ALIAS: Efficacy of Aliskiren Compared to Ramipril in the Treatment of Moderate Systolic Hypertensive Patients

• Sponsor: Novartis (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01042392
• Collaborator: (none)
• Enrollment: 506
• Locations: 99
• Arms: 4
• Duration (Months): 14
• Patients Per Site: 5.1
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This prospective multicenter, double blind study will evaluate the efficacy and safety of aliskiren versus ramipril in patients with moderate systolic essential hypertension.

Condition or Disease	Intervention/Treatment	Phase
Essential Hypertension	Drug: Aliskiren; Drug: Ramipril; Drug: Matching placebo to Aliskiren; Drug: Matching placebo to Ramipril	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 506 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Efficacy of Aliskiren Compared to Ramipril in the Treatment of Moderate Systolic Hypertensive Patients
• Study Start Date: Nov 1, 2009
• Actual Primary Completion Date: Jan 1, 2011
• Actual Study Completion Date: Jan 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Ramipril In period I (washout and single-blind): from visit 1 to visit 2, 2 weeks placebo run-in. In period II (double-blind treatment, randomized): Ramipril 5 mg for 4 weeks (visit 2 - visit 3). At visit 3, medications had to be titrated to Ramipril 10 mg only if BP remained ≥ 140/90 mmHg. Double blind treatment had to be continued for another 4-week period until visit 4. In period III (double-blind withdrawal): At visit 4, part of patients received the active treatment for 1 day. The study ended at visit 5 (48 hours later than visit 4).	Drug: Ramipril; Ramipril 5 mg was given in capsule form.; Drug: Matching placebo to Aliskiren; The tablet of matching placebo to aliskiren 150 mg for period I and III. In period II, matching placebo to Aliskiren was given to Ramipril active treatment arm.
Experimental: Aliskiren In period I (washout and single-blind): from visit 1 to visit 2, 2 weeks placebo run-in. In period II (double-blind treatment, randomized): Aliskiren 150 mg for 4 weeks (visit 2 - visit 3). At visit 3, medications had to be titrated to aliskiren 300 mg only if BP remained ≥ 140/90 mmHg. Double blind treatment had to be continued for another 4-week period until visit 4. In period III (double-blind withdrawal ): At visit 4, part of the patients received the active treatment for 1 day. The study ended at visit 5 (48 hours later than visit 4).	Drug: Aliskiren; 150 mg Aliskiren as film-coated tablet; Drug: Matching placebo to Ramipril; The placebo capsule to ramipril 5 mg for period I and III. In period II, matching placebo to Ramipril was given to Aliskiren active treatment arm.
Placebo Comparator: Placebo to Ramipril In period III (double-blind withdrawal ): At visit 4, part of patients from Ramipril arm received placebo to Ramipril for 1 day. The study ended at visit 5 (48 hours later than visit 4).	Drug: Matching placebo to Ramipril; The placebo capsule to ramipril 5 mg for period I and III. In period II, matching placebo to Ramipril was given to Aliskiren active treatment arm.
Placebo Comparator: Placebo to Aliskiren In period III (double-blind withdrawal ): At visit 4, part of the patients from Aliskiren arm received placebo to Aliskiren for 1 day. The study ended at visit 5 (48 hours later than visit 4).	Drug: Matching placebo to Aliskiren; The tablet of matching placebo to aliskiren 150 mg for period I and III. In period II, matching placebo to Aliskiren was given to Ramipril active treatment arm.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) [Baseline to 8 weeks]

   The arm in which the highest sitting systolic blood pressure (SBP) was found at study entry was used for all subsequent readings. At each study visit, after leaving the patient to rest 5 minutes in a sitting position, the blood pressure (BP) was measured three times with an oscillometric device. The measurements were performed at 1-2 minute intervals. The mean BP was calculated from the 3 readings. The analysis of covariance included treatment factor and baseline mean sitting SBP as covariable.

Secondary Outcome Measures

1. Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) [Baseline to 8 weeks]

   The arm in which the highest sitting systolic blood pressure (SBP) was found at study entry was used for all subsequent readings. At each study visit, after leaving the patient to rest 5 minutes in a sitting position, the blood pressure (BP) was measured three times with an oscillometric device. The measurements were performed at 1-2 minute intervals. The mean BP was calculated from the 3 readings. The analysis of variance included treatment factor and baseline value of mean sitting DBP as covariable.

2. Percentage of Patients With Controlled Blood Pressure [At 4 and 8 weeks]

   The arm in which the highest sitting systolic blood pressure (SBP) was found at study entry was used for all subsequent readings. At each study visit, after leaving the patient to rest 5 minutes in a sitting position, the blood pressure (BP) was measured three times with an oscillometric device. The measurements were performed at 1-2 minute intervals. The mean BP was calculated from the 3 readings. Controlled blood pressure (BP) is defined as mean office systolic BP/ diastolic BP < 140/90 mmHg.

3. Number of the Participants With More Than 55 mmHg Difference Between the Mean SBP Measured at the Morning Surge and the Mean Minimal SBP Measured During the Night [After 8 weeks]

   Ambulatory blood pressure measurement (ABPM) over 24 hours was performed for all patients on the day before visit 4, the device attached to the ambulatory blood pressure non-dominant arm of the patient. The BP morning surge was defined as the average of the measurements taken during the first 2 hours after waking the patient. The minimal night blood pressure was defined as the average of the two lowest BP measures (the lowest hourly average) recorded during night time.

4. Change in msSBP and msDBP From Visit 2 (Baseline) to Visit 3 (at 4 Weeks) [Baseline to 4 weeks]

   The arm in which the highest sitting systolic blood pressure (SBP) was found at study entry was used for all subsequent readings. At each study visit, after leaving the patient to rest 5 minutes in a sitting position, the blood pressure (BP) was measured three times with an oscillometric device. The measurements were performed at 1-2 minute intervals. The mean BP was calculated from the 3 readings. The analysis of covariance included treatment factor and baseline mean sitting SBP and mean sitting DBP as covariables.

5. Difference Between the Maximal and the Minimal Mean-hour SPB Measured Between 1 and 8 am at Week 8 [At week 8]

   Ambulatory blood pressure measurement (ABPM) over 24 hours was performed for all patients on the eve of visit 4 (week 8), the device attached to the ambulatory blood pressure non-dominant arm of the patient. The difference between mean-hour maximum SBP mean-hour minimum SBP between 1 am and 8 am was measured.

6. Change in Mean Sitting DBP and SBP in Specified Sub-groups From Visit 2 (Baseline) to Visit 4 (at 8 Weeks) [Baseline to 8 weeks]

   The sub-groups were: "Riser" = patients with >= 55 mmHg difference between the mean SPB measured at the morning surge and the mean minimal SBP measured during the night. The "Non-risers" in whom the difference is <55 mmHg. Patients called "dippers" in whom there was a decrease in average nocturnal SBP ≥ 10% compared with average daytime SBP, in contrast to patients "non-dippers " in whom this difference was <10%.

7. Change in Mean Sitting Systolic Blood Pressure (msSBP) and Mean Sitting Diastolic Blood Pressure (msDBP) From Last Active Dose Taken to After a One-day Missed-dose [From 8 weeks to 48 hours after week 8]

   The change in blood pressure was measured between visit 4 (end of the period of double-blind active treatment which was at week 8) and visit 5 (48 hours after the last active dose taken) in the group of patients who received aliskiren or placebo and those who received ramipril or placebo. The analysis of covariance included treatment factor and baseline mean sitting SBP and mean sitting DBP as covariables.

8. Number Patients Reported With Adverse Events (AEs), Serious Adverse Events (SAE) and Death (Period II and Period III) [8 weeks + 1 day]

   Adverse events are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Outpatients > 18 years

• Male or female patients. Female patients must have been either post-menopausal for one year, surgically sterile, or using effective contraceptive methods

• Patients with essential hypertension, previously treated with an antihypertensive single-drug therapy, either uncontrolled or intolerant.

• BP thresholds at visit 1:

• For patients previously treated and uncontrolled: 140≤ office SBP<180 mmHg

• For patients previously treated, controlled but intolerant: office SBP≥130 mmHg

• BP thresholds at visit 2 (for all patients):

• 160≤office SBP<180 mmHg AND

• 155≤home SBP<175 mmHg (3-day period of home blood pressure monitoring just before randomization)

Exclusion Criteria:

• Women of child-bearing potential not using any effective methods of contraception

• Severe hypertension (office BP ≥ 180/110 mmHg)

• Impossibility to stop abruptly previous antihypertensive treatments at visit 1

• Patients previously untreated or patients treated with two or three antihypertensive medications

• History or evidence of a secondary form of hypertension

• History of hypersensitivity to ACEi or renin inhibitors

• History of heart failure, stroke or coronary heart disease

• Serum potassium ≥ 5.2 mmol/l

Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Aire Sur Adour		France
2	Novartis Investigative Site	Amboise		France
3	Novartis Investigative Site	Angers		France
4	Novartis Investigative Site	Anzin		France
5	Novartis Investigative Site	Bachant		France
6	Novartis Investigative Site	Bandol		France
7	Novartis Investigative Site	Becon-les-granits		France
8	Novartis Investigative Site	Bersee		France
9	Novartis Investigative Site	Bordeaux		France
10	Novartis Investigative Site	Bouliac		France
11	Novartis Investigative Site	Bourges		France
12	Novartis Investigative Site	Briollay		France
13	Novartis Investigative Site	Bruges		France
14	Novartis Investigative Site	Caen		France
15	Novartis Investigative Site	Carbonne		France
16	Novartis Investigative Site	Chatellerault		France
17	Novartis Investigative Site	Chatillon Sur Colmon		France
18	Novartis Investigative Site	Cherbourg		France
19	Novartis Investigative Site	Château Gontier		France
20	Novartis Investigative Site	Château-gontier		France
21	Novartis Investigative Site	Cournonterral		France
22	Novartis Investigative Site	Croix		France
23	Novartis Investigative Site	Cugnaux		France
24	Novartis Investigative Site	Ecouflant		France
25	Novartis Investigative Site	Equeurdreville		France
26	Novartis Investigative Site	Falaise		France
27	Novartis Investigative Site	Fondettes		France
28	Novartis Investigative Site	Guerigny		France
29	Novartis Investigative Site	Hautmont		France
30	Novartis Investigative Site	L'aigle		France
31	Novartis Investigative Site	La Farlede		France
32	Novartis Investigative Site	La Riche		France
33	Novartis Investigative Site	La Rochelle		France
34	Novartis Investigative Site	Labarthe Sur Leze		France
35	Novartis Investigative Site	Lambersart		France
36	Novartis Investigative Site	Laval		France
37	Novartis Investigative Site	Le Bouscat		France
38	Novartis Investigative Site	Le Cailar		France
39	Novartis Investigative Site	Le Fousseret		France
40	Novartis Investigative Site	Le Pradet		France
41	Novartis Investigative Site	Les Maguelone		France
42	Novartis Investigative Site	Luynes		France
43	Novartis Investigative Site	Marcheprime		France
44	Novartis Investigative Site	Marseille		France
45	Novartis Investigative Site	Marsilly		France
46	Novartis Investigator Site	Marsilly		France
47	Novartis Investigative Site	Mayenne		France
48	Novartis Investigative Site	Medis		France
49	Novartis Investigative Site	Mont-de-marsan		France
50	Novartis Investigative Site	Montpellier		France
51	Novartis Investigative Site	Montrevault		France
52	Novartis Investigative Site	Monts sur guesnes		France
53	Novartis Investigative Site	Mortagne-sur-sevre		France
54	Novartis Investigative Site	Mourmelon-le-petit		France
55	Novartis Investigative Site	Nantes		France
56	Novartis Investigative Site	Nevers		France
57	Novartis Investigative Site	Nieul sur mer		France
58	Novartis Investigative Site	Orchies		France
59	Novartis Investigative Site	Paris		France
60	Novartis Investigative Site	Perigny		France
61	Novartis Investigative Site	Potigny		France
62	Novartis Investigative Site	Reims		France
63	Novartis Investigative Site	Roquevaire		France
64	Novartis Investigative Site	Rouen		France
65	Novartis Investigative Site	Saint Avertin		France
66	Novartis Investigative Site	Saint Benoit		France
67	Novartis Investigative Site	Saint Germain de marencennes		France
68	Novartis Investigative Site	Saint loubes		France
69	Novartis Investigative Site	Saint Rogatien		France
70	Novartis Investigative Site	Saint Xandre		France
71	Novartis Investigative Site	Saint-CYR-SUR-MER		France
72	Investigative Site	Saint-orens-de-gameville		France
73	Novartis Investigative Site	Saint-orens-de-gameville		France
74	Novartis Investigative Site	Sainte marie de re		France
75	Novartis Investigative Site	Sanary sur mer		France
76	Novartis Investigative Site	Savonnieres		France
77	Novartis Investigative Site	Scorbe clairvaux		France
78	Investigative Site	Scorbe-clairvaux		France
79	Novartis Investigative Site	Segre		France
80	Novartis Investigative Site	Seysses		France
81	Novartis Investigative Site	Sotteville les rouen		France
82	Novartis Investigative Site	ST Cyr Sur Loire		France
83	Novartis Investigative Site	St Georges D'Orques		France
84	Novartis Investigative Site	St Martin D'Oney		France
85	Novartis Investigative Site	St Seurin De Cursac		France
86	Novartis Investigative Site	Strasbourg		France
87	Novartis Investigative Site	Thun St Amand		France
88	Novartis Investigative Site	Tierce		France
89	Investigative Site	Toulon		France
90	Novartis Investigative Site	Toulon		France
91	Novartis Investigative Site	Toulouse		France
92	Novartis Investigative Site	Tours		France
93	Novartis Investigative Site	Trelaze		France
94	Novartis Investigative Site	Vendome		France
95	Novartis Investigative Site	Vereneque		France
96	Novartis Investigative Site	Verzy		France
97	Novartis Investigative Site	Vierzon		France
98	Novartis Investigative Site	Vieux Conde		France
99	Novartis Investigative Site	Witry-Les-Reims		France

Sponsors and Collaborators

• Novartis

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis
• ClinicalTrials.gov Identifier: NCT01042392
• Other Study ID Numbers: CSPP100AFR01; 2009-011296-80
• First Posted: Jan 5, 2010
• Last Update Posted: Apr 3, 2012
• Last Verified: Mar 1, 2012

• Keywords provided by Novartis: Moderate systolic hypertension - adults - aliskiren -ramipril
• Additional relevant MeSH terms: Hypertension; Essential Hypertension; Systolic Murmurs; Ramipril

Study Results

Participant Flow

Arm/Group Title	Ramipril	Placebo to Ramipril	Aliskiren	Placebo to Aliskiren
Arm/Group Description	In period I (washout and single-blind): from visit 1 to visit 2, 2 weeks placebo run-in. In period II (double-blind treatment, randomized): Ramipril 5 mg for 4 weeks (visit 2 - visit 3). At visit 3, medications had to be titrated to Ramipril 10 mg only if BP remained ≥ 140/90 mmHg. Double blind treatment had to be continued for another 4-week period until visit 4. In period III (double-blind withdrawal): At visit 4, patients received the active treatment for 1 day. The study ended at visit 5 (48 hours later than visit 4).	In period III (double-blind withdrawal): At visit 4, part of the patients from Ramipril arm received placebo to Ramipril for 1 day. The study ended at visit 5 (48 hours later than visit 4).	In period I (washout and single-blind): from visit 1 to visit 2, 2 weeks placebo run-in. In period II (double-blind treatment, randomized): Aliskiren 150 mg for 4 weeks (visit 2 - visit 3). At visit 3, medications had to be titrated to aliskiren 300 mg only if BP remained ≥ 140/90 mmHg. Double blind treatment had to be continued for another 4-week period until visit 4. In period III (double-blind withdrawal): At visit 4, part of patients received the active treatment for 1 day. The study ended at visit 5 (48 hours later than visit 4).	In period III (double-blind withdrawal): At visit 4, part of patients from Aliskiren arm received placebo for 1 day. The study ended at visit 5 (48 hours later than visit 4).
Period Title: Period II(Randomized,Double Blinded,8wk)
STARTED	257	0	249	0
Intent to Treat (ITT)	222	0	222	0
COMPLETED	247	0	241	0
NOT COMPLETED	10	0	8	0
Period Title: Period II(Randomized,Double Blinded,8wk)
STARTED	129	118	119	122
Per Protocol Missed-dose (PPMD)	98	73	93	82
COMPLETED	127	117	115	121
NOT COMPLETED	2	1	4	1

Baseline Characteristics

Arm/Group Title	Ramipril	Aliskiren	Total
Arm/Group Description	In period I (washout and single-blind): from visit 1 to visit 2, 2 weeks placebo run-in. In period II (double-blind treatment, randomized): Ramipril 5 mg for 4 weeks (visit 2 - visit 3). At visit 3, medications had to be titrated to Ramipril 10 mg only if BP remained ≥ 140/90 mmHg. Double blind treatment had to be continued for another 4-week period until visit 4. In period III (double-blind withdrawal): At visit 4, patients received placebo or the active treatment for 1 day. The study ended at visit 5 (48 hours later than visit 4).	In period I (washout and single-blind): from visit 1 to visit 2, 2 weeks placebo run-in. In period II (double-blind treatment, randomized): Aliskiren 150 mg for 4 weeks (visit 2 - visit 3). At visit 3, medications had to be titrated to aliskiren 300 mg only if BP remained ≥ 140/90 mmHg. Double blind treatment had to be continued for another 4-week period until visit 4. In period III (double-blind withdrawal): At visit 4, patients received placebo or the active treatment for 1 day. The study ended at visit 5 (48 hours later than visit 4).	Total of all reporting groups
Overall Participants	257	249	506
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.8 (11.6)	61.0 (11.4)	60.4 (11.5)
Age, Customized (Number) [Number]
< 50 years	56 21.8%	39 15.7%	95 18.8%
50 - 64 years	119 46.3%	115 46.2%	234 46.2%
65 - 74 years	56 21.8%	64 25.7%	120 23.7%
>= 75 years	26 10.1%	31 12.4%	57 11.3%
Sex: Female, Male (Count of Participants)
Female	142 55.3%	133 53.4%	275 54.3%
Male	115 44.7%	116 46.6%	231 45.7%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP)
Description	The arm in which the highest sitting systolic blood pressure (SBP) was found at study entry was used for all subsequent readings. At each study visit, after leaving the patient to rest 5 minutes in a sitting position, the blood pressure (BP) was measured three times with an oscillometric device. The measurements were performed at 1-2 minute intervals. The mean BP was calculated from the 3 readings. The analysis of covariance included treatment factor and baseline mean sitting SBP as covariable.
Time Frame	Baseline to 8 weeks

Outcome Measure Data

Analysis Population Description

Intent to treat population included all randomized patients who had received at least one dose of study drug. It also excluded all those patients from centers that reported more than 90% of BP measurements rounded to 0 or 5.

Arm/Group Title	Ramipril	Aliskiren
Arm/Group Description	In period I (washout and single-blind): from visit 1 to visit 2, 2 weeks placebo run-in. In period II (double-blind treatment, randomized): Ramipril 5 mg for 4 weeks (visit 2 - visit 3). At visit 3, medications had to be titrated to Ramipril 10 mg only if BP remained ≥ 140/90 mmHg. Double blind treatment had to be continued for another 4-week period until visit 4. In period III (double-blind withdrawal): At visit 4, patients received placebo or the active treatment for 1 day. The study ended at visit 5 (48 hours later than visit 4).	In period I (washout and single-blind): from visit 1 to visit 2, 2 weeks placebo run-in. In period II (double-blind treatment, randomized): Aliskiren 150 mg for 4 weeks (visit 2 - visit 3). At visit 3, medications had to be titrated to aliskiren 300 mg only if BP remained ≥ 140/90 mmHg. Double blind treatment had to be continued for another 4-week period until visit 4. In period III (double-blind withdrawal): At visit 4, patients received placebo or the active treatment for 1 day. The study ended at visit 5 (48 hours later than visit 4).
Measure Participants	213	213
Least Squares Mean (Standard Error) [mmHg]	-18.80 (0.92)	-20.78 (0.92)

2. Secondary Outcome

Title	Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP)
Description	The arm in which the highest sitting systolic blood pressure (SBP) was found at study entry was used for all subsequent readings. At each study visit, after leaving the patient to rest 5 minutes in a sitting position, the blood pressure (BP) was measured three times with an oscillometric device. The measurements were performed at 1-2 minute intervals. The mean BP was calculated from the 3 readings. The analysis of variance included treatment factor and baseline value of mean sitting DBP as covariable.
Time Frame	Baseline to 8 weeks

Outcome Measure Data

Analysis Population Description

Intent to treat population included all randomized patients who had received at least one dose of study drug. It also excluded all those patients from centers that reported more than 90% of BP measurements rounded to 0 or 5. Patients with observation at both time points were included in this analysis.

Arm/Group Title	Ramipril	Aliskiren
Arm/Group Description	In period I (washout and single-blind): from visit 1 to visit 2, 2 weeks placebo run-in. In period II (double-blind treatment, randomized): Ramipril 5 mg for 4 weeks (visit 2 - visit 3). At visit 3, medications had to be titrated to Ramipril 10 mg only if BP remained ≥ 140/90 mmHg. Double blind treatment had to be continued for another 4-week period until visit 4. In period III (double-blind withdrawal): At visit 4, patients received placebo or the active treatment for 1 day. The study ended at visit 5 (48 hours later than visit 4).	In period I (washout and single-blind): from visit 1 to visit 2, 2 weeks placebo run-in. In period II (double-blind treatment, randomized): Aliskiren 150 mg for 4 weeks (visit 2 - visit 3). At visit 3, medications had to be titrated to aliskiren 300 mg only if BP remained ≥ 140/90 mmHg. Double blind treatment had to be continued for another 4-week period until visit 4. In period III (double-blind withdrawal): At visit 4, patients received placebo or the active treatment for 1 day. The study ended at visit 5 (48 hours later than visit 4).
Measure Participants	213	213
Least Squares Mean (Standard Error) [mmHg]	-5.23 (0.60)	-6.39 (0.60)

3. Secondary Outcome

Title	Percentage of Patients With Controlled Blood Pressure
Description	The arm in which the highest sitting systolic blood pressure (SBP) was found at study entry was used for all subsequent readings. At each study visit, after leaving the patient to rest 5 minutes in a sitting position, the blood pressure (BP) was measured three times with an oscillometric device. The measurements were performed at 1-2 minute intervals. The mean BP was calculated from the 3 readings. Controlled blood pressure (BP) is defined as mean office systolic BP/ diastolic BP < 140/90 mmHg.
Time Frame	At 4 and 8 weeks

Outcome Measure Data

Analysis Population Description

Intent to treat population included all randomized patients who had received at least one dose of study drug. It also excluded all those patients from centers that reported more than 90% of BP measurements rounded to 0 or 5. Patients with observation at each time point were included in this analysis.

Arm/Group Title	Ramipril	Aliskiren
Arm/Group Description	In period I (washout and single-blind): from visit 1 to visit 2, 2 weeks placebo run-in. In period II (double-blind treatment, randomized): Ramipril 5 mg for 4 weeks (visit 2 - visit 3). At visit 3, medications had to be titrated to Ramipril 10 mg only if BP remained ≥ 140/90 mmHg. Double blind treatment had to be continued for another 4-week period until visit 4. In period III (double-blind withdrawal): At visit 4, patients received placebo or the active treatment for 1 day. The study ended at visit 5 (48 hours later than visit 4).	In period I (washout and single-blind): from visit 1 to visit 2, 2 weeks placebo run-in. In period II (double-blind treatment, randomized): Aliskiren 150 mg for 4 weeks (visit 2 - visit 3). At visit 3, medications had to be titrated to aliskiren 300 mg only if BP remained ≥ 140/90 mmHg. Double blind treatment had to be continued for another 4-week period until visit 4. In period III (double-blind withdrawal): At visit 4, patients received placebo or the active treatment for 1 day. The study ended at visit 5 (48 hours later than visit 4).
Measure Participants	222	222
At week 4 (N= 218, 217)	36.7	40.1
At week 8 (N= 213, 213)	26.8	32.4

4. Secondary Outcome

Title	Number of the Participants With More Than 55 mmHg Difference Between the Mean SBP Measured at the Morning Surge and the Mean Minimal SBP Measured During the Night
Description	Ambulatory blood pressure measurement (ABPM) over 24 hours was performed for all patients on the day before visit 4, the device attached to the ambulatory blood pressure non-dominant arm of the patient. The BP morning surge was defined as the average of the measurements taken during the first 2 hours after waking the patient. The minimal night blood pressure was defined as the average of the two lowest BP measures (the lowest hourly average) recorded during night time.
Time Frame	After 8 weeks

Outcome Measure Data

Analysis Population Description

Intent to treat population included all randomized patients who had received at least one dose of study drug. It also excluded all those patients from centers that reported more than 90% of BP measurements rounded to 0 or 5. Patients with ABPM to evaluate the occurrence or absence of a morning peak were included in this analysis.

Arm/Group Title	Ramipril	Aliskiren
Arm/Group Description	In period I (washout and single-blind): from visit 1 to visit 2, 2 weeks placebo run-in. In period II (double-blind treatment, randomized): Ramipril 5 mg for 4 weeks (visit 2 - visit 3). At visit 3, medications had to be titrated to Ramipril 10 mg only if BP remained ≥ 140/90 mmHg. Double blind treatment had to be continued for another 4-week period until visit 4. In period III (double-blind withdrawal): At visit 4, patients received placebo or the active treatment for 1 day. The study ended at visit 5 (48 hours later than visit 4).	In period I (washout and single-blind): from visit 1 to visit 2, 2 weeks placebo run-in. In period II (double-blind treatment, randomized): Aliskiren 150 mg for 4 weeks (visit 2 - visit 3). At visit 3, medications had to be titrated to aliskiren 300 mg only if BP remained ≥ 140/90 mmHg. Double blind treatment had to be continued for another 4-week period until visit 4. In period III (double-blind withdrawal): At visit 4, patients received placebo or the active treatment for 1 day. The study ended at visit 5 (48 hours later than visit 4).
Measure Participants	114	112
Number [Participants]	3 1.2%	9 3.6%

5. Secondary Outcome

Title	Change in msSBP and msDBP From Visit 2 (Baseline) to Visit 3 (at 4 Weeks)
Description	The arm in which the highest sitting systolic blood pressure (SBP) was found at study entry was used for all subsequent readings. At each study visit, after leaving the patient to rest 5 minutes in a sitting position, the blood pressure (BP) was measured three times with an oscillometric device. The measurements were performed at 1-2 minute intervals. The mean BP was calculated from the 3 readings. The analysis of covariance included treatment factor and baseline mean sitting SBP and mean sitting DBP as covariables.
Time Frame	Baseline to 4 weeks

Outcome Measure Data

Analysis Population Description

Intent to treat population included all randomized patients who had received at least one dose of study drug. It also excluded all those patients from centers that reported more than 90% of BP measurements rounded to 0 or 5.

Arm/Group Title	Ramipril	Aliskiren
Arm/Group Description	In period I (washout and single-blind): from visit 1 to visit 2, 2 weeks placebo run-in. In period II (double-blind treatment, randomized): Ramipril 5 mg for 4 weeks (visit 2 - visit 3). At visit 3, medications had to be titrated to Ramipril 10 mg only if BP remained ≥ 140/90 mmHg. Double blind treatment had to be continued for another 4-week period until visit 4. In period III (double-blind withdrawal): At visit 4, patients received placebo or the active treatment for 1 day. The study ended at visit 5 (48 hours later than visit 4).	In period I (washout and single-blind): from visit 1 to visit 2, 2 weeks placebo run-in. In period II (double-blind treatment, randomized): Aliskiren 150 mg for 4 weeks (visit 2 - visit 3). At visit 3, medications had to be titrated to aliskiren 300 mg only if BP remained ≥ 140/90 mmHg. Double blind treatment had to be continued for another 4-week period until visit 4. In period III (double-blind withdrawal): At visit 4, patients received placebo or the active treatment for 1 day. The study ended at visit 5 (48 hours later than visit 4).
Measure Participants	218	217
Change in msSBP	-19.42 (0.92)	-19.75 (0.92)
Change in msDBP	-5.37 (0.56)	-5.60 (0.56)

6. Secondary Outcome

Title	Difference Between the Maximal and the Minimal Mean-hour SPB Measured Between 1 and 8 am at Week 8
Description	Ambulatory blood pressure measurement (ABPM) over 24 hours was performed for all patients on the eve of visit 4 (week 8), the device attached to the ambulatory blood pressure non-dominant arm of the patient. The difference between mean-hour maximum SBP mean-hour minimum SBP between 1 am and 8 am was measured.
Time Frame	At week 8

Outcome Measure Data

Analysis Population Description

Intent to treat population included all randomized patients who had received at least one dose of study drug. It also excluded all those patients from centers that reported more than 90% of BP measurements rounded to 0 or 5. Patients with ABPM measurements over 24 hours were included in this analysis.

Arm/Group Title	Ramipril	Aliskiren
Arm/Group Description	In period I (washout and single-blind): from visit 1 to visit 2, 2 weeks placebo run-in. In period II (double-blind treatment, randomized): Ramipril 5 mg for 4 weeks (visit 2 - visit 3). At visit 3, medications had to be titrated to Ramipril 10 mg only if BP remained ≥ 140/90 mmHg. Double blind treatment had to be continued for another 4-week period until visit 4. In period III (double-blind withdrawal): At visit 4, patients received placebo or the active treatment for 1 day. The study ended at visit 5 (48 hours later than visit 4).	In period I (washout and single-blind): from visit 1 to visit 2, 2 weeks placebo run-in. In period II (double-blind treatment, randomized): Aliskiren 150 mg for 4 weeks (visit 2 - visit 3). At visit 3, medications had to be titrated to aliskiren 300 mg only if BP remained ≥ 140/90 mmHg. Double blind treatment had to be continued for another 4-week period until visit 4. In period III (double-blind withdrawal): At visit 4, patients received placebo or the active treatment for 1 day. The study ended at visit 5 (48 hours later than visit 4).
Measure Participants	175	186
Mean (Standard Deviation) [mmHg]	33.6 (14.04)	35.5 (15.05)

7. Secondary Outcome

Title	Change in Mean Sitting DBP and SBP in Specified Sub-groups From Visit 2 (Baseline) to Visit 4 (at 8 Weeks)
Description	The sub-groups were: "Riser" = patients with >= 55 mmHg difference between the mean SPB measured at the morning surge and the mean minimal SBP measured during the night. The "Non-risers" in whom the difference is <55 mmHg. Patients called "dippers" in whom there was a decrease in average nocturnal SBP ≥ 10% compared with average daytime SBP, in contrast to patients "non-dippers " in whom this difference was <10%.
Time Frame	Baseline to 8 weeks

Outcome Measure Data

Analysis Population Description

Intent to treat population included all randomized patients who had received at least one dose of study drug. It also excluded all those patients from centers that reported more than 90% of BP measurements rounded to 0 or 5. Patients with observation at different categories were included in this analysis.

Arm/Group Title	Ramipril	Aliskiren
Arm/Group Description	In period I (washout and single-blind): from visit 1 to visit 2, 2 weeks placebo run-in. In period II (double-blind treatment, randomized): Ramipril 5 mg for 4 weeks (visit 2 - visit 3). At visit 3, medications had to be titrated to Ramipril 10 mg only if BP remained ≥ 140/90 mmHg. Double blind treatment had to be continued for another 4-week period until visit 4. In period III (double-blind withdrawal): At visit 4, patients received placebo or the active treatment for 1 day. The study ended at visit 5 (48 hours later than visit 4).	In period I (washout and single-blind): from visit 1 to visit 2, 2 weeks placebo run-in. In period II (double-blind treatment, randomized): Aliskiren 150 mg for 4 weeks (visit 2 - visit 3). At visit 3, medications had to be titrated to aliskiren 300 mg only if BP remained ≥ 140/90 mmHg. Double blind treatment had to be continued for another 4-week period until visit 4. In period III (double-blind withdrawal): At visit 4, patients received placebo or the active treatment for 1 day. The study ended at visit 5 (48 hours later than visit 4).
Measure Participants	222	222
Change in msSBP: Risers (n= 3, 9)	-19.7 (6.11)	-16.9 (10.52)
Change in msSBP: Non-risers (n=109, 103)	-19.2 (13.99)	-20.5 (14.49)
Change in msSBP: Dippers (n= 80, 94)	-18.1 (11.86)	-19.8 (12.05)
Change in msSBP: Non-dippers (n= 93, 92)	-19.2 (14.93)	-21.1 (15.06)
Change in msDBP: Risers (n= 3, 9)	-7.3 (10.60)	-6.6 (9.11)
Change in msDBP: Non-risers(n=109, 103)	-4.2 (9.51)	-5.7 (9.61)
Change in msDBP: Dippers (n= 80, 94)	-5.5 (9.63)	-6.3 (9.81)
Change in msDBP: Non-dippers (n= 93, 92)	-5.3 (9.59)	-6.5 (9.56)

8. Secondary Outcome

Title	Change in Mean Sitting Systolic Blood Pressure (msSBP) and Mean Sitting Diastolic Blood Pressure (msDBP) From Last Active Dose Taken to After a One-day Missed-dose
Description	The change in blood pressure was measured between visit 4 (end of the period of double-blind active treatment which was at week 8) and visit 5 (48 hours after the last active dose taken) in the group of patients who received aliskiren or placebo and those who received ramipril or placebo. The analysis of covariance included treatment factor and baseline mean sitting SBP and mean sitting DBP as covariables.
Time Frame	From 8 weeks to 48 hours after week 8

Outcome Measure Data

Analysis Population Description

Per-protocol missed dose population included all per protocol population patients who had received the study treatment for period 3 according to the protocol (duration of period 3 and treatment intake). Patients with observation at both time points were included in this analysis.

Arm/Group Title	Ramipril	Placebo to Ramipril	Aliskiren	Placebo to Aliskiren
Arm/Group Description	In period I (washout and single-blind): from visit 1 to visit 2, 2 weeks placebo run-in. In period II (double-blind treatment, randomized): Ramipril 5 mg for 4 weeks (visit 2 - visit 3). At visit 3, medications had to be titrated to Ramipril 10 mg only if BP remained ≥ 140/90 mmHg. Double blind treatment had to be continued for another 4-week period until visit 4. In period III (double-blind withdrawal): At visit 4, patients received the active treatment for 1 day. The study ended at visit 5 (48 hours later than visit 4).	In period III (double-blind withdrawal): At visit 4, part of the patients from Ramipril arm received placebo to Ramipril for 1 day. The study ended at visit 5 (48 hours later than visit 4).	In period I (washout and single-blind): from visit 1 to visit 2, 2 weeks placebo run-in. In period II (double-blind treatment, randomized): Aliskiren 150 mg for 4 weeks (visit 2 - visit 3). At visit 3, medications had to be titrated to aliskiren 300 mg only if BP remained ≥ 140/90 mmHg. Double blind treatment had to be continued for another 4-week period until visit 4. In period III (double-blind withdrawal): At visit 4, part of patients received the active treatment for 1 day. The study ended at visit 5 (48 hours later than visit 4).	In period III (double-blind withdrawal): At visit 4, part of patients from Aliskiren arm received placebo for 1 day. The study ended at visit 5 (48 hours later than visit 4).
Measure Participants	95	73	88	81
Change in msSBP	-0.50 (1.05)	-1.28 (1.10)	0.52 (1.06)	3.27 (1.10)
Change in msDBP	0.76 (0.69)	0.32 (0.79)	-0.40 (0.78)	0.97 (0.81)

9. Secondary Outcome

Title	Number Patients Reported With Adverse Events (AEs), Serious Adverse Events (SAE) and Death (Period II and Period III)
Description	Adverse events are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards.
Time Frame	8 weeks + 1 day

Outcome Measure Data

Analysis Population Description

All randomized patients except one patient from Aliskiren arm who was lost to follow up after visit 2.

Arm/Group Title	Ramipril	Aliskiren
Arm/Group Description	In period I (washout and single-blind): from visit 1 to visit 2, 2 weeks placebo run-in. In period II (double-blind treatment, randomized): Ramipril 5 mg for 4 weeks (visit 2 - visit 3). At visit 3, medications had to be titrated to Ramipril 10 mg only if BP remained ≥ 140/90 mmHg. Double blind treatment had to be continued for another 4-week period until visit 4. In period III (double-blind withdrawal): At visit 4, patients received placebo or the active treatment for 1 day. The study ended at visit 5 (48 hours later than visit 4).	In period I (washout and single-blind): from visit 1 to visit 2, 2 weeks placebo run-in. In period II (double-blind treatment, randomized): Aliskiren 150 mg for 4 weeks (visit 2 - visit 3). At visit 3, medications had to be titrated to aliskiren 300 mg only if BP remained ≥ 140/90 mmHg. Double blind treatment had to be continued for another 4-week period until visit 4. In period III (double-blind withdrawal): At visit 4, patients received placebo or the active treatment for 1 day. The study ended at visit 5 (48 hours later than visit 4).
Measure Participants	257	248
Patients with at least 1 AE	55 21.4%	43 17.3%
Patients with at least 1 SAE	3 1.2%	1 0.4%
Death	0 0%	0 0%

Adverse Events

Time Frame	8 weeks of period II + 1 day of Period III
Adverse Event Reporting Description	The adverse events and serious adverse events are reported on randomized population except one patient who lost to follow up after visit 2.
Arm/Group Title	Ramipril (Period II and III)		Placebo to Ramipril (Period III)		Aliskiren (Period II and III)		Placebo to Aliskiren (Period III)
Arm/Group Description	In period I (washout and single-blind): from visit 1 to visit 2, 2 weeks placebo run-in. In period II (double-blind treatment, randomized): Ramipril 5 mg for 4 weeks (visit 2 - visit 3). At visit 3, medications had to be titrated to Ramipril 10 mg only if BP remained ≥ 140/90 mmHg. Double blind treatment had to be continued for another 4-week period until visit 4. In period III (double-blind withdrawal): At visit 4, patients received the active treatment for 1 day. The study ended at visit 5 (48 hours later than visit 4).		In period III (double-blind withdrawal): At visit 4, part of the patients from Ramipril arm received placebo to Ramipril for 1 day. The study ended at visit 5 (48 hours later than visit 4).		In period I (washout and single-blind): from visit 1 to visit 2, 2 weeks placebo run-in. In period II (double-blind treatment, randomized): Aliskiren 150 mg for 4 weeks (visit 2 - visit 3). At visit 3, medications had to be titrated to aliskiren 300 mg only if BP remained ≥ 140/90 mmHg. Double blind treatment had to be continued for another 4-week period until visit 4. In period III (double-blind withdrawal): At visit 4, part of patients received the active treatment for 1 day. The study ended at visit 5 (48 hours later than visit 4).		In period III (double-blind withdrawal): At visit 4, part of patients from Aliskiren arm received placebo for 1 day. The study ended at visit 5 (48 hours later than visit 4).
All Cause Mortality
	Ramipril (Period II and III)		Placebo to Ramipril (Period III)		Aliskiren (Period II and III)		Placebo to Aliskiren (Period III)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Ramipril (Period II and III)		Placebo to Ramipril (Period III)		Aliskiren (Period II and III)		Placebo to Aliskiren (Period III)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/257 (1.2%)		0/118 (0%)		1/248 (0.4%)		0/122 (0%)
Blood and lymphatic system disorders
normochromic normocytic anemia	0/257 (0%)		0/118 (0%)		1/248 (0.4%)		0/122 (0%)
Cardiac disorders
cardiac failure	0/257 (0%)		0/118 (0%)		1/248 (0.4%)		0/122 (0%)
atrial fibrillation	1/257 (0.4%)		0/118 (0%)		0/248 (0%)		0/122 (0%)
Gastrointestinal disorders
abdominal pain	1/257 (0.4%)		0/118 (0%)		0/248 (0%)		0/122 (0%)
General disorders
asthenia	1/257 (0.4%)		0/118 (0%)		0/248 (0%)		0/122 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
spine metastasis	0/257 (0%)		0/118 (0%)		1/248 (0.4%)		0/122 (0%)
bladder cancer	0/257 (0%)		0/118 (0%)		1/248 (0.4%)		0/122 (0%)
liver metastatis	0/257 (0%)		0/118 (0%)		1/248 (0.4%)		0/122 (0%)
pancreatic adenocarcinoma	1/257 (0.4%)		0/118 (0%)		0/248 (0%)		0/122 (0%)
Respiratory, thoracic and mediastinal disorders
dyspnea	1/257 (0.4%)		0/118 (0%)		0/248 (0%)		0/122 (0%)
Other (Not Including Serious) Adverse Events
	Ramipril (Period II and III)		Placebo to Ramipril (Period III)		Aliskiren (Period II and III)		Placebo to Aliskiren (Period III)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/257 (0%)		0/118 (0%)		0/248 (0%)		0/122 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.