E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hypertensive pediatric subjects (1 to <6 years of age) |
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MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to characterize the dose response relationship of candesartan cilexetil (once-daily) in hypertensive pediatric subjects (1 to <6 years of age) by evaluation of the slope of the linear regression for the change in trough SiSBP from baseline (Day 0) to the end of the 4-week double-blind treatment period (Day 28) as a function of dose. |
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E.2.2 | Secondary objectives of the trial |
Dose response relationship of Atacand for the change in trough SiSBP from baseline to the end of the double-blind treatment period as a function of dose for each of the 2 body weight panels
Dose response relationship of Atacand for the change in trough SiDBP, SuSBP, and SuDBP from baseline to the end of the double-blind treatment period as a function of dose
Mean change in trough SiSBP, SuSBP, SiDBP, and SuDBP for Atacand from baseline to the end of the double-blind treatment period
Change in urinary protein/creatinine and urinary albumin/creatinine ratio from baseline to the end of the double-blind treatment period and to the end of the open-label treatment period
Safety as assessed by adverse events, adverse events that necessitate study drug discontinuation, serious adverse events, physical exam findings, ECG, and laboratory tests during the double-blind treatment period and the open-label treatment period
Pharmacokinetics
Medication adherence
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
For study inclusion, subjects must fulfill all eligibility criteria
1) Signed informed consent by a parent or a legal guardian
2) Age 1 to less than 6 years
3) Weight ≥10 kg and ≤ 40 kg
4) 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 heightadjusted charts for age and gender (Appendices C through H). The blood pressure values that determine eligibility at screening and randomization are based on the average of three SiSBP measurements within a 7 mmHg range (consecutive or non-consecutive) in the arm with the higher BP measurement. Up to a maximum of six blood pressure measurements may be obtained to achieve the three SiSBP values within the 7 mmHg range. |
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E.4 | Principal exclusion criteria |
The following exclude subjects from study participation:
1) 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
2) Weight < 10 kg and > 40 kg
3) Less than 80% compliance with study medication during single-blind placebo screening as assessed by residual medication volume
4) Hypertension secondary to pheochromocytoma, hyperthyroidism, or Cushing’s syndrome
5) Uncorrected coarctation of the aorta, bilateral renal artery stenosis, or unilateral renal artery stenosis in a single kidney
6) Estimated glomerular filtration rate (GFR) < 30 mL/min/1.73m2 for non-transplant patients and < 40 mL/min/1.73m2 for transplant patients based on the Schwartz Formula (Schwartz et al, 1987)
7) 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 ≥40 mL/min/1.73m2, 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
8) Nephrotic syndrome not in remission
9) Unstable insulin dependent diabetes mellitus
10) Known bleeding, coagulation, or platelet disorder that could interfere with blood sampling
11) Clinically significant valvular heart disease
12) Clinical diagnosis of heart failure
13) Clinically significant arrhythmia (eg, any arrhythmia requiring medical therapy or that causes symptoms)
14) Second or third degree AV block
15) 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)
16) Known hypersensitivity to ARBs
17) Currently receiving an angiotensin receptor blocker or an angiotensin converting enzyme inhibitor that in the investigator’s judgement 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/exclusion criteria.
Subjects currently receiving other classes of antihypertensive medications (eg, diuretics, calcium channel blockers or beta-blockers) and whose BP values meet inclusion/exclusion criteria may participate in the study while continuing their current antihypertensive medication regimen. Up to 2 concomitant antihypertensive medications are permitted. Doses and dose regimens of concomitant antihypertensive medications must remain unchanged during the 4-week double-blind period of the study.
18) Currently using, or used within 14 days prior to receiving double-blind medication, any concomitant medications which in the opinion of the investigator could negatively affect the subject
19) Unable or unwilling to comply with the study requirements including blood sampling and swallowing study drug suspension
20) Received an investigational agent within 30 days prior to receiving study medication
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint of this study is the slope of linear regression for the change in trough SiSBP from baseline (Day 0) to the end of the 4-week double-blind treatment period (Day 28) as a function of dose for subjects 1 to less than 6 years of age with hypertension based on the ITT population.
Safety endpoints include
1) Incidence of AEs 2) Incidence of discontinuations due to any AE 3) SAEs 4) Heart rate and change in heart rate 5) Clinical laboratory test results 6) Physical examination and ECG findings 7) Height/Length, Weight, and Head circumference (in children of age <24 months at study entry) 8) Echocardiogram findings
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Medication adherence of patients to candesartan cilexetil & Paediatric Quality Of Life-Questionnaire |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
3 groups with different doses of candesartan cilexetil |
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E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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End of study is definded as date of database lock which is the timepoint after which no patient will be exposed to study-related activities. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 11 |