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:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00549757
First received: October 24, 2007
Last updated: February 3, 2014
Last verified: February 2014
  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
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, 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:

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) ] [ Designated as safety issue: No ]

    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) ] [ Designated as safety issue: No ]
  • Percentage of Participants With Resuscitated Sudden Death (Core: Active Treatment Phase) [ Time Frame: Time from randomization to the first event (Maximum 50 Months) ] [ Designated as safety issue: No ]
  • 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) ] [ Designated as safety issue: No ]
  • Percentage of Participants With Fatal/Non-fatal Stroke (Core: Active Treatment Phase) [ Time Frame: Time from randomization to the first event (Maximum 50 Months) ] [ Designated as safety issue: No ]
  • 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) ] [ Designated as safety issue: No ]
    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) ] [ Designated as safety issue: No ]
    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) ] [ Designated as safety issue: No ]
  • Percentage of Participants With All Cause Mortality (Core: Active Treatment Phase) [ Time Frame: Time from randomization to the first event (Maximum 50 months) ] [ Designated as safety issue: No ]
  • 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) ] [ Designated as safety issue: No ]

    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) ] [ Designated as safety issue: No ]
  • 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) ] [ Designated as safety issue: No ]
  • 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) ] [ Designated as safety issue: No ]
  • 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) ] [ Designated as safety issue: No ]
  • 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) ] [ Designated as safety issue: No ]
    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) ] [ Designated as safety issue: No ]
    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) ] [ Designated as safety issue: No ]
  • 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) ] [ Designated as safety issue: No ]

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) ] [ Designated as safety issue: No ]

    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) ] [ Designated as safety issue: No ]

    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) ] [ Designated as safety issue: No ]

    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) ] [ Designated as safety issue: No ]

    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) ] [ Designated as safety issue: Yes ]
    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) ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: No ]

    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) ] [ Designated as safety issue: Yes ]
    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
Genders Eligible for Study:   Both
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
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

No publications provided by Novartis

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT00549757     History of Changes
Other Study ID Numbers: CSPP100E2337, 2007-000860-25
Study First Received: October 24, 2007
Results First Received: February 3, 2014
Last Updated: February 3, 2014
Health Authority: United States: Food and Drug Administration
Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica
Austria: Federal Office for Safety in Health Care
Belgium: Federal Agency for Medicinal Products and Health Products
Brazil: Ministry of Health
Canada: Health Canada
China: Food and Drug Administration
Colombia: INVIMA Instituto Nacional de Vigilancia de Medicamentos y Alimentos
Czech Republic: State Institute for Drug Control
Denmark: Danish Medicines Agency
Finland: Finnish Medicines Agency
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Federal Institute for Drugs and Medical Devices
Greece: National Organization of Medicines
Guatemala: Ministry of Public Health and Social Assistance
Hungary: National Institute of Pharmacy
India: Central Drugs Standard Control Organization
Italy: National Institute of Health
Japan: Pharmaceuticals and Medical Devices Agency
Korea: Food and Drug Administration
Lithuania: State Medicine Control Agency - Ministry of Health
Netherlands: Medicines Evaluation Board (MEB)
Norway: Norwegian Medicines Agency
Peru: General Directorate of Pharmaceuticals, Devices, and Drugs
Portugal: National Pharmacy and Medicines Institute
Singapore: Center for Drug Administration
Slovakia: State Institute for Drug Control
South Africa: Medicines Control Council
Spain: Spanish Agency of Medicines
Sweden: Medical Products Agency
Switzerland: Swissmedic
Taiwan: Department of Health
Thailand: Ministry of Public Health
Turkey: General Directorate of Pharmaceuticals and Pharmacy
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Venezuela: Ministry of Health and Social Development

Keywords provided by Novartis:
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:
Cardiovascular Diseases
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases

ClinicalTrials.gov processed this record on April 17, 2014