A Randomized Controlled Trial of Aliskiren in the Prevention of Major Cardiovascular Events in Elderly People

Phase 3

Terminated

• Conditions: Cardiovascular Events
• Interventions: Drug: Aliskiren; Drug: Hydrochlorothiazide (HCTZ); Drug: Placebo for Amlodipine; Drug: Placebo for Aliskiren; Drug: Placebo for Hydrochlorothiazide (HCTZ); Drug: Amlodipine

• Registration Number: NCT01259297
• Lead Sponsor: Novartis Pharmaceuticals

Brief Summary

This study was planned to provide new information regarding the role of aliskiren (with or without additional therapy with a diuretic or a Calcium channel blockers (CCB)) in elderly individuals (≥ 65 years) with systolic blood pressure (SBP) 130 to 159 mmHg, in preventing major cardiovascular (CV) events and on global measures of physical, executive and cognitive function.

Detailed Description

This was 2x2 factorial design study with 2 strata. As per protocol, the first co- Primary analysis as well as secondary analysis were aliskiren based regimen vs non-aliskiren based regimen. All aliskiren based arm were combined into the aliskiren based regimen and all non-aliskiren based arms were combined into non-aliskiren based regimen.

Study Timeline

• Study First Submitted: 2010-12-10
• Study First Submitted QC: 2010-12-13
• Study First Posted: 2010-12-14
• Study Start: 2011-01
• Primary Completion: 2012-11
• Study Completion: 2012-11
• Results First Submitted: 2013-12-18
• Status Verified: 2014-02
• Results First Submitted QC: 2014-02-27
• Last Update Submitted: 2014-02-27
• Results First Posted: 2014-04-08
• Last Update Posted: 2014-04-08

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 2336

Inclusion Criteria

Systolic blood pressure 130 - 159 mmHg with any one of the following (1, 2 or 3):

1. Men and women aged ≥ 65 years if they have at least one of the following: (secondary prevention) Coronary heart disease

   • Previous myocardial infarction or
   • Stable angina or unstable angina with documented multi-vessel coronary artery disease, > 50% stenosis in at least 2 major coronary arteries on coronary angiography, or positive stress test (ECG or nuclear perfusion scintogram), or
   • Multi-vessel PCI, or
   • Multi-vessel CABG surgery > 4 years prior to informed consent, or with recurrent angina or ischemia following surgery Stroke/TIA Previous documented stroke or documented TIA < 1 year before informed consent Peripheral artery disease
   • Previous limb bypass surgery or percutaneous transluminal angioplasty, or
   • Previous limb or foot amputation, or
   • History of intermittent claudication, with an ankle:arm BP ratio ≤ 0.80 on at least one side, or significant peripheral artery stenosis (> 50%) documented by angiography or non-invasive testing
   • Diabetes mellitus: High-risk diabetics with evidence of end-organ damage

2. Men and women aged ≥ 65 years with no history of CVD, and with at least 1 CV risk factor (primary prevention):

   • History of dyslipidemia, defined as LDL cholesterol > 3.5 mmol/L (135 mg/dL) or HDL< 1.3 mmol/L (50 mg/dL) in women or < 1.0 mmol/L (39 mg/dL) in men or total cholesterol/HDL ratio > 5
   • History of current or recent smoking (regular tobacco use within 5 years)
   • Abdominal adiposity defined as waist/hip ratio ≥ 0.90 in women and ≥ 0.95 in men
   • History of dysglycemia defined as impaired fasting glucose (IFG - fasting plasma glucose 5.6 to 6.9 mmol/L [101 to 124 mg/dL]), or impaired glucose tolerance (IGT - fasting plasma glucose < 7 mmol/L [126 mg/dL] but 2 hour glucose 7.8 to 11.0 mmol/L [140 to 198 mg/dL]) or type 2 diabetes
   • Renal dysfunction: eGFR< 60 ml/min/1.73m2 but > 30 ml/min/1.73m2 (MDRD formula) and/or microalbuminurea/macroalbuminurea
   • Clinical evidence of left ventricular hypertrophy

3. Men and women aged ≥ 70 years if they do not have any of the above (primary prevention)

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Exclusion Criteria

1. Current treatment with aliskiren, an ACE-inhibitor, an ARB or an aldosterone antagonist and unable to discontinue this therapy in those without clinical vascular disease. Individuals with CVD or type 2 diabetes and/or renal dysfunction may receive an ACE-inhibitor or an ARB, but not both, contraindications to Aliskiren, Amlodipine or Hydrochlorothiazide.
2. Use of both thiazide diuretic and amlodipine or another calcium channel blocker. Patients on only one of these two classes of drugs are eligible
3. Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg)
4. Symptomatic heart failure, requiring the use of loop diuretics
5. Hemodynamically significant primary valvular or outflow tract obstruction (e.g. aortic or mitral valve stenosis, asymmetric septal hypertrophy, malfunctioning prosthetic valve). Constrictive pericarditis. Complex congenital heart disease.
6. Acute stroke < 3 months or TIA ≤ 7 days before informed consent, acute coronary syndrome < 1 months before informed consent
7. Planned cardiac surgery or angioplasty < 3 months after informed consent or having had the procedure < 3 months before informed consent
8. Severe renal impairment eGFR ≤ 30 ml/min/1.73m2 (MDRD formula); known renal artery stenosis ; serum potassium ≥ 5.3 mmol/L
9. Chronic liver disease (i.e. cirrhosis, esophageal varices, portocaval shunt or persistent hepatitis) or abnormal liver function, i.e., alanine transaminase (ALT) or AST > 3x upper limit of normal (ULN)
10. Concurrent treatment with cyclosporine or quinidine; chronic use of non-steroidal anti-inflammatory drug (NSAIDs) or cyclooxygenase-2 (COX 2) inhibitors in patients with eGFR < 60 ml/min/1.73m2 (MDRD formula)
11. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years regardless of whether there is evidence of local recurrence or metastases
12. Other serious condition(s) likely to interfere with study participation or with the ability to complete the study. Significant psychiatric illness, senility, dementia, alcohol or substance abuse, which could impair the ability to provide informed consent and to adhere to the study procedures

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
Aliskiren + Hydrochlorothiazide (HCTZ)	Hydrochlorothiazide (HCTZ)	In run-in period (4-5 weeks) , patients on CCB background therapy and approximately 50% of patients on neither thiazide nor CCB background therapy: received Hydrochlorothiazide 12.5/25 mg and Aliskiren 150/300 mg daily in a titrated manner as per protocol. In double blind period, all patients who successfully completed run-in with HCTZ plus Aliskiren were randomized equally to the 4 arms of the HCTZ add-on stratum. Patients randomized to this arm received Aliskiren 300 mg + HCTZ 25 mg once daily.
Aliskiren + Placebo for Amlodipine	Placebo for Amlodipine	In double blind period, all patients who successfully completed run-in with Amlodipine plus Aliskiren were randomized equally to the 4 arms of the Amlodipine add-on stratum. In double blind period, randomized patients to this arm received Aliskiren 300 mg + Placebo for Amlodipine 5 mg
Amlodipine + Placebo for Aliskiren	Placebo for Aliskiren	In double blind period, all patients who successfully completed run-in with Amlodipine plus Aliskiren were randomized equally to the 4 arms of the Amlodipine add-on stratum. In double blind period, randomized patients to this arm received Amlodipine 5 mg + placebo for Aliskiren 300 mg once daily
HCTZ + Placebo for Aliskiren	Hydrochlorothiazide (HCTZ)	In double blind period, all patients who successfully completed run-in with HCTZ plus Aliskiren were randomized equally to the 4 arms of the HCTZ add-on stratum. In double blind period, randomized patients to this arm received HCTZ 25 mg + placebo for Aliskiren 300 mg once daily
HCTZ + Placebo for Aliskiren	Placebo for Aliskiren	In double blind period, all patients who successfully completed run-in with HCTZ plus Aliskiren were randomized equally to the 4 arms of the HCTZ add-on stratum. In double blind period, randomized patients to this arm received HCTZ 25 mg + placebo for Aliskiren 300 mg once daily
Placebo for Aliskiren + Placebo for Amlodipine	Placebo for Amlodipine	In double blind period, all patients who successfully completed run-in with Amlodipine plus Aliskiren were randomized equally to the 4 arms of the Amlodipine add-on stratum. In double blind period, randomized patients to this arm received placebo for Aliskiren 300 mg + placebo for Amlodipine 5 mg once daily
Placebo for Aliskiren + Placebo for HCTZ	Placebo for Aliskiren	In double blind period, all patients who successfully completed run-in with HCTZ plus Aliskiren were randomized equally to the 4 arms of the HCTZ add-on stratum. In double blind period, randomized patients to this arm received placebo for Aliskiren 300 mg + placebo for HCTZ 25 mg once daily
Placebo for Aliskiren + Placebo for HCTZ	Placebo for Hydrochlorothiazide (HCTZ)	In double blind period, all patients who successfully completed run-in with HCTZ plus Aliskiren were randomized equally to the 4 arms of the HCTZ add-on stratum. In double blind period, randomized patients to this arm received placebo for Aliskiren 300 mg + placebo for HCTZ 25 mg once daily
Placebo for Aliskiren + Placebo for Amlodipine	Placebo for Aliskiren	In double blind period, all patients who successfully completed run-in with Amlodipine plus Aliskiren were randomized equally to the 4 arms of the Amlodipine add-on stratum. In double blind period, randomized patients to this arm received placebo for Aliskiren 300 mg + placebo for Amlodipine 5 mg once daily
Aliskiren + Placebo for HCTZ	Placebo for Hydrochlorothiazide (HCTZ)	In double blind period, all patients who successfully completed run-in with HCTZ plus Aliskiren were randomized equally to the 4 arms of the HCTZ add-on stratum. In double blind period, randomized patients to this arm received Aliskiren 300 mg + Placebo for HCTZ 25 mg once daily
Aliskiren + Amlodipine	Aliskiren	In run-in period (4-5 weeks) , patients on thiazide background therapy and approximately 50% of patients on neither CCB nor thiazide background therapy received Amlodipine 5 mg and Aliskiren 150/300 mg daily in a titrated manner as per protocol. In double blind period, patients who successfully completed run-in with Amlodipine plus Aliskiren were randomized equally to the 4 arms of the Amlodipine add-on stratum. Patients randomized to this arm received Aliskiren 300 mg + Amlodipine 5 mg once daily during the double blind period.
Aliskiren + Amlodipine	Amlodipine	In run-in period (4-5 weeks) , patients on thiazide background therapy and approximately 50% of patients on neither CCB nor thiazide background therapy received Amlodipine 5 mg and Aliskiren 150/300 mg daily in a titrated manner as per protocol. In double blind period, patients who successfully completed run-in with Amlodipine plus Aliskiren were randomized equally to the 4 arms of the Amlodipine add-on stratum. Patients randomized to this arm received Aliskiren 300 mg + Amlodipine 5 mg once daily during the double blind period.
Aliskiren + Hydrochlorothiazide (HCTZ)	Aliskiren	In run-in period (4-5 weeks) , patients on CCB background therapy and approximately 50% of patients on neither thiazide nor CCB background therapy: received Hydrochlorothiazide 12.5/25 mg and Aliskiren 150/300 mg daily in a titrated manner as per protocol. In double blind period, all patients who successfully completed run-in with HCTZ plus Aliskiren were randomized equally to the 4 arms of the HCTZ add-on stratum. Patients randomized to this arm received Aliskiren 300 mg + HCTZ 25 mg once daily.
Aliskiren + Placebo for Amlodipine	Aliskiren	In double blind period, all patients who successfully completed run-in with Amlodipine plus Aliskiren were randomized equally to the 4 arms of the Amlodipine add-on stratum. In double blind period, randomized patients to this arm received Aliskiren 300 mg + Placebo for Amlodipine 5 mg
Aliskiren + Placebo for HCTZ	Aliskiren	In double blind period, all patients who successfully completed run-in with HCTZ plus Aliskiren were randomized equally to the 4 arms of the HCTZ add-on stratum. In double blind period, randomized patients to this arm received Aliskiren 300 mg + Placebo for HCTZ 25 mg once daily
Amlodipine + Placebo for Aliskiren	Amlodipine	In double blind period, all patients who successfully completed run-in with Amlodipine plus Aliskiren were randomized equally to the 4 arms of the Amlodipine add-on stratum. In double blind period, randomized patients to this arm received Amlodipine 5 mg + placebo for Aliskiren 300 mg once daily

Primary Outcome Measures

Name	Time	Method
Number of Participants With Composite Cardiovascular Endpoints in Aliskiren Based Regimen Versus Non-Aliskiren Based Regimen	End of study (209 days (median))	The composite CV endpoint is based on the following first adjudicated events: CV death, non-fatal MI,non-fatal stroke, significant heart failure
Number of Participants With Composite Cardiovascular Endpoints in Aliskiren+Amlodipine/HCTZ Group Versus All Placebo Group	End of study (209 days (median))	The composite CV endpoint is based on the following first adjudicated events: CV death, non-fatal MI,non-fatal stroke, significant heart failure

Secondary Outcome Measures

Name	Time	Method
Change From Baseline to End of Study in Standard Assessment of Global Activities in the Elderly (SAGE) Dimensions (Part I)	Baseline, End of study (209 days [median])	Decline in ability to perform everyday activities independently was measured primarily by using the Standard Assessment of Global Activities in the Elderly (SAGE) scale. The SAGE comprised of 15 questions, each describing an activity. Patient had to indicate how much difficulty he/she had encountered in performing the activity in last month. Each question's score ranges from 0 (No difficulty) to 3 (difficulty levels were mild (score = 1), moderate (score =2) and severe (score=3)). Part I of SAGE included 4 dimensions: * Community Cognition (maximum of scores of questions 1 to 6); * Instrumental Activities of daily Living (IADL) (maximum of scores of questions 7 to 10); * Mobility (maximum of scores of questions 11 and 12);.; * Basic Activities of daily Living (ADL) (maximum of scores of questions 13 to 15) Each dimension's total score ranged from 0 to 3. 0=best, 3=worst A negative change in value from baseline means improvement in the ability to perform everyday activities.
Percentage of Participants With Standard Assessment of Global Activities in the Elderly (SAGE) Dimensions (Part II)	End of study (209 days [median])	Decline in ability to perform everyday activities independently was measured primarily by using the Standard Assessment of Global Activities in the Elderly (SAGE) scale. The SAGE was comprised of 15 questions, each describing an activity. Patient had to indicate how much difficulty he/she had encountered in performing the activity in the last month. Each question's score ranges from 0 (No difficulty) to 3 (difficulty levels were mild (score = 1), moderate (score =2) and severe (score=3)).; Part II of SAGE included 2 dimensions: * "Normal" if the scores of all SAGE questions is 0 (i.e., No difficulty); * "Mobility Only" if scores of both SAGE questions 11 and 12 are 0
Number of Participants With Renal Dysfunction in Aliskiren Based Regimen Versus Non-Aliskiren Based Regimen	End of study (209 days (median))	The renal dysfunction (composite endpoint) was defined as the first occurrence of either of the following: * End-stage renal disease \[ESRD\] requiring dialysis or transplantation; * Doubling of serum creatinine and reaching an eGFR \< 45 ml/min/1.73 m\^2.
Number of Participants With Total Mortality in Aliskiren Based Regimen Versus Non-aliskiren Based Regimen	End of study (209 days (median))	The total mortality endpoint was defined as time to death from any cause. Total mortality analysis used the date of last follow-up including the washout period as the censoring date.

Trial Locations

Locations (1)

Novartis Investigative Site; 🇸🇪 Stockholm, Sweden