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Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints (Core and Extension Phases) (ALTITUDE)
This study has been terminated.
(Lack of benefit and safety concern)
Sponsor:
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00549757
First received: October 24, 2007
Last updated: April 1, 2014
Last verified: April 2014
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Purpose
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.
| Condition | Intervention | Phase |
|---|---|---|
| Type 2 Diabetes Mellitus Cardiovascular Disease | Drug: Aliskiren Drug: Placebo | Phase 3 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Intervention Model: Parallel Assignment Masking: Double Blind (Participant, Investigator) Primary Purpose: Treatment |
| Official Title: | 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 |
Resource links provided by NLM:
Further study details as provided by Novartis ( Novartis Pharmaceuticals ):
Primary Outcome Measures:
- Percentage of Participants With Occurrence of Primary Composite Endpoint (Core : Active Treatment Phase) [ Time Frame: 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 Frame: Time from randomization to the first event (Maximum 50 months) ]
- Percentage of Participants With Resuscitated Sudden Death (Core: Active Treatment Phase) [ Time Frame: 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 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) [ Time Frame: 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 Frame: 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 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) ]
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) [ 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) [ Time Frame: 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) [ Time Frame: 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) [ 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 Outcome Measures:
- Percentage of Participants With Occurrence of Secondary Cardiovascular Composite Endpoint (Core: Active Treatment Phase) [ Time Frame: 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 Renal Composite Endpoint (Core: Active Treatment Phase) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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.
Other Outcome Measures:
- Percentage of Participants With Angioedema/Angioedema-like or Colorectal Events (Core : Active Treatment Phase) [ Time Frame: 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
- Change From Baseline in Urinary Albumin to Creatinine Ratio (UACR) to Month 6 and to Last Measurement (Core : Active Treatment Phase) [ Time Frame: 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.
- Mean Changes in Estimated Glomerular Filtration Rate (eGFR) From Baseline to Month 3 and Month 6 (Core : Active Treatment Phase) [ Time Frame: 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) [ Time Frame: 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.
| Enrollment: | 8606 |
| Study Start Date: | October 2007 |
| Study Completion Date: | February 2013 |
| Primary Completion Date: | February 2013 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: 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 |
Drug: Aliskiren
Aliskiren 150 mg film-coated tablets
|
|
Placebo Comparator: 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. |
Drug: Placebo
Placebo to match aliskiren 150 mg film-coated tablets
|
Eligibility| Ages Eligible for Study: | 35 Years and older (Adult, Senior) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
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
Contacts and Locations
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For general information, see Learn About Clinical Studies.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00549757
Show 778 Study Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00549757
Show 778 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
| Study Director: | Novartis Pharmaceuticals | Novartis Pharmaceuticals |
| Study Chair: | Novartis | Novartis |
More Information
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | Novartis Pharmaceuticals |
| ClinicalTrials.gov Identifier: | NCT00549757 History of Changes |
| Other Study ID Numbers: |
CSPP100E2337 2007-000860-25 ( EudraCT Number ) |
| Study First Received: | October 24, 2007 |
| Results First Received: | February 3, 2014 |
| Last Updated: | April 1, 2014 |
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
|
Type 2 diabetes mellitus renal morbidity and mortality cardiovascular disease micro-albuminuria |
macro-albuminuria RAAS renin inhibitor Reduced estimated glomerular filtration rate |
Additional relevant MeSH terms:
|
Diabetes Mellitus Diabetes Mellitus, Type 2 Cardiovascular Diseases |
Glucose Metabolism Disorders Metabolic Diseases Endocrine System Diseases |
ClinicalTrials.gov processed this record on June 26, 2017