Cardiovascular Disease, Type 2 Diabetes Mellitus
Conditions
Keywords
Type 2 diabetes mellitus, renal morbidity and mortality, cardiovascular disease, micro-albuminuria, macro-albuminuria, RAAS, renin inhibitor, Reduced estimated glomerular filtration rate
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.
Interventions
DRUGAliskiren
Aliskiren 150 mg film-coated tablets
DRUGPlacebo
Placebo to match aliskiren 150 mg film-coated tablets
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
35 Years to No maximum
Healthy volunteers
No
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 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 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) | 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. |
| 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 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 (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) | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 (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. |
| 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) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Angioedema/Angioedema-like or Colorectal Events (Core : Active Treatment Phase) | Time from randomization to the first event (Maximum 50 months) | AEs of special interest were reported according to a post-marketing commitment to Health Authorities and included angioedema/angioedema-like events and colorectal events/ procedures |
| Mean Changes in Estimated Glomerular Filtration Rate (eGFR) From Baseline to Month 3 and Month 6 (Core : Active Treatment Phase) | Baseline to Month 3 and Month 6 | The eGFR calculation was based on the Abbreviated Modification of Diet in Renal Disease (MDRD) Study Equation. Using this method, the applicable MDRD formula to calculate eGFR was as follows: Estimated GFR (mL/min/1.73 m\^2) = 175 x (serum creatinine in mg/dL) -1.154 x (Age in years) -0.203 x (0.742 if female) x (1.210 if Black) Mean changes in eGFR from baseline to month 3 and month 6 were included for analysis. The LS Mean and Standard Error were based on an ANCOVA repeated-measure model with treatment, visit, treatment-by-visit and baseline eGFR as effect terms. |
| Percentage of Participants With Angioedema/Angioedema-like Events or Colorectal Events (Extension Phase) | From cut-off date (20Dec2011/End of Treatment (EOT) ) to the first event after cut-off date (9 months in average) | AEs of special interest were reported according to a post-marketing commitment to Health Authorities and included angioedema/angioedema-like events and colorectal events/ procedures. |
| Change From Baseline in Urinary Albumin to Creatinine Ratio (UACR) to Month 6 and to Last Measurement (Core : Active Treatment Phase) | Baseline, Month 6 , last measurement (maximum at 50 months) | Baseline is the geometric mean of last 3 measurements before visit 3, Post-baseline value is the geometric mean of last 3 measurements during each visit. Change from Baseline = Post - Baseline. |
Countries
Argentina, Austria, Belgium, Brazil, Canada, China, Colombia, Czechia, Denmark, Finland, France, Germany, Greece, Guatemala, Hungary, India, Italy, Japan, Lithuania, Netherlands, Norway, Peru, Portugal, Puerto Rico, Singapore, Slovakia, South Africa, South Korea, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States, Venezuela
Participant flow
Pre-assignment details
Per data monitoring committee (DMC) recommendation all patients were required to permanently stop study medication by 06Jan2012. A follow-up period (actual duration, 9 months in average) post study drug discontinuation on 7590 patients was implemented upon request of Health Authority following the recommendation of DMC to cease study treatment.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 4,274 |
| 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. | 4,287 |
| Total | 8,561 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Active Treatment Phase: Max. 50 Months | Abnormal laboratory value(s) | 98 | 58 |
| Active Treatment Phase: Max. 50 Months | Abnormal test procedure result(s) | 7 | 7 |
| Active Treatment Phase: Max. 50 Months | Administrative problems | 2,857 | 3,019 |
| Active Treatment Phase: Max. 50 Months | Adverse Event | 590 | 462 |
| Active Treatment Phase: Max. 50 Months | Death | 188 | 200 |
| Active Treatment Phase: Max. 50 Months | Incorrect Entry | 69 | 55 |
| Active Treatment Phase: Max. 50 Months | Lost to Follow-up | 41 | 29 |
| Active Treatment Phase: Max. 50 Months | Missing data | 8 | 9 |
| Active Treatment Phase: Max. 50 Months | Patient's request | 353 | 380 |
| Active Treatment Phase: Max. 50 Months | Subject withdrew consent | 38 | 38 |
| Active Treatment Phase: Max. 50 Months | Unsatisfactory therapeutic effect | 47 | 53 |
| Extension Period (in Average 9 Months) | Death | 143 | 136 |
| Extension Period (in Average 9 Months) | Lost to Follow-up | 52 | 47 |
| Extension Period (in Average 9 Months) | Patient's request | 421 | 436 |
| Extension Period (in Average 9 Months) | Withdrawal by Subject | 9 | 16 |
Baseline characteristics
| Characteristic | Aliskiren | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 64.6 Years STANDARD_DEVIATION 9.62 | 64.4 Years STANDARD_DEVIATION 9.87 | 64.5 Years STANDARD_DEVIATION 9.75 |
| Sex: Female, Male Female | 1393 Participants | 1342 Participants | 2735 Participants |
| Sex: Female, Male Male | 2881 Participants | 2945 Participants | 5826 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3,205 / 4,272 | 3,069 / 4,285 | 995 / 3,773 | 1,023 / 3,817 |
| serious Total, serious adverse events | 1,988 / 4,272 | 1,893 / 4,285 | 704 / 3,773 | 682 / 3,817 |
Outcome results
Primary
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.
Time frame: From cut-off date (20Dec2011/End of Treatment (EOT) ) to the first event after cut-off date (9 months in average)
Population: Extension-phase Analysis Set (EAS) - All patients who had at least one scheduled or unscheduled visit or who died post cut-off date 20-Dec-2011/EOT.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aliskiren | Percentage of Participants Doubling of Baseline Serum Creatinine Concentration, Sustained for at Least One Month (Extension Phase) | 2.4 percentage of participants |
| Placebo | Percentage of Participants Doubling of Baseline Serum Creatinine Concentration, Sustained for at Least One Month (Extension Phase) | 2.5 percentage of participants |
Primary
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)
Population: Extension-phase Analysis Set (EAS) - All patients who had at least one scheduled or unscheduled visit or who died post cut-off date 20-Dec-2011/EOT.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aliskiren | Percentage of Participants Fatal/Non-fatal Myocardial Infarction (MI) (Extension Phase) | 1.4 percentage of participants |
| Placebo | Percentage of Participants Fatal/Non-fatal Myocardial Infarction (MI) (Extension Phase) | 1.1 percentage of participants |
Primary
Percentage of Participants With All Cause Mortality (Core: Active Treatment Phase)
Time frame: Time from randomization to the first event (Maximum 50 months)
Population: Full Analysis Set (FAS) - All patients randomized except mis-randomized patients who did not receive study drug. Mis-randomized patients were defined as not qualified for randomization and were inadvertently randomized into the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aliskiren | Percentage of Participants With All Cause Mortality (Core: Active Treatment Phase) | 8.4 percentage of participants |
| Placebo | Percentage of Participants With All Cause Mortality (Core: Active Treatment Phase) | 8.0 percentage of participants |
Primary
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)
Population: Extension-phase Analysis Set (EAS) - All patients who had at least one scheduled or unscheduled visit or who died post cut-off date 20-Dec-2011/EOT.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aliskiren | Percentage of Participants With All Cause Mortality (Extension Phase) | 3.8 percentage of participants |
| Placebo | Percentage of Participants With All Cause Mortality (Extension Phase) | 3.6 percentage of participants |
Primary
Percentage of Participants With Cardiovascular (CV) Death (Core: Active Treatment Phase)
Time frame: Time from randomization to the first event (Maximum 50 months)
Population: Full Analysis Set (FAS) - All patients randomized except mis-randomized patients who did not receive study drug. Mis-randomized patients were defined as not qualified for randomization and were inadvertently randomized into the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aliskiren | Percentage of Participants With Cardiovascular (CV) Death (Core: Active Treatment Phase) | 5.5 percentage of participants |
| Placebo | Percentage of Participants With Cardiovascular (CV) Death (Core: Active Treatment Phase) | 4.8 percentage of participants |
Primary
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)
Population: Extension-phase Analysis Set (EAS) - All patients who had at least one scheduled or unscheduled visit or who died post cut-off date 20-Dec-2011/EOT.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aliskiren | Percentage of Participants With Cardiovascular (CV) Death (Extension Phase) | 2.1 percentage of participants |
| Placebo | Percentage of Participants With Cardiovascular (CV) Death (Extension Phase) | 1.9 percentage of participants |
Primary
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)
Population: Full Analysis Set (FAS) - All patients randomized except mis-randomized patients who did not receive study drug. Mis-randomized patients were defined as not qualified for randomization and were inadvertently randomized into the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aliskiren | Percentage of Participants With Doubling of Baseline Serum Creatinine Concentration, Sustained for at Least One Month (Core: Active Treatment Phase) | 4.6 percentage of participants |
| Placebo | Percentage of Participants With Doubling of Baseline Serum Creatinine Concentration, Sustained for at Least One Month (Core: Active Treatment Phase) | 4.7 percentage of participants |
Primary
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)
Population: Full Analysis Set (FAS) - All patients randomized except mis-randomized patients who did not receive study drug. Mis-randomized patients were defined as not qualified for randomization and were inadvertently randomized into the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aliskiren | Percentage of Participants With Fatal/Non-fatal Myocardial Infarction (MI) (Core: Active Treatment Phase) | 3.3 percentage of participants |
| Placebo | Percentage of Participants With Fatal/Non-fatal Myocardial Infarction (MI) (Core: Active Treatment Phase) | 3.2 percentage of participants |
Primary
Percentage of Participants With Fatal/Non-fatal Stroke (Core: Active Treatment Phase)
Time frame: Time from randomization to the first event (Maximum 50 Months)
Population: Full Analysis Set (FAS) - All patients randomized except mis-randomized patients who did not receive study drug. Mis-randomized patients were defined as not qualified for randomization and were inadvertently randomized into the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aliskiren | Percentage of Participants With Fatal/Non-fatal Stroke (Core: Active Treatment Phase) | 3.4 percentage of participants |
| Placebo | Percentage of Participants With Fatal/Non-fatal Stroke (Core: Active Treatment Phase) | 2.7 percentage of participants |
Primary
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)
Population: Extension-phase Analysis Set (EAS) - All patients who had at least one scheduled or unscheduled visit or who died post cut-off date 20-Dec-2011/EOT.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aliskiren | Percentage of Participants With Fatal/Non-fatal Stroke (Extension Phase) | 0.9 percentage of participants |
| Placebo | Percentage of Participants With Fatal/Non-fatal Stroke (Extension Phase) | 1.0 percentage of participants |
Primary
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)
Population: Full Analysis Set (FAS) - All patients randomized except mis-randomized patients who did not receive study drug. Mis-randomized patients were defined as not qualified for randomization and were inadvertently randomized into the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aliskiren | Percentage of Participants With Occurrence of Primary Composite Endpoint (Core : Active Treatment Phase) | 17.6 percentage of participants |
| Placebo | Percentage of Participants With Occurrence of Primary Composite Endpoint (Core : Active Treatment Phase) | 16.3 percentage of participants |
Primary
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.
Time frame: From cut-off date (20Dec2011/End of Treatment (EOT) ) to the first event after cut-off date (9 months in average)
Population: Extension-phase Analysis Set (EAS) - All patients who had at least one scheduled or unscheduled visit or who died post cut-off date 20-Dec-2011/EOT.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aliskiren | Percentage of Participants With Occurrence of Primary Composite Endpoint (Extension Phase) | 8.0 percentage of participants |
| Placebo | Percentage of Participants With Occurrence of Primary Composite Endpoint (Extension Phase) | 8.0 percentage of participants |
Primary
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)
Population: Full Analysis Set (FAS) - All patients randomized except mis-randomized patients who did not receive study drug. Mis-randomized patients were defined as not qualified for randomization and were inadvertently randomized into the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aliskiren | Percentage of Participants With Onset of End-stage Renal Disease (ESRD) (Core: Active Treatment Phase) | 2.7 percentage of participants |
| Placebo | Percentage of Participants With Onset of End-stage Renal Disease (ESRD) (Core: Active Treatment Phase) | 2.5 percentage of participants |
Primary
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)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aliskiren | Percentage of Participants With Onset of End-stage Renal Disease (ESRD) (Extension Phase) | 1.4 percentage of participants |
| Placebo | Percentage of Participants With Onset of End-stage Renal Disease (ESRD) (Extension Phase) | 1.5 percentage of participants |
Primary
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)
Population: Full Analysis Set (FAS) - All patients randomized except mis-randomized patients who did not receive study drug. Mis-randomized patients were defined as not qualified for randomization and were inadvertently randomized into the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aliskiren | Percentage of Participants With Resuscitated Sudden Death (Core: Active Treatment Phase) | 0.4 percentage of participants |
| Placebo | Percentage of Participants With Resuscitated Sudden Death (Core: Active Treatment Phase) | 0.2 percentage of participants |
Primary
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)
Population: Extension-phase Analysis Set (EAS) - All patients who had at least one scheduled or unscheduled visit or who died post cut-off date 20-Dec-2011/EOT.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aliskiren | Percentage of Participants With Resuscitated Sudden Death (Extension Phase) | 0.1 percentage of participants |
| Placebo | Percentage of Participants With Resuscitated Sudden Death (Extension Phase) | 0.1 percentage of participants |
Primary
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)
Population: Full Analysis Set (FAS) - All patients randomized except mis-randomized patients who did not receive study drug. Mis-randomized patients were defined as not qualified for randomization and were inadvertently randomized into the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aliskiren | Percentage of Participants With Unplanned Hospitalization for Heart Failure (Core: Active Treatment Phase) | 4.7 percentage of participants |
| Placebo | Percentage of Participants With Unplanned Hospitalization for Heart Failure (Core: Active Treatment Phase) | 5.0 percentage of participants |
Primary
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)
Population: Extension-phase Analysis Set (EAS) - All patients who had at least one scheduled or unscheduled visit or who died post cut-off date 20-Dec-2011/EOT.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aliskiren | Percentage of Participants With Unplanned Hospitalization for Heart Failure (Extension Phase) | 1.7 percentage of participants |
| Placebo | Percentage of Participants With Unplanned Hospitalization for Heart Failure (Extension Phase) | 1.5 percentage of participants |
Secondary
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)
Population: Full Analysis Set (FAS) - All patients randomized except mis-randomized patients who did not receive study drug. Mis-randomized patients were defined as not qualified for randomization and were inadvertently randomized into the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aliskiren | Percentage of Participants With Occurrence of Secondary Cardiovascular Composite Endpoint (Core: Active Treatment Phase) | 13.4 percentage of participants |
| Placebo | Percentage of Participants With Occurrence of Secondary Cardiovascular Composite Endpoint (Core: Active Treatment Phase) | 12.1 percentage of participants |
Secondary
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)
Time frame: From cut-off date (20Dec2011/End of Treatment (EOT) ) to the first event after cut-off date (9 months in average)
Population: Extension-phase Analysis Set (EAS) - All patients who had at least one scheduled or unscheduled visit or who died post cut-off date 20-Dec-2011/end of treatment (EOT).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aliskiren | Percentage of Participants With Occurrence of Secondary Cardiovascular Composite Endpoint (Extension Phase) | 5.0 percentage of participants |
| Placebo | Percentage of Participants With Occurrence of Secondary Cardiovascular Composite Endpoint (Extension Phase) | 4.8 percentage of participants |
Secondary
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)
Population: Full Analysis Set (FAS) - All patients randomized except mis-randomized patients who did not receive study drug. Mis-randomized patients were defined as not qualified for randomization and were inadvertently randomized into the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aliskiren | Percentage of Participants With Occurrence of Secondary Renal Composite Endpoint (Core: Active Treatment Phase) | 5.6 percentage of participants |
| Placebo | Percentage of Participants With Occurrence of Secondary Renal Composite Endpoint (Core: Active Treatment Phase) | 5.5 percentage of participants |
Secondary
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.
Time frame: From cut-off date (20Dec2011/End of Treatment (EOT) ) to the first event after cut-off date (9 months in average)
Population: Extension-phase Analysis Set (EAS) - All patients who had at least one scheduled or unscheduled visit or who died post cut-off date 20-Dec-2011/end of treatment (EOT).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aliskiren | Percentage of Participants With Occurrence of Secondary Renal Composite Endpoint (Extension Phase) | 3.3 percentage of participants |
| Placebo | Percentage of Participants With Occurrence of Secondary Renal Composite Endpoint (Extension Phase) | 3.6 percentage of participants |
Other Pre-specified
Change From Baseline in Urinary Albumin to Creatinine Ratio (UACR) to Month 6 and to Last Measurement (Core : Active Treatment Phase)
Baseline is the geometric mean of last 3 measurements before visit 3, Post-baseline value is the geometric mean of last 3 measurements during each visit. Change from Baseline = Post - Baseline.
Time frame: Baseline, Month 6 , last measurement (maximum at 50 months)
Population: Full Analysis Set (FAS) - All patients randomized except mis-randomized patients who did not receive study drug. Last observation carried forward (LOCF) computation technique was used for month 6 data. At each visit, only patients with values at both baseline and this time point are included.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Aliskiren | Change From Baseline in Urinary Albumin to Creatinine Ratio (UACR) to Month 6 and to Last Measurement (Core : Active Treatment Phase) | Baseline to Month 6 (n= 4021, 4040) | 0.841 mg/mmol |
| Aliskiren | Change From Baseline in Urinary Albumin to Creatinine Ratio (UACR) to Month 6 and to Last Measurement (Core : Active Treatment Phase) | Baseline to Last Measurement (n= 4045, 4080) | 0.872 mg/mmol |
| Placebo | Change From Baseline in Urinary Albumin to Creatinine Ratio (UACR) to Month 6 and to Last Measurement (Core : Active Treatment Phase) | Baseline to Month 6 (n= 4021, 4040) | 0.945 mg/mmol |
| Placebo | Change From Baseline in Urinary Albumin to Creatinine Ratio (UACR) to Month 6 and to Last Measurement (Core : Active Treatment Phase) | Baseline to Last Measurement (n= 4045, 4080) | 1.043 mg/mmol |
Other Pre-specified
Mean Changes in Estimated Glomerular Filtration Rate (eGFR) From Baseline to Month 3 and Month 6 (Core : Active Treatment Phase)
The eGFR calculation was based on the Abbreviated Modification of Diet in Renal Disease (MDRD) Study Equation. Using this method, the applicable MDRD formula to calculate eGFR was as follows: Estimated GFR (mL/min/1.73 m\^2) = 175 x (serum creatinine in mg/dL) -1.154 x (Age in years) -0.203 x (0.742 if female) x (1.210 if Black) Mean changes in eGFR from baseline to month 3 and month 6 were included for analysis. The LS Mean and Standard Error were based on an ANCOVA repeated-measure model with treatment, visit, treatment-by-visit and baseline eGFR as effect terms.
Time frame: Baseline to Month 3 and Month 6
Population: Full Analysis Set (FAS) - All patients randomized except mis-randomized patients who did not receive study drug. At each visit (baseline, Month 3 and Month 6) , only patients with values at both baseline and post-baseline time point are included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aliskiren | Mean Changes in Estimated Glomerular Filtration Rate (eGFR) From Baseline to Month 3 and Month 6 (Core : Active Treatment Phase) | -2.048 mL/min/1.73 m^2 | Standard Error 0.15 |
| Placebo | Mean Changes in Estimated Glomerular Filtration Rate (eGFR) From Baseline to Month 3 and Month 6 (Core : Active Treatment Phase) | -0.825 mL/min/1.73 m^2 | Standard Error 0.15 |
Other Pre-specified
Percentage of Participants With Angioedema/Angioedema-like Events or Colorectal Events (Extension Phase)
AEs of special interest were reported according to a post-marketing commitment to Health Authorities and included angioedema/angioedema-like events and colorectal events/ procedures.
Time frame: From cut-off date (20Dec2011/End of Treatment (EOT) ) to the first event after cut-off date (9 months in average)
Population: Extension-phase Analysis Set (EAS) - All patients who had at least one scheduled or unscheduled visit or who died post cut-off date 20-Dec-2011/end of treatment (EOT).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Aliskiren | Percentage of Participants With Angioedema/Angioedema-like Events or Colorectal Events (Extension Phase) | Angioedema/ Angioedema-like event | 0.8 percentage of participants |
| Aliskiren | Percentage of Participants With Angioedema/Angioedema-like Events or Colorectal Events (Extension Phase) | Colorectal events | 0.7 percentage of participants |
| Placebo | Percentage of Participants With Angioedema/Angioedema-like Events or Colorectal Events (Extension Phase) | Angioedema/ Angioedema-like event | 1.2 percentage of participants |
| Placebo | Percentage of Participants With Angioedema/Angioedema-like Events or Colorectal Events (Extension Phase) | Colorectal events | 0.8 percentage of participants |
Other Pre-specified
Percentage of Participants With Angioedema/Angioedema-like or Colorectal Events (Core : Active Treatment Phase)
AEs of special interest were reported according to a post-marketing commitment to Health Authorities and included angioedema/angioedema-like events and colorectal events/ procedures
Time frame: Time from randomization to the first event (Maximum 50 months)
Population: Safety Set (SAF) - All patients who received at least one dose of trial medication. Patients were analyzed according to the treatment they received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Aliskiren | Percentage of Participants With Angioedema/Angioedema-like or Colorectal Events (Core : Active Treatment Phase) | Angioedema / angioedema-like events | 4.4 percentage of participants |
| Aliskiren | Percentage of Participants With Angioedema/Angioedema-like or Colorectal Events (Core : Active Treatment Phase) | Colorectal events | 2.4 percentage of participants |
| Placebo | Percentage of Participants With Angioedema/Angioedema-like or Colorectal Events (Core : Active Treatment Phase) | Angioedema / angioedema-like events | 4.8 percentage of participants |
| Placebo | Percentage of Participants With Angioedema/Angioedema-like or Colorectal Events (Core : Active Treatment Phase) | Colorectal events | 2.4 percentage of participants |