E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10020772 |
E.1.2 | Term | Hypertension |
E.1.2 | System Organ Class | 10047065 - Vascular disorders |
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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 |
(1) To define a dose-response relationship for losartan in hypertensive children aged 6 months to 6 years, after a 21-day open-label treatment period (response assessed by change from baseline in mean trough SBP).
(2) To investigate the safety and tolerability of losartan at doses up to 1.4 mg/kg/day in hypertensive children aged 6 months to 6 years after 12 weeks of treatment.
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E.2.2 | Secondary objectives of the trial |
(1) To define a dose-response relationship for losartan in hypertensive children aged 6 months to 6 years, after a 21-day open-label treatment period (response as assessed by change from baseline in mean trough DBP).
(2) To estimate the change from baseline in SBP in each dose regimen by Day 21.
(3) To estimate the change from baseline in DBP in each dose regimen by Day 21.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patient is male or female from 6 months to 6 years of age. (Patient has not reached 7th birthday at time of randomization).
Patient age refers to chronological age not corrected age as in the prematurely born
infant population
2. Patient is determined to be hypertensive according to one of the following criteria:
Patient is 6 months to <1 year old with a mean systolic blood pressure ≥ 95th
percentile based on gender and age.
OR
Patient is ≥1 year old with a mean systolic and/or diastolic blood pressure ≥ 95th
percentile based on gender, height and age.
OR
Patient has co-morbidities or evidence of end organ damage with:
a. mean systolic blood pressure ≥ 90th percentile (6 month to <1 year old) based on
gender and age.
OR
b. mean systolic and/or diastolic blood pressure ≥ 90th percentile (≥1 year old)
based on gender, height, and age.
3. Informed parental consent has been obtained. Patient assent (when feasible) has been obtained as required by local regulations. |
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E.4 | Principal exclusion criteria |
1. Patient has a history of severe or symptomatic hypertension (e.g.hypertensioninduced seizures, stroke, encephalopathy) within 1 year of Visit 1 including patients whose SBP or DBP >99th percentile for gender/age/height plus 10 mm Hg.
2. Patient has a history of clinically significant heart failure, rhythm disturbance or
cardiomyopathy, or hemodynamically significant obstructive valvular disease.
3. Patient has clinically significant neurologic, respiratory, gastrointestinal, hepatobiliary, or hematologic disease.
4. Patient has a known history of uncorrected coarctation of the aorta, bilateral renal
artery stenosis, or renal artery stenosis to a single kidney.
5. Patient has a glomerular filtration rate of <30 ml/min/1.73m2 as determined by the
Schwartz Formula, based on the baseline serum creatinine:
GFR = 0.55 x height (cm)/Serum creatinine (mg/dL)
[Note: For patients <1 year of age, the constant 0.45 will be used in place of 0.55.
For patients <1 year of age who were born with low birth weight (regardless of
gestational age), the constant 0.33 will be used in place of 0.55.]
Low birth weight is defined as <2500 grams (2.5 kilograms).
The constant that is used for an individual patient at the start of the study will be used for that patient for the duration of the base study. During the extension phase, the constant appropriate for the child’s chronological age will be used.
6. Patient has clinically significant laboratory values (as determined by the investigator) at Visit 1 outside of the established normal range including but not limited to any of the following parameters:
SGOT (AST) or SGPT (ALT) >2X the upper limit of normal
Total bilirubin or direct bilirubin >2X the upper limit of normal
White blood cell count <3000/mm3
Platelet count <100,000/mm3
Serum potassium ≥5.5 mEq/L (≥5.0 mEq/L if concomitantly
on ACE-inhibitor)
Serum sodium ≤130 mEq/L
7. Patient has a known sensitivity to losartan or other ARB, or any history of
angioneurotic edema.
8. Patient or patient’s guardian who, in the opinion of the investigator, will not fully
cooperate, keep appointments, or who has been generally unreliable.
9. Patient has any other factors limiting participation (e.g., significant, concurrent, or
life-threatening diseases such as cancer, or mental incapacitation).
10. Patient is currently being treated with any of the following:
angiotensin II type I receptor blocker (ARB)
cyclosporine or tacrolimus (FK-506)
potassium-sparing diuretics (triamterene, amiloride, spironolactone and
eplerenone)
herbal supplements
pentamidine
trimethoprim
lithium
potassium supplements
chronic analgesics (NSAIDS, opioids, acetaminophen, aspirin)
11. Patient has used any investigational compounds within 30 days of Visit 1.
12. Patient has started any new concomitant antihypertensive medications within 30 days of Visit 1. Dosage of concomitant antihypertensive medications should be stable for 30 days before Visit 1. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in sitting systolic blood pressure (SBP) after 21 days of treatment (the end of the 1st dose period) compared to baseline as a function of dose |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
after 21 days of treatment |
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E.5.2 | Secondary end point(s) |
Change in sitting diastolic blood pressure (SBP) after 21 days of treatment (the end of the 1st dose period) compared to baseline as a function of dose |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
after 21 days of treatment |
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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 | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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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 |
No comparator. Patients randomised to one of three starting doses of open label losartan. |
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E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
Will this trial be conducted at a single site globally?
| No |
E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
Argentina |
Brazil |
Chile |
Colombia |
Guatemala |
India |
Mexico |
Peru |
Philippines |
Romania |
Russian Federation |
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E.8.7 | Trial has a data monitoring committee | Yes |
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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In this study, end of trial will be when last patient randomized has final visit. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |