)	Time from randomization to the first event (Maximum 50 Months)	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
Percentage of Participants With Doubling of Baseline Serum Creatinine Concentration, Sustained for at Least One Month (Core: Active Treatment Phase)	Time from randomization to the first event (Maximum 50 Months)	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.
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)	From cut-off date (20Dec2011/End of Treatment (EOT) ) to the first event after cut-off date (9 months in average)	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.
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 Occurrence of Primary Composite Endpoint (Core : Active Treatment Phase)	Time from randomization to the first event (Maximum 50 months)	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.
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)	Time from randomization to the first event (Maximum 50 Months)	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.
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 (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 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)
Percentage of Participants With Onset of End-stage Renal Disease (ESRD) (Extension Phase)	From cut-off date (20Dec2011/End of Treatment (EOT) ) to the first event after cut-off date (9 months in average)	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
Percentage of Participants Doubling of Baseline Serum Creatinine Concentration, Sustained for at Least One Month (Extension Phase)	From cut-off date (20Dec2011/End of Treatment (EOT) ) to the first event after cut-off date (9 months in average)	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.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Occurrence of Secondary Renal Composite Endpoint (Core: Active Treatment Phase)	Time from randomization to the first event (Maximum 50 months)	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.
Percentage of Participants With Occurrence of Secondary Cardiovascular Composite Endpoint (Core: Active Treatment Phase)	Time from randomization to the first event (Maximum 50 months)	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)
Percentage of Participants With Occurrence of Secondary Cardiovascular Composite Endpoint (Extension Phase)	From cut-off date (20Dec2011/End of Treatment (EOT) ) to the first event after cut-off date (9 months in average)	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)
Percentage of Participants With Occurrence of Secondary Renal Composite Endpoint (Extension Phase)	From cut-off date (20Dec2011/End of Treatment (EOT) ) to the first event after cut-off date (9 months in average)	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.