Hypertension
Conditions
Keywords
Hypertension/*etiology, Blood Pressure, Pediatric, Adolescent, Child
Brief summary
The primary purpose of this study is to evaluate the blood pressure lowering effects of ramipril, an FDA-approved drug for the treatment of hypertension in adults, in children and adolescents aged 6 to 16 years with hypertension.
Detailed description
Information is needed on the treatment of hypertension in children and adolescents with antihypertensive drugs like ramipril. The study will assess the safety and blood pressure effects of several doses of the antihypertensive drug ramipril in children and adolescents age 6-16 years. Approximately 450 children will be given placebo, or 1 of the 3 doses of ramipril. The treatment assigned will be done by chance, like flipping a coin. Approximately 120 study centers throughout the world will participate in the trial. Each child will complete a 1- to 4-week Screening Period where they will stop taking their current blood pressure lowering drug(s), a 4-week Treatment Period where they will receive placebo or one of the ramipril doses, and a Follow-up visit 1 week after completion of the Treatment Period. Children diagnosed with hypertension according to the fourth report on the diagnosis, evaluation and treatment of high blood pressure in children and adolescents (U.S. report), will be included in the study if their blood pressure meets certain values. Each child will complete a minimum of 6 and up to 9 clinic visits over the course of the study during which procedures and assessments of blood pressure and safety will be performed. In addition, a child's parents/guardians will be instructed to measure their child's blood pressure at home between clinic visits. A planned interim analysis was performed after approximately 240 subjects completed the trial. The study was stopped, as permitted by protocol, after the analysis.
Interventions
DRUGramipril
once a day oral ramipril capsules given for 4 weeks
DRUGplacebo
once a day oral placebo capsule for 4 weeks
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Years to 16 Years
Healthy volunteers
No
Inclusion criteria
1. Previous, documented diagnosis of hypertension, or newly diagnosed hypertension according to the fourth report on the diagnosis, evaluation and treatment of high blood pressure in children and adolescents (United States). SiSBP greater than or equal to the 95th percentile for age, gender, and height. 2. The subject can be safely withdrawn from antihypertensive medications during the screening period, and if given placebo during the treatment period in the judgment of the Investigator. 3. The subject is male or female age 6 to 16 years (inclusive), and weighs greater than or equal to 20 kg. 4. Female subjects greater than or equal to 12 years of age, or who have had greater than or equal to 1 menstruation must: (a) have a negative serum pregnancy test at screening (i.e., subject is not pregnant), (b) not be lactating, and (c) use an acceptable method of contraception. 5. Parents/guardians are able to demonstrate their ability to (a) use a home blood pressure monitor supplied for the study to monitor their child's blood pressure, and (2) mix and administer a liquid dose of study drug if needed.
Exclusion criteria
1. Bilateral renal artery stenosis. 2. Uncorrected coarctation of the aorta or corrected coarctation with a right arm/right leg blood pressure gradient greater than 10 mmHg. 3. Severe hypertension. 4. Renal transplantation or other previous solid organ transplantation less than 6 months prior to entering the study. 5. Subjects with nephrotic syndrome not on stable maintenance therapy of prednisone or cyclosporine. 6. A history of cardiomyopathy, clinically significant structural heart disease, or atrioventricular conduction disturbance, sick sinus syndrome, atrial flutter, atrial fibrillation, clinically significant bradycardia or an accessory bypass tract, or clinical symptoms of congestive heart failure. 7. Clinically significant hematologic, hepatobiliary, or renal disease including a Schwartz formula GFR less than 40 mL/min/1.73 m2, and/or serum potassium (K+) greater than 5.5 mEq/L. 8. History of pancreatitis (active or inactive). 9. Known sensitivity to angiotensin converting enzyme inhibitors or a history of angioneurotic edema.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to 4 Weeks in Trough Sitting Systolic Blood Pressure | Baseline to 4 weeks | Value at end of treatment minus value at baseline, comparing the high-dose ramipril group with placebo |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to 4 Weeks in Trough Sitting Diastolic Blood Pressure | Baseline to 4 weeks | Value at end of treatment minus value at baseline, comparing the high-dose ramipril group with placebo |
| Change From Baseline to 4 Weeks in Serum Creatinine | Baseline up to 4 weeks | Value at end of treatment (up to 4 weeks) minus value at baseline |
| Change From Baseline to 4 Weeks in Serum Potassium | Baseline up to 4 weeks | Value at end of treatment (up to 4 weeks) minus value at baseline |
| Change From Baseline to 4 Weeks in Schwartz Formula Glomerular Filtration Rate (GFR) | Baseline up to 4 weeks | Value at end of treatment (up to 4 weeks) minus value at baseline; GFR is a measure of kidney function. |
Countries
Argentina, Chile, Colombia, India, Poland, South Africa, Turkey (Türkiye), Ukraine, United States
Participant flow
Recruitment details
Study was conducted from October 2006 to November 2007 at 56 international sites
Pre-assignment details
Subjects entered placebo run-in prior to randomization
Participants by arm
| Arm | Count |
|---|---|
| Placebo | 81 |
| Ramipril Low Dose | 41 |
| Ramipril Mid Dose | 40 |
| Ramipril High Dose | 80 |
| Total | 242 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Placebo Run-In | Did not meet blood pressure criteria | 119 | 0 | 0 | 0 |
| Placebo Run-In | Reason not specified | 40 | 0 | 0 | 0 |
| Placebo Run-In | Withdrawal by Subject | 19 | 0 | 0 | 0 |
| Randomized | Did not receive study drug | 2 | 0 | 0 | 0 |
| Treated | Adverse Event | 1 | 0 | 0 | 2 |
| Treated | Reason not specified | 1 | 1 | 0 | 2 |
Baseline characteristics
| Characteristic | Placebo | Ramipril Low Dose | Ramipril Mid Dose | Ramipril High Dose | Total |
|---|---|---|---|---|---|
| Age Continuous | 12.2 years STANDARD_DEVIATION 3.06 | 12.3 years STANDARD_DEVIATION 3.03 | 12.1 years STANDARD_DEVIATION 2.81 | 12.3 years STANDARD_DEVIATION 3.06 | 12.2 years STANDARD_DEVIATION 2.99 |
| Race/Ethnicity, Customized Asian | 8 participants | 1 participants | 4 participants | 10 participants | 23 participants |
| Race/Ethnicity, Customized Black | 21 participants | 11 participants | 10 participants | 20 participants | 62 participants |
| Race/Ethnicity, Customized Caucasian | 27 participants | 15 participants | 13 participants | 29 participants | 84 participants |
| Race/Ethnicity, Customized Hispanic | 25 participants | 14 participants | 13 participants | 20 participants | 72 participants |
| Race/Ethnicity, Customized Other | 0 participants | 0 participants | 0 participants | 1 participants | 1 participants |
| Sex: Female, Male Female | 32 Participants | 16 Participants | 11 Participants | 29 Participants | 88 Participants |
| Sex: Female, Male Male | 49 Participants | 25 Participants | 29 Participants | 51 Participants | 154 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 | 11 / 81 | 8 / 41 | 6 / 40 | 12 / 80 |
| serious Total, serious adverse events | 0 / 81 | 1 / 41 | 1 / 40 | 0 / 80 |
Outcome results
Primary
Change From Baseline to 4 Weeks in Trough Sitting Systolic Blood Pressure
Value at end of treatment minus value at baseline, comparing the high-dose ramipril group with placebo
Time frame: Baseline to 4 weeks
Population: Intent to treat (ITT) analysis including only treated participants who had at least one post-baseline assessment (1 placebo patient was treated but had no post-baseline assessment); last observation carried forward (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to 4 Weeks in Trough Sitting Systolic Blood Pressure | -8.1 mm Hg | Standard Deviation 7.92 |
| Ramipril Low Dose | Change From Baseline to 4 Weeks in Trough Sitting Systolic Blood Pressure | -9.7 mm Hg | Standard Deviation 10.68 |
| Ramipril Mid Dose | Change From Baseline to 4 Weeks in Trough Sitting Systolic Blood Pressure | -11.1 mm Hg | Standard Deviation 8.88 |
| Ramipril High Dose | Change From Baseline to 4 Weeks in Trough Sitting Systolic Blood Pressure | -11.3 mm Hg | Standard Deviation 8.76 |
Comparison: Planned interim efficacy analysis: 80 placebo and 80 high-dose ramipril subjects provided 93% power, alpha=0.032, to detect 5 mmHg difference in primary outcome. SD of 8.5 mmHg assumed. Alpha of 0.032 required for the planned interim efficacy analysis.~If study continued: 450 total subjects would provide 90% power, alpha=0.027, to detect 3 mmHg difference between placebo and combined ramipril dose groups. Alpha of 0.027 required for the final analysis.p-value: 0.044ANCOVA
Secondary
Change From Baseline to 4 Weeks in Schwartz Formula Glomerular Filtration Rate (GFR)
Value at end of treatment (up to 4 weeks) minus value at baseline; GFR is a measure of kidney function.
Time frame: Baseline up to 4 weeks
Population: Number of participants analyzed is less than number treated in the participant flow section because analysis includes only treated participants who had both a baseline and a post-baseline assessment; LOCF
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to 4 Weeks in Schwartz Formula Glomerular Filtration Rate (GFR) | -4.2 mL/min per 1.73 m2 | Standard Deviation 27.85 |
| Ramipril Low Dose | Change From Baseline to 4 Weeks in Schwartz Formula Glomerular Filtration Rate (GFR) | -6.0 mL/min per 1.73 m2 | Standard Deviation 24.74 |
| Ramipril Mid Dose | Change From Baseline to 4 Weeks in Schwartz Formula Glomerular Filtration Rate (GFR) | -5.9 mL/min per 1.73 m2 | Standard Deviation 26.29 |
| Ramipril High Dose | Change From Baseline to 4 Weeks in Schwartz Formula Glomerular Filtration Rate (GFR) | -6.9 mL/min per 1.73 m2 | Standard Deviation 30.58 |
Secondary
Change From Baseline to 4 Weeks in Serum Creatinine
Value at end of treatment (up to 4 weeks) minus value at baseline
Time frame: Baseline up to 4 weeks
Population: Number of participants analyzed is less than number treated in the participant flow section because analysis includes only treated participants who had both a baseline and a post-baseline assessment; LOCF
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to 4 Weeks in Serum Creatinine | 0.04 mg/dL | Standard Deviation 0.305 |
| Ramipril Low Dose | Change From Baseline to 4 Weeks in Serum Creatinine | 0.06 mg/dL | Standard Deviation 0.275 |
| Ramipril Mid Dose | Change From Baseline to 4 Weeks in Serum Creatinine | 0.03 mg/dL | Standard Deviation 0.133 |
| Ramipril High Dose | Change From Baseline to 4 Weeks in Serum Creatinine | 0.06 mg/dL | Standard Deviation 0.211 |
Secondary
Change From Baseline to 4 Weeks in Serum Potassium
Value at end of treatment (up to 4 weeks) minus value at baseline
Time frame: Baseline up to 4 weeks
Population: Number of participants analyzed is less than number treated in the participant flow section because analysis includes only treated participants who had both a baseline and a post-baseline assessment; LOCF
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to 4 Weeks in Serum Potassium | 0.01 mg/dL | Standard Deviation 0.742 |
| Ramipril Low Dose | Change From Baseline to 4 Weeks in Serum Potassium | -0.20 mg/dL | Standard Deviation 0.475 |
| Ramipril Mid Dose | Change From Baseline to 4 Weeks in Serum Potassium | -0.08 mg/dL | Standard Deviation 0.418 |
| Ramipril High Dose | Change From Baseline to 4 Weeks in Serum Potassium | 0.07 mg/dL | Standard Deviation 0.559 |
Secondary
Change From Baseline to 4 Weeks in Trough Sitting Diastolic Blood Pressure
Value at end of treatment minus value at baseline, comparing the high-dose ramipril group with placebo
Time frame: Baseline to 4 weeks
Population: Intent to treat (ITT) analysis including only treated participants who had at least one post-baseline assessment (1 placebo patient was treated but had no post-baseline assessment); last observation carried forward (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to 4 Weeks in Trough Sitting Diastolic Blood Pressure | -5.0 mm Hg | Standard Deviation 10.04 |
| Ramipril Low Dose | Change From Baseline to 4 Weeks in Trough Sitting Diastolic Blood Pressure | -5.8 mm Hg | Standard Deviation 10.17 |
| Ramipril Mid Dose | Change From Baseline to 4 Weeks in Trough Sitting Diastolic Blood Pressure | -6.1 mm Hg | Standard Deviation 8.03 |
| Ramipril High Dose | Change From Baseline to 4 Weeks in Trough Sitting Diastolic Blood Pressure | -8.4 mm Hg | Standard Deviation 9.14 |
p-value: 0.006ANCOVA