Extension Study to Assess Long Term Safety, Tolerability, and Efficacy of Valsartan and Enalapril Combined and Alone in Children With Hypertension

Study Overview
=================
Brief Summary
-----------------
The purpose of this extension study is to compare the long-term safety of valsartan versus enalapril, and the effectiveness of the combination of valsartan and enalapril versus enalapril alone in children with hypertension.

Official Title
-----------------
An Extension to Study Protocol CVAL489K2302 to Evaluate the Long Term Safety, Tolerability and Efficacy of Valsartan in Children 6 to 17 Years of Age With Hypertension, Versus Enalapril Treatment for 14 Weeks, or Combined With Enalapril Versus Enalapril for 66 Weeks in Chronic Kidney Disease Patients.

Conditions
-----------------
Hypertension

Intervention / Treatment
-----------------
* Drug: Valsartan
* Drug: Enalapril
* Drug: placebo matched to enalapril
* Drug: placebo matched to valsartan


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Successful completion of 12 weeks of double-blind treatment in core protocol CVAL489K2302. Patients participating in study CVAL489K2302 who may have discontinued prematurely due to uncontrolled hypertension defined as MSSBP > 20%, but < 25% above the 95th percentile for age, gender, and height after visit 5, qualifies a patient for entry into this extension study. Exclusion Criteria: Renal artery stenosis. Current diagnosis of heart failure (NYHA Class II-IV). Second or third degree heart block without a pacemaker. Concurrent potentially life threatening arrhythmia or symptomatic arrhythmia. Clinically significant valvular heart disease. Patient that demonstrates clinically significant ECG abnormalities other than those associated with left ventricular hypertrophy and AV block controlled with a pacemaker. Previous solid organ transplantation except renal, liver or heart transplantation. Renal, liver or heart transplant must have occurred at least 6 months prior to enrollment. Patient must be on stable doses of immunosuppressive therapy for 3 months and deemed clinically stable by the investigator. Patients who experienced any adverse events considered serious and drug related in protocol CVAL489K2302. Other protocol-defined inclusion/exclusion criteria applied to the study.

Ages Eligible for Study
-----------------
Minimum Age: 6 Years
Maximum Age: 17 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CKD patients: Valsartan+enalapril<br> | Drug: Valsartan<br>* Valsartan (80, 160, and 320 mg, weight stratified). All study medications were taken orally once daily, at approximately the same time each day, with or without food.<br>Drug: Enalapril<br>* Enalapril (10, 20, and 40 mg, weight stratified). All study medications were taken orally once daily, at approximately the same time each day, with or without food.<br>|
| Active Comparator: CKD patients: Enalapril<br> | Drug: Enalapril<br>* Enalapril (10, 20, and 40 mg, weight stratified). All study medications were taken orally once daily, at approximately the same time each day, with or without food.<br>Drug: placebo matched to valsartan<br>* placebo matched to valsartan. All study medications were taken orally once daily, at approximately the same time each day, with or without food.<br>|
| Experimental: Non-CKD patients: Valsartan<br> | Drug: Valsartan<br>* Valsartan (80, 160, and 320 mg, weight stratified). All study medications were taken orally once daily, at approximately the same time each day, with or without food.<br>Drug: placebo matched to enalapril<br>* Placebo matched to enalapril. All study medications were taken orally once daily, at approximately the same time each day, with or without food.<br>|
| Active Comparator: Non-CKD patients: Enalapril<br> | Drug: Enalapril<br>* Enalapril (10, 20, and 40 mg, weight stratified). All study medications were taken orally once daily, at approximately the same time each day, with or without food.<br>Drug: placebo matched to valsartan<br>* placebo matched to valsartan. All study medications were taken orally once daily, at approximately the same time each day, with or without food.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Adverse Events |  | Start of extension (week 13) to end of study (Week 26 in non-CKD patients and Week 50 in CKD patients) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Mean Sitting Diastolic Blood Pressure (msDBP) From Baseline to Week 26 | After the patient had been sitting for 5 minutes, with the back supported and both feet placed on the floor, systolic and diastolic blood pressures were measured 3 times using a calibrated standard sphygmomanometer and appropriate size cuff. The repeat sitting measurements were made at 1-2 minute intervals and the mean of these 3 sitting blood pressure measurements was used as the average sitting blood pressure for that visit. A negative number indicates lowered blood pressure. | Core Baseline (Week 0) to Week 26 | 
| Percentage of Non-CKD Patients Achieving Systolic and Diastolic BP Control at Week 26 | Systolic and diastolic blood pressure (BP) control was defined as msSBP and msDBP < 95th percentile for gender, age, and height. After the patient had been sitting for 5 minutes, with the back supported and both feet placed on the floor, systolic and diastolic blood pressures were measured 3 times using a calibrated standard sphygmomanometer and appropriate size cuff. The repeat sitting measurements were made at 1-2 minute intervals and the mean of these 3 sitting blood pressure measurements was used as the average sitting blood pressure for that visit. | Week 26 | 
| Change From Baseline in Post-dosing 24-hour Mean Systolic and Diastolic Ambulatory Blood Pressure at Week 20 | 24-hour ambulatory blood pressure monitoring (ABPM) was conducted once during the extension in a subset of patients at selected centers. For all patients who completed a qualifying ABPM at baseline, an ABPM was to be performed at Week 20. The ABPM monitor was placed on the non-dominant arm. | Core Baseline (Week 0) to Week 20 | 
| Change in Mean Sitting Systolic Blood Pressure (msSBP) From Baseline to Week 26 | After the patient had been sitting for 5 minutes, with the back supported and both feet placed on the floor, systolic and diastolic blood pressures were measured 3 times using a calibrated standard sphygmomanometer and appropriate size cuff. The repeat sitting measurements were made at 1-2 minute intervals and the mean of these 3 sitting blood pressure measurements was used as the average sitting blood pressure for that visit. A negative number indicates lowered blood pressure. | Core Baseline (Week 0) to Week 26 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
children, pediatrics, high blood pressure, hypertension, valsartan, enalapril