Hypertension
Conditions
Keywords
children, pediatrics, high blood pressure, hypertension, valsartan, enalapril
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.
Interventions
DRUGValsartan
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.
DRUGEnalapril
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.
DRUGplacebo matched to enalapril
Placebo matched to enalapril. All study medications were taken orally once daily, at approximately the same time each day, with or without food.
DRUGplacebo matched to valsartan
placebo matched to valsartan. All study medications were taken orally once daily, at approximately the same time each day, with or without food.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
6 Years to 17 Years
Healthy volunteers
No
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/
Design outcomes
Primary
| Measure | 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
| Measure | Time frame | Description |
|---|---|---|
| Change in Mean Sitting Diastolic Blood Pressure (msDBP) From Baseline to Week 26 | Core Baseline (Week 0) 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. |
| Percentage of Non-CKD Patients Achieving Systolic and Diastolic BP Control at Week 26 | 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. |
| Change From Baseline in Post-dosing 24-hour Mean Systolic and Diastolic Ambulatory Blood Pressure at Week 20 | Core Baseline (Week 0) to 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. |
| Change in Mean Sitting Systolic Blood Pressure (msSBP) From Baseline to Week 26 | Core Baseline (Week 0) 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. |
Countries
Belgium, France, Germany, Hungary, India, Italy, Poland, Turkey (Türkiye), United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CKD Patients: Valsartan+Enalapril Chronic kidney disease (CKD) patients assigned to valsartan in the core study received combination therapy of valsartan and enalapril in the extension: Valsartan+enalapril (80/10, 160/20, 320/40 mg, weight stratified). All study medications were taken orally once daily, at approximately the same time each day, with or without food. | 21 |
| CKD Patients: Enalapril Chronic kidney disease (CKD) patients assigned to enalapril in the core study received enalapril and valsartan placebo in the extension: Enalapril (10, 20, 40, weight stratified) and matching placebo to valsartan (80, 160, 320 mg). All study medications were taken orally once daily, at approximately the same time each day, with or without food. | 17 |
| Non-CKD Patients: Valsartan Non-chronic kidney disease (CKD) patients assigned to valsartan in the core study continued their valsartan monotherapy treatment in the extension: Valsartan (80, 160, 320 mg, weight stratified)+enalapril placebo. All study medications were taken orally once daily, at approximately the same time each day, with or without food. | 103 |
| Non-CKD Patients: Enalapril Non-chronic kidney disease (CKD) patients assigned to enalapril in the core study continued their enalapril monotherapy treatment in the extension: Enalapril (10, 20, 40, weight stratified)+valsartan placebo. All study medications were taken orally once daily, at approximately the same time each day, with or without food. | 109 |
| Total | 250 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Administrative Problems | 3 | 0 | 4 | 1 |
| Overall Study | Adverse Event | 7 | 2 | 3 | 1 |
| Overall Study | Protocol Violation | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 3 |
Baseline characteristics
| Characteristic | CKD Patients: Valsartan+Enalapril | CKD Patients: Enalapril | Non-CKD Patients: Valsartan | Non-CKD Patients: Enalapril | Total |
|---|---|---|---|---|---|
| Age Continuous | 11.4 years STANDARD_DEVIATION 3.4 | 12.1 years STANDARD_DEVIATION 3.07 | 13.1 years STANDARD_DEVIATION 2.75 | 13.3 years STANDARD_DEVIATION 2.81 | 13.0 years STANDARD_DEVIATION 2.89 |
| Sex: Female, Male Female | 8 Participants | 5 Participants | 41 Participants | 27 Participants | 81 Participants |
| Sex: Female, Male Male | 13 Participants | 12 Participants | 62 Participants | 82 Participants | 169 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 14 / 21 | 25 / 103 | 11 / 17 | 42 / 109 |
| serious Total, serious adverse events | 7 / 21 | 1 / 103 | 0 / 17 | 2 / 109 |
Outcome results
Primary
Number of Patients With Adverse Events
Time frame: Start of extension (week 13) to end of study (Week 26 in non-CKD patients and Week 50 in CKD patients)
Population: Extension safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CKD Patients: Valsartan+Enalapril | Number of Patients With Adverse Events | 16 Participants |
| CKD Patients: Enalapril | Number of Patients With Adverse Events | 11 Participants |
| Non-CKD Patients: Valsartan | Number of Patients With Adverse Events | 51 Participants |
| Non-CKD Patients: Enalapril | Number of Patients With Adverse Events | 53 Participants |
Secondary
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.
Time frame: Core Baseline (Week 0) to Week 20
Population: ABPM population: All ITT patients who received the 24-hour ambulatory blood pressure monitoring (ABPM) measurements at both baseline and Week 20. Patients were excluded if their baseline ABPM was measured after active treatment dose (considered invalid baseline).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CKD Patients: Valsartan+Enalapril | Change From Baseline in Post-dosing 24-hour Mean Systolic and Diastolic Ambulatory Blood Pressure at Week 20 | Systolic BP | -23.3 mmHg | Standard Deviation 11.6 |
| CKD Patients: Valsartan+Enalapril | Change From Baseline in Post-dosing 24-hour Mean Systolic and Diastolic Ambulatory Blood Pressure at Week 20 | Diastolic BP | -17.8 mmHg | Standard Deviation 3.2 |
| CKD Patients: Enalapril | Change From Baseline in Post-dosing 24-hour Mean Systolic and Diastolic Ambulatory Blood Pressure at Week 20 | Systolic BP | -0.3 mmHg | Standard Deviation 14.42 |
| CKD Patients: Enalapril | Change From Baseline in Post-dosing 24-hour Mean Systolic and Diastolic Ambulatory Blood Pressure at Week 20 | Diastolic BP | 2.9 mmHg | Standard Deviation 10.81 |
| Non-CKD Patients: Valsartan | Change From Baseline in Post-dosing 24-hour Mean Systolic and Diastolic Ambulatory Blood Pressure at Week 20 | Systolic BP | -11.5 mmHg | Standard Deviation 7.81 |
| Non-CKD Patients: Valsartan | Change From Baseline in Post-dosing 24-hour Mean Systolic and Diastolic Ambulatory Blood Pressure at Week 20 | Diastolic BP | -12.2 mmHg | Standard Deviation 6.6 |
| Non-CKD Patients: Enalapril | Change From Baseline in Post-dosing 24-hour Mean Systolic and Diastolic Ambulatory Blood Pressure at Week 20 | Diastolic BP | -4.5 mmHg | Standard Deviation 7.59 |
| Non-CKD Patients: Enalapril | Change From Baseline in Post-dosing 24-hour Mean Systolic and Diastolic Ambulatory Blood Pressure at Week 20 | Systolic BP | -4.1 mmHg | Standard Deviation 11.49 |
Secondary
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.
Time frame: Core Baseline (Week 0) to Week 26
Population: Extension ITT population: All patients that had both baseline and at least 1 post-Week 12 assessment of any efficacy variable (sitting systolic/diastolic BP) during the extension. Baseline is the Week 0 value. Extension endpoint is the Week 26 or last observation after the core endpoint but before Week 26 carried forward value.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CKD Patients: Valsartan+Enalapril | Change in Mean Sitting Diastolic Blood Pressure (msDBP) From Baseline to Week 26 | -20.4 mmHg | Standard Deviation 11.48 |
| CKD Patients: Enalapril | Change in Mean Sitting Diastolic Blood Pressure (msDBP) From Baseline to Week 26 | -11.7 mmHg | Standard Deviation 9.55 |
| Non-CKD Patients: Valsartan | Change in Mean Sitting Diastolic Blood Pressure (msDBP) From Baseline to Week 26 | -7.5 mmHg | Standard Deviation 8.47 |
| Non-CKD Patients: Enalapril | Change in Mean Sitting Diastolic Blood Pressure (msDBP) From Baseline to Week 26 | -7.2 mmHg | Standard Deviation 8.99 |
Secondary
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.
Time frame: Core Baseline (Week 0) to Week 26
Population: Extension ITT population: All patients that had both baseline and at least 1 post-Week 12 assessment of any efficacy variable (sitting systolic/diastolic BP) during the extension. Baseline is the Week 0 value. Extension endpoint is the Week 26 or last observation after the core endpoint but before Week 26 carried forward value.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CKD Patients: Valsartan+Enalapril | Change in Mean Sitting Systolic Blood Pressure (msSBP) From Baseline to Week 26 | -23.6 mmHg | Standard Deviation 10.79 |
| CKD Patients: Enalapril | Change in Mean Sitting Systolic Blood Pressure (msSBP) From Baseline to Week 26 | -18.2 mmHg | Standard Deviation 9.51 |
| Non-CKD Patients: Valsartan | Change in Mean Sitting Systolic Blood Pressure (msSBP) From Baseline to Week 26 | -11.6 mmHg | Standard Deviation 9.74 |
| Non-CKD Patients: Enalapril | Change in Mean Sitting Systolic Blood Pressure (msSBP) From Baseline to Week 26 | -10.2 mmHg | Standard Deviation 9.7 |
Secondary
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.
Time frame: Week 26
Population: The extension ITT population consisted of all extension patients that had both baseline and at least one post-Week 12 assessment of any efficacy variable (sitting systolic/diastolic blood pressure) during the extension. Patients were analyzed according to the treatment they were assigned to at the beginning of their extension.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CKD Patients: Valsartan+Enalapril | Percentage of Non-CKD Patients Achieving Systolic and Diastolic BP Control at Week 26 | Systolic BP control | 66.0 Percentage of patients |
| CKD Patients: Valsartan+Enalapril | Percentage of Non-CKD Patients Achieving Systolic and Diastolic BP Control at Week 26 | Diastolic BP control | 95.1 Percentage of patients |
| CKD Patients: Enalapril | Percentage of Non-CKD Patients Achieving Systolic and Diastolic BP Control at Week 26 | Systolic BP control | 63.0 Percentage of patients |
| CKD Patients: Enalapril | Percentage of Non-CKD Patients Achieving Systolic and Diastolic BP Control at Week 26 | Diastolic BP control | 91.7 Percentage of patients |