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

Cardiovascular Events Clinical Trial

— APOLLO  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01259297
• Other study ID #: CSPP100G2301
• Secondary ID: 2009-010170-38
• Status: Terminated
• Phase: Phase 3
• First received: December 10, 2010
• Last updated: February 27, 2014
• Start date: January 2011
• Est. completion date: November 2012

Study information

• Verified date: February 2014
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationArgentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia MedicaBrazil: Ministry of HealthCanada: Health CanadaChile: Ministry of HealthChina: Food and Drug AdministrationColombia: INVIMA Instituto Nacional de Vigilancia de Medicamentos y AlimentosCzech Republic: State Institute for Drug ControlGermany: Federal Institute for Drugs and Medical DevicesHungary: National Institute of PharmacyIndia: Central Drugs Standard Control OrganizationIreland: Ministry of HealthIsrael: Ministry of HealthItaly: National Institute of HealthMalaysia: Ministry of HealthNetherlands: Medicines Evaluation Board (MEB)Philippines: Bureau of Food and Drugs (BFAD)Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal ProductsRussia: Ministry of Health of the Russian FederationSouth Africa: Medicines Control CouncilSpain: Spanish Agency of MedicinesSweden: Medical Products AgencyTurkey: Ministry of Health
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 2336
• Est. completion date: November 2012
• Est. primary completion date: November 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 65 Years and older

Eligibility

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)

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Factorial Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Cardiovascular Events

Intervention

Drug:
• Aliskiren
Aliskiren 150/300 mg once daily
• Amlodipine
Amlodipine 5 mg
• Hydrochlorothiazide (HCTZ)
HCTZ 12.5/25 mg
• Placebo for Aliskiren
Placebo for Aliskiren 300 mg
• Placebo for Amlodipine
Placebo for Amlodipine
• Placebo for Hydrochlorothiazide (HCTZ)
Placebo for HCTZ 12.5/25 mg

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Cipolletti	Rio Negro
Argentina	Novartis Investigative Site	Ciudad Autonoma de Bs As	Buenos Aires
Argentina	Novartis Investigative Site	Cordoba
Argentina	Novartis Investigative Site	Coronel Suarez	Buenos Aires
Argentina	Novartis Investigative Site	Jenin	Buenos Aires
Argentina	Novartis Investigative Site	Mar del Plata	Buenos Aires
Argentina	Novartis Investigative Site	Merlo	Buenos Aires
Argentina	Novartis Investigative Site	Quilmes	Buenos Aires
Argentina	Novartis Investigative Site	Rosario	Santa Fe
Argentina	Novartis Investigative Site	Salta
Argentina	Novartis Investigative Site	San Nicolas	Buenos Aires
Argentina	Novartis Investigative Site	Santa Fe
Argentina	Novartis Investigative Site	Tucuman	San Miguel de Tucuman
Argentina	Novartis Investigative Site	Venado Tuerto	Santa Fe
Brazil	Novartis Investigative Site	Belo Horizonte	MG
Brazil	Novartis Investigative Site	Campina Grande do Sul	PR
Brazil	Novartis Investigative Site	Campinas	SP
Brazil	Novartis Investigative Site	Marilia	SP
Brazil	Novartis Investigative Site	Porto Alegre	RS
Brazil	Novartis Investigative Site	Sao Jose do Rio Preto	SP
Brazil	Novartis Investigative Site	São Paulo	SP
Brazil	Novartis Investigative Site	Uberaba	MG
Brazil	Novartis Investigative Site	Votuporanga	SP
Canada	Novartis Investigative Site	Brampton	Ontario
Canada	Novartis Investigative Site	Calgary	Alberta
Canada	Novartis Investigative Site	Coquitlam	British Columbia
Canada	Novartis Investigative Site	Edmonton	Alberta
Canada	Novartis Investigative Site	Hamilton	Ontario
Canada	Novartis Investigative Site	Hamilton	Ontario
Canada	Novartis Investigative Site	Hamilton	Ontario
Canada	Novartis Investigative Site	Lévis	Quebec
Canada	Novartis Investigative Site	London	Ontario
Canada	Novartis Investigative Site	Markham	Ontario
Canada	Novartis Investigative Site	Missisauga	Ontario
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Newmarket	Ontario
Canada	Novartis Investigative Site	Niagara Falls	Ontario
Canada	Novartis Investigative Site	North York	Ontario
Canada	Novartis Investigative Site	Ottawa	Ontario
Canada	Novartis Investigative Site	Ottawa	Ontario
Canada	Novartis Investigative Site	Quebec
Canada	Novartis Investigative Site	Sainte Foy	Quebec
Canada	Novartis Investigative Site	Sainte-Foy	Quebec
Canada	Novartis Investigative Site	Saskatoon	Saskatchewan
Canada	Novartis Investigative Site	St Catherines	Ontario
Canada	Novartis Investigative Site	St. John's	Newfoundland and Labrador
Canada	Novartis Investigative Site	St.Gorges de Beauce	Quebec
Canada	Novartis Investigative Site	Terrebonne	Quebec
Canada	Novartis Investigative Site	Toronto	Ontario
Canada	Novartis Investigative Site	Toronto	Ontario
Canada	Novartis Investigative Site	Toronto	Ontario
Canada	Novartis Investigative Site	Winnipeg	Manitoba
Chile	Novartis Investigative Site	Osorno
Chile	Novartis Investigative Site	Santiago
Chile	Novartis Investigative Site	Temuca	TX
Chile	Novartis Investigative Site	Temuco	Cautin
Chile	Novartis Investigative Site	Vista Del Mar	I Region
Colombia	Novartis Investigative Site	Armenia
Colombia	Novartis Investigative Site	Baranquilla
Colombia	Novartis Investigative Site	Barranquilla
Colombia	Novartis Investigative Site	Barranquilla	Atlantico
Colombia	Novartis Investigative Site	Bogota
Colombia	Novartis Investigative Site	Bogota	Cundinamarca
Colombia	Novartis Investigative Site	Bogotá
Colombia	Novartis Investigative Site	Cali
Colombia	Novartis Investigative Site	Cartagena	Bolivar
Colombia	Novartis Investigative Site	Cartegena
Colombia	Novartis Investigative Site	Espinal
Colombia	Novartis Investigative Site	Floridablanca	Santander
Colombia	Novartis Investigative Site	Manizoles	Caldas
Colombia	Novartis Investigative Site	Monteria
Colombia	Novartis Investigative Site	Pasto
Colombia	Novartis Investigative Site	Pereira	Risaralda
Czech Republic	Novartis Investigative Site	Beroun
Czech Republic	Novartis Investigative Site	Brandys nad Labem
Czech Republic	Novartis Investigative Site	Novy Jicin
Czech Republic	Novartis Investigative Site	Prague 4
Czech Republic	Novartis Investigative Site	Prague 6
Czech Republic	Novartis Investigative Site	Praha 9
Czech Republic	Novartis Investigative Site	Uherske Hradiste
Czech Republic	Novartis Investigative Site	Usti nad Orlici
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Frankfurt
Germany	Novartis Investigative Site	Melsungen
Germany	Novartis Investigative Site	Nuernberg
Germany	Novartis Investigative Site	Wiesbaden
Germany	Novartis Investigative Site	Witten
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Gyongyos
Hungary	Novartis Investigative Site	Kaposvar
Hungary	Novartis Investigative Site	Komarom
Hungary	Novartis Investigative Site	Mosonmagyarovar
Hungary	Novartis Investigative Site	Pecs
Hungary	Novartis Investigative Site	Sopron
Hungary	Novartis Investigative Site	Szentes
Hungary	Novartis Investigative Site	Veszprem
India	Novartis Investigative Site	Adoni	Andhra Pradesh
India	Novartis Investigative Site	Adoni	Andhra Pradesh
India	Novartis Investigative Site	Ahmedabad	Gujarat
India	Novartis Investigative Site	Ahmedabad	Gujarat
India	Novartis Investigative Site	Bangalore	Karnataka
India	Novartis Investigative Site	Bangalore	Karnataka
India	Novartis Investigative Site	Belgaum	Karnataka
India	Novartis Investigative Site	Bengaluru	Karnataka
India	Novartis Investigative Site	Bikaner	Rajasthan
India	Novartis Investigative Site	Chennai
India	Novartis Investigative Site	Hyderabad
India	Novartis Investigative Site	Hyderabad	Andhra Pradesh
India	Novartis Investigative Site	Jalandhar	Punjab
India	Novartis Investigative Site	Lucknow	Uttar Pradesh
India	Novartis Investigative Site	Ludhiana	Punjab
India	Novartis Investigative Site	Mumbai
India	Novartis Investigative Site	Nagpur
India	Novartis Investigative Site	Nagpur	Maharashtra
India	Novartis Investigative Site	Nagpur	Maharashtra
India	Novartis Investigative Site	Nagpur	Maharashtra
India	Novartis Investigative Site	Pune	Maharashtra
India	Novartis Investigative Site	Tiruvannamalai	Tamil Nadu
India	Novartis Investigative Site	Trichy	Tamil Nadu
India	Novartis Investigative Site	Trichy
India	Novartis Investigative Site	Visakhapatnam	Andhra Pradesh
India	Novartis Investigative Site	Wardha	Maharashtra
Ireland	Novartis Investigative Site	Ballinsloe	Galway
Ireland	Novartis Investigative Site	Galway
Ireland	Novartis Investigative Site	Gorey	Co. Wexford
Israel	Novartis Investigative Site	Givatayim
Israel	Novartis Investigative Site	Haifa
Israel	Novartis Investigative Site	Safed
Malaysia	Novartis Investigative Site	Alor Setar	Kedah
Malaysia	Novartis Investigative Site	Batu Caves	Selangor
Malaysia	Novartis Investigative Site	Kota Bahru	Kelantan
Malaysia	Novartis Investigative Site	Kota Bharu	Kelantan
Malaysia	Novartis Investigative Site	Kuala Lumpur
Malaysia	Novartis Investigative Site	Kuala Lumpur
Malaysia	Novartis Investigative Site	Kuantan	Pahang
Netherlands	Novartis Investigative Site	Breda
Netherlands	Novartis Investigative Site	Eindhoven
Netherlands	Novartis Investigative Site	Groningen
Netherlands	Novartis Investigative Site	Leiderdorp
Netherlands	Novartis Investigative Site	Rotterdam
Netherlands	Novartis Investigative Site	Velp
Netherlands	Novartis Investigative Site	Zoetermeer
Philippines	Novartis Investigative Site	Binan City
Philippines	Novartis Investigative Site	Dasmarinas	Cavite
Philippines	Novartis Investigative Site	Laoag City	Ilocos Norte
Philippines	Novartis Investigative Site	Manila
Philippines	Novartis Investigative Site	Manila
Philippines	Novartis Investigative Site	Pasig City
Philippines	Novartis Investigative Site	Quezon City
Philippines	Novartis Investigative Site	Quezon City	Metro Manila
South Africa	Novartis Investigative Site	Bloemfontein
South Africa	Novartis Investigative Site	Durban
South Africa	Novartis Investigative Site	Paarl	Western Province
South Africa	Novartis Investigative Site	Pretoria
Spain	Novartis Investigative Site	Ferrol	Galicia
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Puerto de Sagunto
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
Sweden	Novartis Investigative Site	Dalby
Sweden	Novartis Investigative Site	Goteborg
Sweden	Novartis Investigative Site	Göteborg
Sweden	Novartis Investigative Site	Malmö
Sweden	Novartis Investigative Site	Rättvik
Sweden	Novartis Investigative Site	Stockholm
United States	Novartis Investigative Site	Birmingham	Alabama
United States	Novartis Investigative Site	Falls Church	Virginia
United States	Novartis Investigative Site	Haverhill	Massachusetts
United States	Novartis Investigative Site	Los Angeles	California
United States	Novartis Investigative Site	Marshfield	Wisconsin
United States	Novartis Investigative Site	Milwaukee	Wisconsin
United States	Novartis Investigative Site	Northridge	California
United States	Novartis Investigative Site	Pocatello	Idaho
United States	Novartis Investigative Site	Portland	Oregon
United States	Novartis Investigative Site	St. Louis	Missouri
United States	Novartis Investigative Site	Sylmar	California
United States	Novartis Investigative Site	Tucker	Georgia
United States	Novartis Investigative Site	Westfiled	New York
United States	Novartis Investigative Site	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Brazil,  Canada,  Chile,  Colombia,  Czech Republic,  Germany,  Hungary,  India,  Ireland,  Israel,  Malaysia,  Netherlands,  Philippines,  South Africa,  Spain,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP)	Mean sitting systolic blood pressure (msSBP) is the average of 2 sitting SBP measurements (2 minutes apart). Since each patient had their final follow-up visit at a different time in the trial, these measurements were classified as falling into the 6 week, 6 month, or 12 month measurement period. All available blood pressures were sorted within these periods and the last value within each time range used for analysis. At each timepoint, a patient must have both baseline and postbaseline values to be included in the analysis.	Baseline (BL), 6 week, 6 month and 12 month	No
Other	Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP)	Mean sitting diastolic blood pressure (msDBP) is the average of 2 sitting DBP measurements (2 minutes apart). Since each patient had their final follow-up visit at a different time in the trial, these measurements were classified as falling into the 6 week, 6 month, or 12 month measurement period. All available blood pressures were sorted within these periods and the last value within each time range used for analysis. At each timepoint, a patient must have both baseline and postbaseline values to be included in the analysis.	Baseline (BL), 6 week, 6 month and 12 month	No
Primary	Number of Participants With Composite Cardiovascular Endpoints in Aliskiren Based Regimen Versus Non-Aliskiren Based Regimen	The composite CV endpoint is based on the following first adjudicated events: CV death, non-fatal MI,non-fatal stroke, significant heart failure	End of study (209 days (median))	No
Primary	Number of Participants With Composite Cardiovascular Endpoints in Aliskiren+Amlodipine/HCTZ Group Versus All Placebo Group	The composite CV endpoint is based on the following first adjudicated events: CV death, non-fatal MI,non-fatal stroke, significant heart failure	End of study (209 days (median))	No
Secondary	Change From Baseline to End of Study in Standard Assessment of Global Activities in the Elderly (SAGE) Dimensions (Part I)	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.	Baseline, End of study (209 days [median])	No
Secondary	Percentage of Participants With Standard Assessment of Global Activities in the Elderly (SAGE) Dimensions (Part II)	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	End of study (209 days [median])	No
Secondary	Number of Participants With Renal Dysfunction in Aliskiren Based Regimen Versus Non-Aliskiren Based Regimen	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.	End of study (209 days (median))	No
Secondary	Number of Participants With Total Mortality in Aliskiren Based Regimen Versus Non-aliskiren Based Regimen	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.	End of study (209 days (median))	Yes