Clinical Trial Results:
A multicenter, randomized, double-blind, parallel-group, evaluation of 12 weeks of valsartan compared to enalapril on sitting systolic blood pressure in children 6 to 17 years of age with hypertension
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Summary
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EudraCT number |
2006-005260-88 |
Trial protocol |
BE FR DE HU SE CZ PL IT SK GB |
Global end of trial date |
17 Feb 2009
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Results information
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Results version number |
v1(current) |
This version publication date |
13 Jul 2016
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First version publication date |
27 Jul 2015
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
CVAL489K2302
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00433836 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Novartis Pharma AG
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Sponsor organisation address |
CH-4002, Basel, Switzerland,
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Public contact |
Clinical Disclosure Office, Novartis Pharma AG, 41 613241111 ,
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Scientific contact |
Clinical Disclosure Office, Novartis Pharma AG, 41 613241111 ,
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
17 Feb 2009
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
17 Feb 2009
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective of this 12-week study was to evaluate the safety and efficacy of three different dose strengths of valsartan (80/160/320 milligrams [mg]) compared with enalapril (10/20/40 mg) on mean sitting systolic blood pressure (MSSBP) in hypertensive children aged 6 to 17 years, with or without chronic kidney disease.
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Protection of trial subjects |
The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
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Background therapy |
- | ||
Evidence for comparator |
Enalapril, an angiotensin-converting-enzyme (ACE) inhibitor, is approved in most European Union (EU) countries for the treatment of hypertension in children aged 2 months – 16 years based on its well-established pharmacokinetics, and on efficacy and safety data in 6 – 16 year old children. Enalapril was used as an active-comparator in this study as it is also dosed once daily, similar to experimental study treatment - valsartan. | ||
Actual start date of recruitment |
31 Jan 2007
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Slovakia: 2
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Country: Number of subjects enrolled |
Sweden: 1
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Country: Number of subjects enrolled |
Belgium: 29
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Country: Number of subjects enrolled |
France: 4
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Country: Number of subjects enrolled |
Germany: 8
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Country: Number of subjects enrolled |
Hungary: 72
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Country: Number of subjects enrolled |
Italy: 6
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Country: Number of subjects enrolled |
Poland: 90
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Country: Number of subjects enrolled |
United States: 45
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Country: Number of subjects enrolled |
Turkey: 14
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Country: Number of subjects enrolled |
India: 29
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Worldwide total number of subjects |
300
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EEA total number of subjects |
212
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
93
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Adolescents (12-17 years) |
207
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
The study was conducted at 60 centres in 11 countries. | |||||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
A total of 348 subjects were enrolled into a single-blind placebo-run in period of the study, out of which 300 subjects completed the single-blind period and were randomized. | |||||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Data analyst, Assessor | |||||||||||||||||||||||||||||||||
Blinding implementation details |
The identity of the treatments was concealed by the use of study drugs that were all identical in packaging, labeling and schedule. Unblinding was allowed only in case of subjects emergencies and at the conclusion of the study.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Valsartan | |||||||||||||||||||||||||||||||||
Arm description |
Subjects received body-weight stratified dose of valsartan tablets (80/160/ 320 mg) once daily through oral route (PO). Subjects whose body weight was greater than (≥ ) 18 kilogram (kg) and less than (<) 35 kg received 80 mg; ≥ 35 kg and < 80 kg received 160 mg and ≥ 80 kg and less than or equal to (≤) 160 kg received 320 mg of valsartan. | |||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Valsartan
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Investigational medicinal product code |
VAL489
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Other name |
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Pharmaceutical forms |
Coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Weight stratified dosages of valsartan 80/160/320 mg once daily PO
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Investigational medicinal product name |
Valsartan
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Investigational medicinal product code |
VAL489
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Other name |
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Pharmaceutical forms |
Coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Weight stratified dosages of valsartan 80/160/320 mg once daily PO
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Arm title
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Enalapril | |||||||||||||||||||||||||||||||||
Arm description |
Subjects received body-weight stratified dose of enalapril tablets (10/20/ 40 mg) once daily PO. Subjects whose body weight was ≥ 18 kg and < 35 kg received 10 mg; ≥ 35 kg and < 80 kg received 20 mg, and ≥ 80 kg and ≤ 160 kg received 40 mg of enalapril. | |||||||||||||||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Enalapril
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Weight stratified dosages of enalapril 10/20/40 mg once daily PO
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Baseline characteristics reporting groups
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Reporting group title |
Valsartan
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Reporting group description |
Subjects received body-weight stratified dose of valsartan tablets (80/160/ 320 mg) once daily through oral route (PO). Subjects whose body weight was greater than (≥ ) 18 kilogram (kg) and less than (<) 35 kg received 80 mg; ≥ 35 kg and < 80 kg received 160 mg and ≥ 80 kg and less than or equal to (≤) 160 kg received 320 mg of valsartan. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Enalapril
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Reporting group description |
Subjects received body-weight stratified dose of enalapril tablets (10/20/ 40 mg) once daily PO. Subjects whose body weight was ≥ 18 kg and < 35 kg received 10 mg; ≥ 35 kg and < 80 kg received 20 mg, and ≥ 80 kg and ≤ 160 kg received 40 mg of enalapril. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Valsartan
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Reporting group description |
Subjects received body-weight stratified dose of valsartan tablets (80/160/ 320 mg) once daily through oral route (PO). Subjects whose body weight was greater than (≥ ) 18 kilogram (kg) and less than (<) 35 kg received 80 mg; ≥ 35 kg and < 80 kg received 160 mg and ≥ 80 kg and less than or equal to (≤) 160 kg received 320 mg of valsartan. | ||
Reporting group title |
Enalapril
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Reporting group description |
Subjects received body-weight stratified dose of enalapril tablets (10/20/ 40 mg) once daily PO. Subjects whose body weight was ≥ 18 kg and < 35 kg received 10 mg; ≥ 35 kg and < 80 kg received 20 mg, and ≥ 80 kg and ≤ 160 kg received 40 mg of enalapril. | ||
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End point title |
Change From Baseline in Mean Sitting Systolic Blood Pressure (MSSBP) at Week 12 | ||||||||||||
End point description |
Sitting blood pressure was measured using a calibrated standard sphygmomanometer after the subject remained in sitting position for 5 minutes at clinic during the visit. The repeat sitting measurements were made at 1-2 minute intervals and the mean of three sitting systolic blood pressure (SSBP) measurements were used as the average sitting office blood pressure for that visit. Analysis was performed in Intent-to-Treat (ITT) population defined as all randomized subjects who had both baseline and at least one post-baseline assessment of any efficacy variable.
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End point type |
Primary
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End point timeframe |
Baseline, Week 12
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Statistical analysis title |
Change from baseline in MSSBP at Week 12 | ||||||||||||
Statistical analysis description |
LS mean, 95% CI and p-value for the difference between valsartan and enalapril were based on the ANCOVA model with region, weight, CKD and treatment as factors, and baseline mean sitting SBP as a covariate.
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Comparison groups |
Valsartan v Enalapril
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Number of subjects included in analysis |
296
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [1] | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Least Square Mean Difference | ||||||||||||
Point estimate |
-1.3
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Confidence interval |
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95% | ||||||||||||
sides |
2-sided
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lower limit |
-3.8 | ||||||||||||
upper limit |
1.17 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
1.26
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| Notes [1] - Non-inferiority margin used in the non-inferiority test was 3.5 mmHg. |
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End point title |
Change From Baseline in Mean Sitting Diastolic Blood Pressure (MSDBP) at Week 12 | ||||||||||||
End point description |
Sitting blood pressure was measured using a calibrated standard sphygmomanometer after the subject remained in sitting position for 5 minutes at clinic during the visit. The repeat sitting measurements were made at 1-2 minute intervals and the mean of three sitting diastolic blood pressure (SDBP) measurements were used as the average sitting office blood pressure for that visit. Analysis was performed in ITT population.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 12
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End point title |
Percentage of subjects achieving a treatment response at Week 12 | ||||||||||||
End point description |
Treatment response or systolic BP control was defined as 'Yes' for subjects whose MSSBP decreased to <95th percentile for gender, age, and height after 12 weeks treatment with valsartan compared to enalapril. Analysis was performed in ITT population.
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End point type |
Secondary
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End point timeframe |
Week 12
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change from baseline in post-dosing 24-hour mean ambulatory systolic and diastolic blood pressure (ASBP, ADBP) at Week 8 | ||||||||||||||||||
End point description |
Ambulatory Blood Pressure Monitoring (ABPM) was performed over a 24-hour period using an automatic ABPM device to record the blood pressure as per study defined criteria. The subjects who were selected for this evaluation wore the ABPM device for 24 hours, returned to the clinic upon completion of the 24-hour monitoring period for removal of device and BP assessments. The patient were then administered with the study medication while in the clinic. Analysis was performed in ABPM set defined as subset of ITT subjects from selected centers who consented to undergo ABPM at baseline and at Week 8.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 8
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| No statistical analyses for this end point | |||||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit
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Adverse event reporting additional description |
Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
12.0
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Reporting groups
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Reporting group title |
Valsartan
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Reporting group description |
Subjects received body-weight stratified dose of valsartan tablets (80/160/ 320 mg) once daily PO. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Enalapril
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Reporting group description |
Subjects received body-weight stratified dose of enalapril tablets (10/20/ 40 mg) once daily PO. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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26 Jun 2007 |
1. The definition of chronic kidney disease was corrected from glomerular filtration rate (GFR) <60 mL/min/1.73m^2 for ≥ 3 months, to GFR <90 mL/min/1.73m^2 for ≥ 3 months
2. The second ABPM was done at Week 8 instead of at end of study
3. The eligibility criterion that excluded subjects with creatinine clearance <30 mL/min/1.73m^2 was corrected to GFR <30 mL/min/1.73m^2
4. Added graft renal artery stenosis to the exclusion criteria
5. Allowed enrollment of subjects with electrocardiogram abnormalities associated with left ventricular hypertrophy
6. Added coarctation of the aorta with a gradient of ≥ 30 mmHg to the exclusion criteria
7. Specifically excluded subjects known to have tested seropositive for the human immunodeficiency virus (HIV) and concomitantly receiving anti-retroviral therapy
8. Stated that the study medication would be packaged in blister packs, not bottles.
9. Changed the dosing from q.d. to o.d.
10. Added potassium sparing diuretics, potassium supplements, potassium containing salt substitutes and/or other medications which raise the serum potassium to the list of prohibited concomitant medications.
11. Stipulated that patients with a decrease from baseline in estimated GFR >50% or serum potassium level >5.5 mmol/L had to be discontinued.
12. Added that patients with acute dehydration were to have their study medication temporarily interrupted until they had been fully hydrated for at least 3 days.
13. The section describing SAE reporting was updated to state that suspected, unexpected serious adverse reactions (SUSARs) were to be collected and reported to the competent authorities and relevant ethics committees in accordance with directive 2001/20/EC as per National regulatory requirements in participating countries.
14. Added a second ECG to the end of study evaluations.
15. Added hemoglobin, hematocrit and WBC count to Visit 5 evaluations for CKD patients |
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30 Sep 2008 |
1. Additional steps for monitoring of serum potassium, renal function and liver function were included.
2. The responsibilities of the External Safety Monitoring Committee (ESMC), a committee independent of Novartis, were added to the protocol. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
