An Extension Study to Evaluate the Long Term Safety, Tolerability and Efficacy of Aliskiren Compared to Enalapril in Pediatric Hypertensive Patients 6-17 Years of Age

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01151410
• Collaborator: (none)
• Enrollment: 208
• Locations: 36
• Arms: 2
• Duration (Months): 60
• Patients Per Site: 5.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate in a randomized, double-blind fashion, the long-term safety, tolerability and efficacy profile of aliskiren compared to the active comparator enalapril in children, 6 - 17 years old with hypertension (msSBP ≥ 95th percentile for age, gender and height, at baseline in study CSPP100A2365). Patients will be randomized to receive either aliskiren or enalapril. Weight-group based doses of aliskiren or enalapril will be administered once daily and children will receive study medication in a double-blind manner. This study is being conducted to support monotherapy registration of aliskiren for the treatment of hypertension in pediatric patients 6-17 years of age (age at baseline in Study CSPP100A2365).

Condition or Disease	Intervention/Treatment	Phase
Hypertension	Drug: Aliskiren; Drug: Enalapril	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 208 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Double-blind, Randomized, 52-week, Extension Study to Evaluate the Long Term Safety, Tolerability and Efficacy of Aliskiren Compared to Enalapril in Pediatric Hypertensive Patients 6-17 Years of Age
• Study Start Date: Aug 1, 2010
• Actual Primary Completion Date: Aug 1, 2015
• Actual Study Completion Date: Aug 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Aliskiren Patients will receive one of the following doses based on the their weight: Low weight (≥20 to <50 kg) patients: Starting dose 37.5 mg with optional titration to 75 and then 150 mg Mid weight (≥50 to <80 kg) patients: Starting dose 75 mg with optional titration to 150 and then 300 mg High weight (≥80 to ≤150 kg) patients: Starting dose 150 mg with optional titration to 300 and then 600 mg	Drug: Aliskiren; Low weight patients: Starting dose 37.5 mg with optional titration to 75 and then 150 mg Mid weight patients: Starting dose 75 mg with optional titration to 150 and then 300 mg High weight patients: Starting dose 150 mg with optional titration to 300 and then 600 mg
Active Comparator: Enalapril Patients will receive one of the following doses based on their weight: Low weight (≥20 to <50 kg) patients: Starting dose 2.5 mg with optional titration to 5 and then 10 mg Mid weight (≥50 to <80 kg) patients: Starting dose 5 mg with optional titration to 10 and then 20 mg High weight (≥80 to ≤150 kg) patients: Starting dose 10 mg with optional titration to 20 and then 40 mg	Drug: Enalapril; Low weight patients: Starting dose 2.5 mg with optional titration to 5 and then 10 mg Mid weight patients: Starting dose 5 mg with optional titration to 10 and then 20 mg High weight patients: Starting dose 10 mg with optional titration to 20 and then 40 mg

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) at to End of Study [Baseline - end of study (Week 52 or Last observation carried forward (LOCF)]

   Sitting blood pressure was measured using a calibrated standard sphygmomanometer after the participants remained in sitting position for 5 minutes at clinic during the visit. The repeat sitting measurements were made at 2 to 3 minute intervals and the mean of three sSBP measurements were used as the average sitting office blood pressure for that visit.

Secondary Outcome Measures

1. Change in Mean Sitting Diastolic Blood Pressure (msDBP) From Baseline to End of Study [Baseline - end of study (Week 52 or Last observation carried forward (LOCF)]

   Sitting blood pressure was measured using a calibrated standard sphygmomanometer after the participants remained in sitting position for 5 minutes at clinic during the visit. The repeat sitting measurements were made at 2 to 3 minute intervals and the mean of three sDBP measurements were used as the average sitting office blood pressure for that visit.

2. Change in Mean Arterial Pressure (MAP) (mmHg) From Baseline to End of Study [Baseline to end of study (Week 52 or LOCF)]

   MAP was defined as the average arterial pressure during a single cardiac cycle. The MAP was measured as sum of diastolic blood pressure (DBP) and one third of difference between systolic blood pressure (SBP) and DBP i.e. MAP = DBP+1/3*(SBP--DBP).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• msSBP (mean of 3 systolic blood pressure measurements) must be ≥ 95th percentile for age, gender and height, at Visit 2 (randomization), in study CSPP100A2365

• Must be ≥ 20 kg and ≤ 150 kg at Visit 2 (randomization), in study CSPP100A2365

• Must be able to swallow minitablets (2mm in diameter) administered in soft food

• Successful completion of Phase 1 (dose response phase) and at least 1 week of Phase 2 (placebo withdrawal phase) of the CSPP100A2365 protocol, with no serious drug-related adverse event(s).

Exclusion Criteria:

• Patient receiving immunosuppressant medication (e.g. cyclosporine, MMF, etc) other than oral/topical steroids, for any medical condition

• Current diagnosis of heart failure (NYHA Class II-IV) or history of cardiomyopathy or obstructive valvular disease

• msSBP ≥ 25% above the 95th percentile

• Second or third degree heart block without a pacemaker

• AST/SGOT or ALT/SGPT >3 times the upper limit of the reference range

• Total bilirubin > 2 times the upper limit of the reference range

• Creatinine clearance < 30 mL/min/1.73m² (calculated using Modified Schwartz formula to estimate glomerular filtration rate [GFR]), based on the serum creatinine concentration obtained at the screening visit)

• WBC count < 3000/mm³

• Platelet count < 100,000/mm³

• Serum potassium > 5.2 mEq/L

• Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Birmingham	Alabama	United States	35294-0006
2	Novartis Investigative Site	Little Rock	Arkansas	United States	72202
3	Novartis Investigative Site	Los Angeles	California	United States	90048
4	Novartis Investigative Site	Dalton	Georgia	United States	30721
5	Novartis Investigative Site	Lewiston	Idaho	United States	83501
6	Novartis Investigative Site	Park Ridge	Illinois	United States	60068
7	Novartis Investigative Site	Louisville	Kentucky	United States	40202
8	Novartis Investigative Site	Hattiesburg	Mississippi	United States	39401
9	Novartis Investigative Site	Jackson	Mississippi	United States	39209
10	Novartis Investigative Site	New York	New York	United States	10016
11	Novartis Investigative Site	Columbus	Ohio	United States	43205
12	Novartis Investigative Site	Toledo	Ohio	United States	43606
13	Novartis Investigative Site	Portland	Oregon	United States	07227
14	Novartis Investigative Site	Portland	Oregon	United States	97225
15	Novartis Investigative Site	Charleston	South Carolina	United States	29425
16	Novartis Investigative Site	Amarillo	Texas	United States	79106
17	Novartis Investigative Site	Charleston	West Virginia	United States	25304
18	Novartis Investigative Site	Guatemala City		Guatemala	01010
19	Novartis Investigative Site	Budapest		Hungary	1083
20	Novartis Investigative Site	Budapest		Hungary	1131
21	Novartis Investigative Site	Debrecen		Hungary	4032
22	Novartis Investigative Site	Miskolc		Hungary	3529
23	Novartis Investigative Site	Nyiregyhaza		Hungary	4400
24	Novartis Investigative Site	Szeged		Hungary	6725
25	Novartis Investigative Site	Veszprem		Hungary	H-8200
26	Novartis Investigative Site	Warszawa		Poland	04-154
27	Novartis Investigative Site	San Juan		Puerto Rico	00907
28	Novartis Investigative Site	Bratislava		Slovakia	84103
29	Novartis Investigative Site	Bratislava		Slovakia	85107
30	Novartis Investigative Site	Martin		Slovakia	03601
31	Novartis Investigative Site	Myjava		Slovakia	90701
32	Novartis Investigative Site	Presov		Slovakia	08001
33	Novartis Investigative Site	Trnava		Slovakia	91701
34	Novartis Investigative Site	Ankara		Turkey	06100
35	Novartis Investigative Site	Ankara		Turkey	06490
36	Novartis Investigative Site	Ankara		Turkey	06500

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01151410
• Other Study ID Numbers: CSPP100A2365E1; 2009-017029-20
• First Posted: Jun 28, 2010
• Last Update Posted: Mar 7, 2016
• Last Verified: Jan 1, 2016

• Keywords provided by Novartis Pharmaceuticals: Pediatric hypertension; primary hypertension; secondary; hypertension
• Additional relevant MeSH terms: Hypertension; Enalapril

Study Results

Participant Flow

Arm/Group Title	Aliskiren	Enalapril
Arm/Group Description	Patients will receive one of the following doses based on the their weight: Low weight (≥20 to <50 kg) patients: Starting dose 37.5 mg with optional titration to 75 and then 150 mg Mid weight (≥50 to <80 kg) patients: Starting dose 75 mg with optional titration to 150 and then 300 mg High weight (≥80 to ≤150 kg) patients: Starting dose 150 mg with optional titration to 300 and then 600 mg	Patients will receive one of the following doses based on their weight: Low weight (≥20 to <50 kg) patients: Starting dose 2.5 mg with optional titration to 5 and then 10 mg Mid weight (≥50 to <80 kg) patients: Starting dose 5 mg with optional titration to 10 and then 20 mg High weight (≥80 to ≤150 kg) patients: Starting dose 10 mg with optional titration to 20 and then 40 mg
Period Title: Overall Study
STARTED	104	104
Safety Set (SAF)	105	103
COMPLETED	93	89
NOT COMPLETED	11	15

Baseline Characteristics

Arm/Group Title	Aliskiren	Enalapril	Total
Arm/Group Description	Patients will receive one of the following doses based on the their weight: Low weight (≥20 to <50 kg) patients: Starting dose 37.5 mg with optional titration to 75 and then 150 mg Mid weight (≥50 to <80 kg) patients: Starting dose 75 mg with optional titration to 150 and then 300 mg High weight (≥80 to ≤150 kg) patients: Starting dose 150 mg with optional titration to 300 and then 600 mg	Patients will receive one of the following doses based on their weight: Low weight (≥20 to <50 kg) patients: Starting dose 2.5 mg with optional titration to 5 and then 10 mg Mid weight (≥50 to <80 kg) patients: Starting dose 5 mg with optional titration to 10 and then 20 mg High weight (≥80 to ≤150 kg) patients: Starting dose 10 mg with optional titration to 20 and then 40 mg	Total of all reporting groups
Overall Participants	104	104	208
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	11.7 (3.40)	11.9 (3.40)	11.8 (3.39)
Age, Customized (participants) [Number]
Children 6 - 11 years	50 48.1%	51 49%	101 48.6%
Adolescents 12 - 17 years	54 51.9%	53 51%	107 51.4%
Sex: Female, Male (Count of Participants)
Female	40 38.5%	32 30.8%	72 34.6%
Male	64 61.5%	72 69.2%	136 65.4%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) at to End of Study
Description	Sitting blood pressure was measured using a calibrated standard sphygmomanometer after the participants remained in sitting position for 5 minutes at clinic during the visit. The repeat sitting measurements were made at 2 to 3 minute intervals and the mean of three sSBP measurements were used as the average sitting office blood pressure for that visit.
Time Frame	Baseline - end of study (Week 52 or Last observation carried forward (LOCF)

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomized patients for this trial

Arm/Group Title	Aliskiren	Enalapril
Arm/Group Description	Patients will receive one of the following doses based on the their weight: Low weight (≥20 to <50 kg) patients: Starting dose 37.5 mg with optional titration to 75 and then 150 mg Mid weight (≥50 to <80 kg) patients: Starting dose 75 mg with optional titration to 150 and then 300 mg High weight (≥80 to ≤150 kg) patients: Starting dose 150 mg with optional titration to 300 and then 600 mg	Patients will receive one of the following doses based on their weight: Low weight (≥20 to <50 kg) patients: Starting dose 2.5 mg with optional titration to 5 and then 10 mg Mid weight (≥50 to <80 kg) patients: Starting dose 5 mg with optional titration to 10 and then 20 mg High weight (≥80 to ≤150 kg) patients: Starting dose 10 mg with optional titration to 20 and then 40 mg
Measure Participants	104	104
Least Squares Mean (Standard Error) [millimeter(s) of mercury (mmHg)]	-7.63 (1.16)	-7.94 (1.14)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aliskiren, Enalapril
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Indicates statistical significance at 0.025 level for one sided non-inferiority testing at 4mmHg margin.
Statistical Test of Hypothesis	p-Value	0.0040
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.31
	Confidence Interval	(1-Sided) 95%; -2.40 to
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change in Mean Sitting Diastolic Blood Pressure (msDBP) From Baseline to End of Study
Description	Sitting blood pressure was measured using a calibrated standard sphygmomanometer after the participants remained in sitting position for 5 minutes at clinic during the visit. The repeat sitting measurements were made at 2 to 3 minute intervals and the mean of three sDBP measurements were used as the average sitting office blood pressure for that visit.
Time Frame	Baseline - end of study (Week 52 or Last observation carried forward (LOCF)

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomized patients for this trial

Arm/Group Title	Aliskiren	Enalapril
Arm/Group Description	Patients will receive one of the following doses based on the their weight: Low weight (≥20 to <50 kg) patients: Starting dose 37.5 mg with optional titration to 75 and then 150 mg Mid weight (≥50 to <80 kg) patients: Starting dose 75 mg with optional titration to 150 and then 300 mg High weight (≥80 to ≤150 kg) patients: Starting dose 150 mg with optional titration to 300 and then 600 mg	Patients will receive one of the following doses based on their weight: Low weight (≥20 to <50 kg) patients: Starting dose 2.5 mg with optional titration to 5 and then 10 mg Mid weight (≥50 to <80 kg) patients: Starting dose 5 mg with optional titration to 10 and then 20 mg High weight (≥80 to ≤150 kg) patients: Starting dose 10 mg with optional titration to 20 and then 40 mg
Measure Participants	104	104
Least Squares Mean (Standard Error) [mmHg]	-3.90 (0.87)	-4.94 (0.85)

3. Secondary Outcome

Title	Change in Mean Arterial Pressure (MAP) (mmHg) From Baseline to End of Study
Description	MAP was defined as the average arterial pressure during a single cardiac cycle. The MAP was measured as sum of diastolic blood pressure (DBP) and one third of difference between systolic blood pressure (SBP) and DBP i.e. MAP = DBP+1/3*(SBP--DBP).
Time Frame	Baseline to end of study (Week 52 or LOCF)

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomized patients for this trial

Arm/Group Title	Aliskiren	Enalapril
Arm/Group Description	Patients will receive one of the following doses based on the their weight: Low weight (≥20 to <50 kg) patients: Starting dose 37.5 mg with optional titration to 75 and then 150 mg Mid weight (≥50 to <80 kg) patients: Starting dose 75 mg with optional titration to 150 and then 300 mg High weight (≥80 to ≤150 kg) patients: Starting dose 150 mg with optional titration to 300 and then 600 mg	Patients will receive one of the following doses based on their weight: Low weight (≥20 to <50 kg) patients: Starting dose 2.5 mg with optional titration to 5 and then 10 mg Mid weight (≥50 to <80 kg) patients: Starting dose 5 mg with optional titration to 10 and then 20 mg High weight (≥80 to ≤150 kg) patients: Starting dose 10 mg with optional titration to 20 and then 40 mg
Measure Participants	104	104
Least Squares Mean (Standard Error) [mmHg]	-5.15 (0.89)	-5.95 (0.87)

Adverse Events

Arm/Group Title	Aliskiren		Enalapril
Arm/Group Description	Patients will receive one of the following doses based on the their weight: Low weight (≥20 to <50 kg) patients: Starting dose 37.5 mg with optional titration to 75 and then 150 mg Mid weight (≥50 to <80 kg) patients: Starting dose 75 mg with optional titration to 150 and then 300 mg High weight (≥80 to ≤150 kg) patients: Starting dose 150 mg with optional titration to 300 and then 600 mg		Patients will receive one of the following doses based on their weight: Low weight (≥20 to <50 kg) patients: Starting dose 2.5 mg with optional titration to 5 and then 10 mg Mid weight (≥50 to <80 kg) patients: Starting dose 5 mg with optional titration to 10 and then 20 mg High weight (≥80 to ≤150 kg) patients: Starting dose 10 mg with optional titration to 20 and then 40 mg
All Cause Mortality
	Aliskiren		Enalapril
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Aliskiren		Enalapril
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/105 (2.9%)		12/103 (11.7%)
Blood and lymphatic system disorders
Lymphadenopathy	0/105 (0%)		1/103 (1%)
Cardiac disorders
Tachycardia	1/105 (1%)		0/103 (0%)
Gastrointestinal disorders
Paraesthesia oral	0/105 (0%)		1/103 (1%)
General disorders
Chest pain	1/105 (1%)		1/103 (1%)
Device malfunction	0/105 (0%)		1/103 (1%)
Infections and infestations
Appendicitis	2/105 (1.9%)		1/103 (1%)
Gastroenteritis	1/105 (1%)		0/103 (0%)
Viral infection	0/105 (0%)		1/103 (1%)
Injury, poisoning and procedural complications
Concussion	0/105 (0%)		1/103 (1%)
Dislocation of vertebra	0/105 (0%)		1/103 (1%)
Head injury	0/105 (0%)		1/103 (1%)
Skull fractured base	0/105 (0%)		1/103 (1%)
Investigations
Weight decreased	0/105 (0%)		1/103 (1%)
Metabolism and nutrition disorders
Tetany	0/105 (0%)		1/103 (1%)
Nervous system disorders
Headache	1/105 (1%)		0/103 (0%)
Paraesthesia	0/105 (0%)		1/103 (1%)
Psychiatric disorders
Abnormal behaviour	0/105 (0%)		1/103 (1%)
Psychosomatic disease	0/105 (0%)		1/103 (1%)
Renal and urinary disorders
Nephrolithiasis	0/105 (0%)		1/103 (1%)
Urethral stenosis	0/105 (0%)		1/103 (1%)
Other (Not Including Serious) Adverse Events
	Aliskiren		Enalapril
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	52/105 (49.5%)		51/103 (49.5%)
Gastrointestinal disorders
Vomiting	8/105 (7.6%)		5/103 (4.9%)
General disorders
Pyrexia	6/105 (5.7%)		5/103 (4.9%)
Infections and infestations
Bronchitis	5/105 (4.8%)		7/103 (6.8%)
Nasopharyngitis	8/105 (7.6%)		6/103 (5.8%)
Pharyngitis	7/105 (6.7%)		2/103 (1.9%)
Upper respiratory tract infection	15/105 (14.3%)		15/103 (14.6%)
Viral infection	10/105 (9.5%)		8/103 (7.8%)
Nervous system disorders
Headache	7/105 (6.7%)		15/103 (14.6%)
Respiratory, thoracic and mediastinal disorders
Cough	8/105 (7.6%)		9/103 (8.7%)
Oropharyngeal pain	6/105 (5.7%)		7/103 (6.8%)

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 (ie, data from all sites) in the clinical trial.