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

Phase 3TerminatedNCT00549757

Novartis Pharmaceuticals8,606 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

8,606

Conditions

Type 2 Diabetes Mellitus Cardiovascular Disease

Interventions

Eligibility

Sex: ALLMin age: 35 Years

Medical Language ↔ Plain English

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

Locations (776)

Novartis Investigative Site

Birmingham, Alabama, United States

Novartis Investigative Site

Birmingham, Alabama, United States

Novartis Investigative Site

Huntsville, Alabama, United States

Novartis Investigative Site

Mobile, Alabama, United States

Novartis Investigative Site

Mobile, Alabama, United States

Outcomes

Primary Outcomes

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 frame: Time from randomization to the first event (Maximum 50 months)

Percentage of Participants With Cardiovascular (CV) Death (Core: Active Treatment Phase)

Time frame: 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 frame: 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 frame: Time from randomization to the first event (Maximum 50 Months)

Percentage of Participants With Fatal/Non-fatal Stroke (Core: Active Treatment Phase)

Time frame: 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 frame: 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 frame: Time from randomization to the first event (Maximum 50 Months)

Percentage of Participants With Unplanned Hospitalization for Heart Failure (Core: Active Treatment Phase)

Time frame: Time from randomization to the first event (Maximum 50 Months)

Percentage of Participants With All Cause Mortality (Core: Active Treatment Phase)

Time frame: Time from randomization to the first event (Maximum 50 months)

Percentage of Participants With Occurrence of Primary Composite Endpoint (Extension Phase)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: from cut-off date (20Dec2011/End of Treatment (EOT) ) to the first event after cut-off date (9 months in average)

Secondary Outcomes

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 frame: 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 frame: Time from randomization to the first event (Maximum 50 months)

Percentage of Participants With Occurrence of Secondary Cardiovascular Composite Endpoint (Extension Phase)

Time frame: 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.