Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints Including 12 Month Safety Follow-up Off-treatment (ALTITUDE)

• Cardiovascular (CV) death [ Time Frame: Time from randomization to the first event ] [ Designated as safety issue: No ]
• Resuscitated sudden death [ Time Frame: Time from randomization to the first event ] [ Designated as safety issue: No ]
• Non-fatal myocardial infarction (MI) [ Time Frame: Time from randomization to the first event ] [ Designated as safety issue: No ]
• Non-fatal stroke [ Time Frame: Time from randomization to the first event ] [ Designated as safety issue: No ]
• Onset of end-stage renal disease (ESRD) 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 ] [ Designated as safety issue: No ]
• Doubling of baseline serum creatinine concentration to above the upper limit of normal according to the central laboratory, sustained for at least one month [ Time Frame: Time from randomization to the first event ] [ Designated as safety issue: No ]

• Cardiovascular (CV) death [ Time Frame: Time from randomization to the first event of the following composite endpoint ]
• Resuscitated sudden death [ Time Frame: Time from randomization to the first event of the following composite endpoint ]
• Non-fatal myocardial infarction (MI) [ Time Frame: Time from randomization to the first event of the following composite endpoint ]
• Non-fatal stroke [ Time Frame: Time from randomization to the first event of the following composite endpoint ]

• Time from randomization to the first event of the following composite CV endpoint: • Cardiovascular (CV) death • Resuscitated sudden death • Non-fatal myocardial infarction (MI) [ Time Frame: time of first event ] [ Designated as safety issue: No ]
• Time from randomization to the first event of the following composite CV endpoint: • Non-fatal stroke • Unplanned hospitalization for heart failure (HF) [ Time Frame: time of first event ] [ Designated as safety issue: No ]
• Onset of end-stage renal disease (ESRD) 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 ] [ Designated as safety issue: No ]
• Doubling of baseline serum creatinine concentration to above the upper limit of normal according to the central laboratory, sustained for at least one month [ Time Frame: time from randomization to the first event ] [ Designated as safety issue: No ]

The purpose of this study is 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 serves to address the data monitoring committee recommendation dated 14 Dec 2011 to discontinue study treatment in all participating patients. It also addresses the subsequent Health Authorities request to implement a 12 month safety follow-up period post study drug discontinuation.

• Type 2 Diabetes Mellitus
• Cardiovascular Disease

• Drug: Aliskiren
  Aliskiren 300 mg OD
• Drug: Placebo
  Placebo

• Experimental: Aliskiren
  Double-blind aliskiren 150 mg o.d.
  Intervention: Drug: Aliskiren
• Placebo Comparator: Placebo
  Double-blind placebo to match aliskiren 150 mg o.d
  Intervention: Drug: Placebo

• Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD, Chaturvedi N, Persson F, Desai AS, Nicolaides M, Richard A, Xiang Z, Brunel P, Pfeffer MA; ALTITUDE Investigators. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012 Dec 6;367(23):2204-13. doi: 10.1056/NEJMoa1208799. Epub 2012 Nov 3.
• Lambers Heerspink HJ, Perkovic V, de Zeeuw D. Renal and cardio-protective effects of direct renin inhibition: a systematic literature review. J Hypertens. 2009 Dec;27(12):2321-31.

Inclusion Criteria:

• Type 2 diabetes and at least one of the following:

  • Macroalbuminuria
  • Microalbuminuria and a reduced kidney function
  • Previous heart attack and a reduced kidney function
  • Previous stroke and a reduced kidney function
  • Heart Failure a reduced kidney function
  • Coronary artery disease a reduced kidney function
• 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 may apply.