Hypertension
Conditions
Keywords
Pediatric hypertension
Brief summary
This is a dose ranging study of candesartan cilexetil in hypertensive pediatric subjects ages 1 to less than 6 years of age. It employs a double blind, randomized, dose ranging design intended for conduct as a multicenter trial. There are 3 study 'periods': a 1-week placebo run-in, a 4-week double blind treatment, and a 52-week open-label, long-term treatment period. Subjects undergo a screening evaluation, then a 1-week single-blind, placebo run-in, after which eligible subjects are allocated to receive 1 of 3 dose levels of candesartan cilexetil (0.05 mg/kg, or 0.20 mg /kg or 0.40 mg /kg), liquid formulation, in a 1:1:1 ratio for 4-weeks. At the end of randomized dose allocation (Day 28), blood pressure assessment will be performed and subjects may begin the 52-week, open-label treatment period of the study.
Interventions
DRUGcandesartan cilexetil (Atacand)
0.05 mg/kg once daily oral liquid dose
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
1 Years to 6 Years
Healthy volunteers
No
Inclusion criteria
* Signed informed consent by a parent or a legal guardian. * Weight \> 10 kg and \< 40 kg. * SiSBP and/or SiDBP \> 95th percentile and \< 20 mm Hg (systolic) and/or 10 mm Hg (diastolic) above the 95th percentile at screening and at randomization based on height-adjusted charts for age and gender.
Exclusion criteria
* Any situation, clinical condition or laboratory abnormality that, in the opinion of the investigator or sponsor, may interfere with the subject's participation in the study or would pose a significant risk to the subject or interfere with the assessment of safety and efficacy endpoints. * Weight \< 10 kg and \> 40 kg. * Less than 80% compliance with study medication during single-blind placebo screening as assessed by residual medication volume. * Hypertension secondary to pheochromocytoma, hyperthyroidism, or Cushing's Syndrome. * Uncorrected coarctation of the aorta, bilateral renal artery renal artery stenosis in a single kidney. * Estimated glomerular filtration rate (GFR) \< 50 mL/min/1.73m 2 based on the Schwartz Formula (Schwartz et al, 1987). * Renal transplant \< 6 months prior to study entry. Subjects who have received a renal transplant \> 6 months prior to study entry may participate in the study if: 1) renal function is stable, 2) estimated GFR \>50 mL/min/1.73m 2, 3) stable doses of immunosuppressive medications are anticipated throughout the 4-week, double-blind period of the study, 4) no episodes of acute allograft rejection have occurred within 30 days of study entry, and 5) the renal allograft has no documented renal artery stenosis. Nephrotic syndrome not in remission. * Unstable insulin dependent diabetes mellitus. * Known bleeding, coagulation, or platelet disorder that could interfere with blood sampling. * Clinically significant valvular heart disease. * Clinical diagnosis of heart failure. * Clinically significant arrhythmia (eg, any arrhythmia requiring medical therapy or that causes symptoms). * Second or third degree AV block. * Impaired liver function defined as either acute liver disease or chronic liver disease with persistent liver enzyme values greater than 1½ times the upper limit of the reference range for aspartate aminotransferase (AST) or alanine aminotransferase (ALT). * Known hypersensitivity to ARBs. * Currently receiving an angiotensin receptor blocker or an angiotensin converting enzyme inhibitor that in the investigator's judgment cannot safely be withdrawn during the study. * Subjects receiving an angiotensin receptor blocker or an angiotensin converting enzyme inhibitor may be eligible if they undergo withdrawal of the antihypertensive medication over a 2-week washout period and subsequently meet BP inclusion/
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Mean Change From Baseline to Week 4 in Systolic Blood Pressure (SBP) | From randomisation to end of double-blind treatment (4 weeks) |
Secondary
| Measure | Time frame |
|---|---|
| Mean Change From Baseline to Week 4 in Diastolic Blood Pressure (DBP) | From randomisation to end of double-blind treatment (4 weeks) |
| Change in Albumin/Creatinine (A/C) Ratio for Each Assigned Dose Level From Baseline to Day 28 | From randomisation to day 28 |
| Change in Protein/Creatinine (P/C) Ratio for Each Assigned Dose Level From Baseline to Day 28 | From randomisation to day 28 |
Countries
Belgium, Denmark, France, Germany, Italy, Poland, Puerto Rico, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
The study population included male and female participants 1 to \<6 years of age with mild to moderate hypertension. The participants were recruited during the time period from 04 November 2004 to 07 August 2008 at pediatric clinics in the USA, Puerto Rico and Europe.
Pre-assignment details
One to 2 weeks following a screening evaluation, participants underwent a 1-week, single-blind, placebo run-in period to reduce the variability in the baseline blood pressure measurements and to stabilize any concurrent antihypertensive medications.
Participants by arm
| Arm | Count |
|---|---|
| Atacand .05 mg candesartan cilexetil (Atacand) 0.05 mg/kg once daily oral liquid dose | 29 |
| Atacand .20 mg candesartan cilexetil (Atacand) 0.20 mg/kg once daily oral liquid dose | 32 |
| Atacand .40 mg candesartan cilexetil (Atacand) 0.40 mg/kg once daily oral liquid dose | 32 |
| Total | 93 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Double-blind Treatment Period | Lack of Efficacy | 0 | 1 | 0 |
| Double-blind Treatment Period | Lost to Follow-up | 0 | 0 | 1 |
| Double-blind Treatment Period | Multiple Reasons | 2 | 1 | 1 |
| Double-blind Treatment Period | Withdrawal by Subject | 0 | 1 | 0 |
| Open-label Treatment Period | Adverse Event | 0 | 0 | 1 |
| Open-label Treatment Period | Lost to Follow-up | 0 | 1 | 0 |
| Open-label Treatment Period | Moved abroad | 0 | 0 | 1 |
| Open-label Treatment Period | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Atacand .05 mg | Atacand .20 mg | Atacand .40 mg | Total |
|---|---|---|---|---|
| Age, Customized 1 to <2 years | 6 Participants | 5 Participants | 5 Participants | 16 Participants |
| Age, Customized 2 to <6 years | 23 Participants | 27 Participants | 27 Participants | 77 Participants |
| Sex: Female, Male Female | 11 Participants | 10 Participants | 12 Participants | 33 Participants |
| Sex: Female, Male Male | 18 Participants | 22 Participants | 20 Participants | 60 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 29 | 0 / 32 | 0 / 32 |
| serious Total, serious adverse events | 6 / — | 5 / — | 4 / — |
Outcome results
Primary
Mean Change From Baseline to Week 4 in Systolic Blood Pressure (SBP)
Time frame: From randomisation to end of double-blind treatment (4 weeks)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Atacand .05 mg | Mean Change From Baseline to Week 4 in Systolic Blood Pressure (SBP) | -6.0 mm Hg | Standard Deviation 9.4 |
| Atacand .20 mg | Mean Change From Baseline to Week 4 in Systolic Blood Pressure (SBP) | -8.9 mm Hg | Standard Deviation 9.2 |
| Atacand .40 mg | Mean Change From Baseline to Week 4 in Systolic Blood Pressure (SBP) | -12.0 mm Hg | Standard Deviation 8.3 |
Secondary
Change in Albumin/Creatinine (A/C) Ratio for Each Assigned Dose Level From Baseline to Day 28
Time frame: From randomisation to day 28
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Atacand .05 mg | Change in Albumin/Creatinine (A/C) Ratio for Each Assigned Dose Level From Baseline to Day 28 | -11.1 Percent change |
| Atacand .20 mg | Change in Albumin/Creatinine (A/C) Ratio for Each Assigned Dose Level From Baseline to Day 28 | -40.6 Percent change |
| Atacand .40 mg | Change in Albumin/Creatinine (A/C) Ratio for Each Assigned Dose Level From Baseline to Day 28 | -50.0 Percent change |
Secondary
Change in Protein/Creatinine (P/C) Ratio for Each Assigned Dose Level From Baseline to Day 28
Time frame: From randomisation to day 28
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Atacand .05 mg | Change in Protein/Creatinine (P/C) Ratio for Each Assigned Dose Level From Baseline to Day 28 | 0.0 Percent change |
| Atacand .20 mg | Change in Protein/Creatinine (P/C) Ratio for Each Assigned Dose Level From Baseline to Day 28 | -29.2 Percent change |
| Atacand .40 mg | Change in Protein/Creatinine (P/C) Ratio for Each Assigned Dose Level From Baseline to Day 28 | 0.0 Percent change |
Secondary
Mean Change From Baseline to Week 4 in Diastolic Blood Pressure (DBP)
Time frame: From randomisation to end of double-blind treatment (4 weeks)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Atacand .05 mg | Mean Change From Baseline to Week 4 in Diastolic Blood Pressure (DBP) | -5.2 mm Hg | Standard Deviation 6.7 |
| Atacand .20 mg | Mean Change From Baseline to Week 4 in Diastolic Blood Pressure (DBP) | -7.9 mm Hg | Standard Deviation 12.9 |
| Atacand .40 mg | Mean Change From Baseline to Week 4 in Diastolic Blood Pressure (DBP) | -11.1 mm Hg | Standard Deviation 9.2 |