A Randomized Controlled Trial of Aliskiren in the Prevent... | NCT01259297

NCT01259297

ID	Type	Description	Link
2009-010170-38	EudraCT Number

Status Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Aliskiren + Amlodipine	Experimental	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.	Drug: Aliskiren Drug: Amlodipine
Aliskiren + Hydrochlorothiazide (HCTZ)	Experimental	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.	Drug: Aliskiren Drug: Hydrochlorothiazide (HCTZ)
Aliskiren + Placebo for Amlodipine	Experimental	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	Drug: Aliskiren Drug: Placebo for Amlodipine
Aliskiren + Placebo for HCTZ

Name	Type	Description	Arm Group Labels	Other Names
Aliskiren	Drug	Aliskiren 150/300 mg once daily	Aliskiren + Amlodipine Aliskiren + Hydrochlorothiazide (HCTZ) Aliskiren + Placebo for Amlodipine

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
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))
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))

Secondary Outcomes

Measure	Description	Time Frame
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.

Other Outcomes

Measure	Description	Time Frame
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.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

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

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

Exclusion Criteria:

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.
Use of both thiazide diuretic and amlodipine or another calcium channel blocker. Patients on only one of these two classes of drugs are eligible
Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg)
Symptomatic heart failure, requiring the use of loop diuretics
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.
Acute stroke < 3 months or TIA ≤ 7 days before informed consent, acute coronary syndrome < 1 months before informed consent
Planned cardiac surgery or angioplasty < 3 months after informed consent or having had the procedure < 3 months before informed consent
Severe renal impairment eGFR ≤ 30 ml/min/1.73m2 (MDRD formula); known renal artery stenosis ; serum potassium ≥ 5.3 mmol/L
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)
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)
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
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

Name	Affiliation	Role
Novartis Pharmaceuticals	Novartis Pharmaceuticals	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Novartis Investigative Site		Birmingham	Alabama	35205	United States
Novartis Investigative Site

PubMed Identifier	Type	Citation	Retractions
24616335	Derived	Teo KK, Pfeffer M, Mancia G, O'Donnell M, Dagenais G, Diaz R, Dans A, Liu L, Bosch J, Joseph P, Copland I, Jung H, Pogue J, Yusuf S; Aliskiren Prevention of Later Life Outcomes trial Investigators. Aliskiren alone or with other antihypertensives in the elderly with borderline and stage 1 hypertension: the APOLLO trial. Eur Heart J. 2014 Jul;35(26):1743-51. doi: 10.1093/eurheartj/ehu079. Epub 2014 Mar 9.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Aliskiren + 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.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Arm/Group Information

ID	Title	Description
BG000	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. Patients randomized to this arm received Aliskiren 300 mg + HCTZ 25 mg once daily.
BG001	Aliskiren + Placebo for 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
BG002	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. Patients randomized to this arm received Aliskiren 300 mg + Amlodipine 5 mg once daily during the double blind period.
BG003	Aliskiren + 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
BG004	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 HCTZ 25 mg + placebo for Aliskiren 300 mg once daily
BG005	Placebo for Aliskiren + Placebo for 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
BG006	Amlodipine + Placebo for Aliskiren	In double blind period, all patients who successfully completed run-in with Amlodipine plus Aliskiren were run-in stratum 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
BG007	Placebo for Aliskiren + 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
BG008	Total	Total of all reporting groups

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

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

Full Analysis set. 1759 patients were randomized as against the originally planned 11,000. A total of 25 primary CV composite endpoints had accrued during median follow-up of 209 days versus planned 2000 primary endpoints during planned follow-up of average 5 years. These low numbers significantly limit interpretation of the results.

Posted

Number

participants

End of study (209 days (median))

ID	Title	Description
OG000	Aliskiren Based Regimen	This regimen includes all the patients who were randomized to the treatment arms that included Aliskiren such as Aliskiren + hydrochlorothiazide (HCTZ), Aliskiren + placebo for HCTZ, Aliskiren + Amlodipine, Aliskiren + placebo for Amlodipine.
OG001	Non-Aliskiren Based Regimen	This regimen includes all the patients who were randomized to the treatment arms that did not include Aliskiren such as HCTZ + Placebo for Aliskiren, Placebo for Aliskiren + Placebo for HCTZ, Amlodipine + Placebo for Aliskiren, Placebo for Aliskiren + Placebo for Amlodipine

Units	Counts
Participants	OG000860 OG001899

Title

Denominators

Categories

Title	Measurements
	OG00011 OG00114

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.

Full Analysis Set: Due to the sparse post-baseline data following early termination of the study, this analysis was not performed as planned in protocol.Hence, no meaningful conclusion could be drawn. Patients who completed both baseline and post-baseline SAGE questionnaires (Part II) were included in this analysis.

Posted

Mean

Standard Deviation

units on a scale

Baseline, End of study (209 days [median])

ID	Title	Description
OG000	Aliskiren Based Regimen	This regimen includes all the patients who were randomized to the treatment arms that included Aliskiren such as Aliskiren + Hydrochlorothiazide (HCTZ), Aliskiren + placebo for HCTZ, Aliskiren + Amlodipine, Aliskiren + placebo for Amlodipine.

Other Pre-specified

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.

Full analysis Set : All randomized patients, regardless of receiving study medication. n=number of patients with non-missing assessments at baseline and each post-baseline visit.

Posted

Least Squares Mean

Standard Error

mmHg

Baseline (BL), 6 week, 6 month and 12 month

ID	Title	Description
OG000	Aliskiren Based Regimen	This regimen includes all the patients who were randomized to the treatment arms that included Aliskiren such as Aliskiren + Hydrochlorothiazide (HCTZ), Aliskiren + placebo for HCTZ, Aliskiren + Amlodipine, Aliskiren + placebo for Amlodipine.
OG001	Non-Aliskiren Based Regimen	This regimen includes all the patients who were randomized to the treatment arms that did not include Aliskiren such as HCTZ + Placebo for Aliskiren, Placebo for Aliskiren + Placebo for HCTZ, Amlodipine + Placebo for Aliskiren, Placebo for Aliskiren + Placebo for Amlodipine

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

Posted

Number

participants

End of study (209 days (median))

ID	Title	Description
OG000	Aliskiren+Amlodipine/HCTZ Group	This reporting group includes all the patients who has received Aliskiren plus an additional BP lowering drug (Amlodipine or Hydrochlorothiazide). This reporting group includes patients from arms such as Aliskiren + Hydrochlorothiazide (HCTZ) and Aliskiren + Amlodipine.
OG001	Placebo	This reporting group includes all the patients who has received placebo of aliskiren plus placebo of an additional BP lowering drug (amlodipine or hydrochlorothiazide). This reporting group includes patients from arms such as Placebo for Aliskiren + Placebo for HCTZ and Placebo for aliskiren + Placebo for Amlodipine .

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

Full Analysis Set. Number of patients with all SAGE questions non-missing for the specific visit are included in this population. Due to the sparse post-baseline data following early termination of the study, this analysis was not performed as planned in protocol.Hence, no meaningful conclusion could be drawn.

Posted

Number

percentage of participants

End of study (209 days [median])

ID	Title	Description
OG000	Aliskiren Based Regimen	This regimen includes all the patients who were randomized to the treatment arms that included Aliskiren such as Aliskiren + hydrochlorothiazide (HCTZ), Aliskiren + placebo for HCTZ, Aliskiren + Amlodipine, Aliskiren + placebo for Amlodipine.
OG001	Non-Aliskiren Based Regimen

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.

Full Analysis set. 1759 patients were randomized as against the originally planned 11,000. The duration of study follow-up was 209 days (median) as against the planned follow-up of average 5 years. These low numbers significantly limit interpretation of the results.

Posted

Number

participants

End of study (209 days (median))

ID	Title	Description
OG000	Aliskiren Based Regimen	This regimen includes all the patients who were randomized to the treatment arms that included Aliskiren such as Aliskiren + Hydrochlorothiazide (HCTZ), Aliskiren + placebo for HCTZ, Aliskiren + Amlodipine, Aliskiren + placebo for Amlodipine.
OG001	Non-Aliskiren Based Regimen	This regimen includes all the patients who were randomized to the treatment arms that did not include Aliskiren such as HCTZ + Placebo for Aliskiren, Placebo for Aliskiren + Placebo for HCTZ, Amlodipine + Placebo for Aliskiren, Placebo for Aliskiren + Placebo for Amlodipine

Other Pre-specified

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.

Full analysis Set : All randomized patients, regardless of receiving study medication. n=number of patients with non-missing assessments at baseline and each post-baseline visit.

Posted

Least Squares Mean

Standard Error

mmHg

Baseline (BL), 6 week, 6 month and 12 month

ID	Title	Description
OG000	Aliskiren Based Regimen	This regimen includes all the patients who were randomized to the treatment arms that included Aliskiren such as Aliskiren + Hydrochlorothiazide (HCTZ), Aliskiren + placebo for HCTZ, Aliskiren + Amlodipine, Aliskiren + placebo for Amlodipine.
OG001	Non-Aliskiren Based Regimen	This regimen includes all the patients who were randomized to the treatment arms that did not include Aliskiren such as HCTZ + Placebo for Aliskiren, Placebo for Aliskiren + Placebo for HCTZ, Amlodipine + Placebo for Aliskiren, Placebo for Aliskiren + Placebo for Amlodipine

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.

Posted

Number

Participants

End of study (209 days (median))

ID	Title	Description
OG000	Aliskiren Based Regimen	This regimen includes all the patients who were randomized to the treatment arms that included Aliskiren such as Aliskiren + Hydrochlorothiazide (HCTZ), Aliskiren + placebo for HCTZ, Aliskiren + Amlodipine, Aliskiren + placebo for Amlodipine.
OG001	Non-Aliskiren Based Regimen	This regimen includes all the patients who were randomized to the treatment arms that did not include Aliskiren such as HCTZ + Placebo for Aliskiren, Placebo for Aliskiren + Placebo for HCTZ, Amlodipine + Placebo for Aliskiren, Placebo for Aliskiren + Placebo for Amlodipine

Arm/Groups

ID	Title	Description	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Run-in Period: Aliskiren + 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. Patients randomized to this arm received Aliskiren 300 mg + HCTZ 25 mg once daily.	10	1,335	7	1,335
EG001	Run-in Period: Aliskiren + 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. Patients randomized to this arm received Aliskiren 300 mg + Amlodipine 5 mg once daily during the double blind period.	10	1,001	19	1,001
EG002	Double Blind Period: 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. Patients randomized to this arm received Aliskiren 300 mg + HCTZ 25 mg once daily.	8	244	6	244
EG003	Double Blind Period: Aliskiren + Placebo for 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	5	232	5	232
EG004	Double Blind Period: Aliskiren + Amlodipine	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.	7	189	9	189
EG005	Double Blind Period: Aliskiren + 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	8	195	8	195
EG006	Double Blind Period: 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 HCTZ 25 mg + placebo for Aliskiren 300 mg once daily	4	251	6	251
EG007	Double Blind Period: Placebo for Aliskiren + Placebo for 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	6	253	5	253
EG008	Double Blind Period: 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 Amlodipine 5 mg + placebo for Aliskiren 300 mg once daily	3	196	14	196
EG009	Double Blind Period: Placebo for Aliskiren + Placebo for Amlod	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	7	199	3	199

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0011 affected1,001 at risk EG0021 affected244 at risk EG0030 affected232 at risk EG0040 affected189 at risk EG0050 affected195 at risk EG0060 affected251 at risk EG0070 affected253 at risk EG0080 affected196 at risk EG0090 affected199 at risk
Angina pectoris	Cardiac disorders	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0021 affected244 at risk EG003
Atrial fibrillation	Cardiac disorders	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Cardiac arrest	Cardiac disorders	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Ventricular fibrillation	Cardiac disorders	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Abdominal hernia	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Diarrhoea	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Gastrointestinal haemorrhage	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0011 affected1,001 at risk EG0020 affected244 at risk EG003
Haematochezia	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Intestinal perforation	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Pancreatitis acute	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Chest pain	General disorders	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0011 affected1,001 at risk EG0020 affected244 at risk EG003
Drug interaction	General disorders	MedDRA	Systematic Assessment	EG0001 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Drug intolerance	General disorders	MedDRA	Systematic Assessment	EG0001 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Cholecystitis	Hepatobiliary disorders	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Cholecystitis acute	Hepatobiliary disorders	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Bronchitis	Infections and infestations	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0011 affected1,001 at risk EG0020 affected244 at risk EG003
Cellulitis	Infections and infestations	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Gastroenteritis	Infections and infestations	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Herpes zoster	Infections and infestations	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Pneumonia	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Urinary tract infection	Infections and infestations	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Viral infection	Infections and infestations	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0021 affected244 at risk EG003
Femur fracture	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Subdural haematoma	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Blood creatinine increased	Investigations	MedDRA	Systematic Assessment	EG0001 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Blood urea increased	Investigations	MedDRA	Systematic Assessment	EG0001 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Diabetes mellitus	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Electrolyte imbalance	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Hyperkalaemia	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0002 affected1,335 at risk EG0011 affected1,001 at risk EG0021 affected244 at risk EG003
Hypokalaemia	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0002 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Hyponatraemia	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0001 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Basal cell carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0021 affected244 at risk EG003
Colon cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0011 affected1,001 at risk EG0020 affected244 at risk EG003
Colon cancer metastatic	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0011 affected1,001 at risk EG0020 affected244 at risk EG003
Small intestine carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Cerebral hypoperfusion	Nervous system disorders	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Cerebrovascular accident	Nervous system disorders	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Coma	Nervous system disorders	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Hemiparesis	Nervous system disorders	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Loss of consciousness	Nervous system disorders	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0011 affected1,001 at risk EG0020 affected244 at risk EG003
Paraesthesia	Nervous system disorders	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Syncope	Nervous system disorders	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0011 affected1,001 at risk EG0023 affected244 at risk EG003
Psychotic disorder	Psychiatric disorders	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Azotaemia	Renal and urinary disorders	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Renal disorder	Renal and urinary disorders	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Renal failure	Renal and urinary disorders	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0022 affected244 at risk EG003
Renal failure acute	Renal and urinary disorders	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Renal impairment	Renal and urinary disorders	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Pulmonary oedema	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Angioedema	Skin and subcutaneous tissue disorders	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0012 affected1,001 at risk EG0020 affected244 at risk EG003
Arterial occlusive disease	Vascular disorders	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Hypertensive crisis	Vascular disorders	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG003
Hypotension	Vascular disorders	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0012 affected1,001 at risk EG0020 affected244 at risk EG003

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Gastritis	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0010 affected1,001 at risk EG0020 affected244 at risk EG0030 affected232 at risk EG0040 affected189 at risk EG0052 affected195 at risk EG0060 affected251 at risk EG0070 affected253 at risk EG0081 affected196 at risk EG0091 affected199 at risk
Oedema peripheral	General disorders	MedDRA	Systematic Assessment	EG0000 affected1,335 at risk EG0017 affected1,001 at risk EG0020 affected244 at risk EG003
Hyperkalaemia	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0001 affected1,335 at risk EG0010 affected1,001 at risk EG0021 affected244 at risk EG003
Dizziness	Nervous system disorders	MedDRA	Systematic Assessment	EG0003 affected1,335 at risk EG0017 affected1,001 at risk EG0021 affected244 at risk EG003
Hypotension	Vascular disorders	MedDRA	Systematic Assessment	EG0003 affected1,335 at risk EG0015 affected1,001 at risk EG0024 affected244 at risk EG003

ID	Term
D004095	Dihydropyridines
D011725	Pyridines
D006573	Heterocyclic Compounds, 1-Ring
D006571	Heterocyclic Compounds
D002740	Chlorothiazide
D001581	Benzothiadiazines
D013449	Sulfonamides
D013450	Sulfones
D013457	Sulfur Compounds
D009930	Organic Chemicals
D049971	Thiazides
D006574	Heterocyclic Compounds, 2-Ring
D000072471	Heterocyclic Compounds, Fused-Ring