An Extension Study Designed to Assess Effects of Losartan on Proteinuria in Pediatric Populations (MK-0954-326 AM1,EXT1(AM2))

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effects of losartan on proteinuria in pediatric patients.

Detailed Description
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The study included a 12-week double-blind treatment phase and a 36-month open-label extension phase. Participants who completed or discontinued the initial 12-week phase of the study and who opted to participate in the open label extension phase were randomized to either losartan or enalapril at a dose of the investigator's choosing for the duration of the extension. The open label extension was designed to continue until the 100th participant completed 3 years of follow-up.

Official Title
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A Randomized, Double-Blind, Parallel, Placebo or Amlodipine-Controlled Study of the Effects of Losartan on Proteinuria in Pediatric Patients With or Without Hypertension

Conditions
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Proteinuria

Intervention / Treatment
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* Drug: Losartan Potassium
* Other: Comparator: Placebo (Losartan)
* Drug: Comparator: amlodipine besylate
* Other: Comparator: Placebo (amlodipine besylate)
* Other: Placebo (Losartan)
* Drug: Enalapril Maleate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant is 1 to 17 years of age Able to provide a first-morning urine sample each day during the study Documented history of proteinuria associated with chronic kidney disease of any origin Signed consent of parent and/or legal guardian Exclusion Criteria: Pregnant and/or nursing Requires more than 2 medications to control high blood pressure Has undergone major organ transplantation (e.g. heart, kidney, liver) Known sensitivity to losartan or other similar drugs, or any history of angioneurotic edema Known sensitivity to amlodipine or other calcium channel blocker Requires cyclosporine to treat renal disease (kidney disease)

Ages Eligible for Study
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Minimum Age: 12 Months
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Losartan Double-Blind Base Study (12-weeks)<br>Normotensive participants received losartan. Hypertensive participants received either active losartan (plus amlodipine placebo) OR active amlodipine (plus losartan placebo). | Drug: Losartan Potassium<br>* Losartan Use During the Double-Blind Treatment Phase: Losartan potassium was administered orally as tablets; 25 or 50 milligrams (mg); or as a liquid suspension 2.5 mg/mL prepared for participants who weighed less than 25 kilograms (kg) or for those participants unable to swallow tablets. During the double-blind period, participants were initially randomized to either a once-daily weight-dependent dose of approximately 0.7 mg/kg (25 mg tablet; up to 50 mg per day) and at 2-weeks the dose was increased to a once-daily maximum weight-dependent dose of 1.4 mg/kg. The maximum dose of losartan, as specified in the protocol, was 50 mg/day (if the patient weighed <50 kg) or 100 mg/day (if the patient weighed ≥50 kg). Losartan Use During the Treatment Extension Phase: Dose modifications of the drug were left up to the discretion of the Investigators based on each participant's level of tolerance.<br>* Other names: Cozaar®;Other: Comparator: Placebo (Losartan)<br>* Placebo (losartan suspension), administered orally, once daily for 12 weeks<br>|
| Active Comparator: Amlodipine Double-Blind Base Study (12-weeks)<br>Hypertensive participants were randomized to receive either active losartan (plus amlodipine placebo) OR active amlodipine (plus losartan placebo) for 12 weeks. | Other: Comparator: Placebo (Losartan)<br>* Placebo (losartan suspension), administered orally, once daily for 12 weeks<br>Drug: Comparator: amlodipine besylate<br>* Amlodipine besylate (1 mg/mL) liquid suspension, oral administration, titrated to 0.2 mg/kg/day (5 mg maximum dose) per day for 12 Weeks<br>* Other names: NORVASC®;Other: Comparator: Placebo (amlodipine besylate)<br>* Liquid suspension, 1mg/mL, titrated to 0.2 mg/kg/day (5 mg maximum dose) once daily, for 12 weeks<br>* Other names: NORVASC®;Other: Placebo (Losartan)<br>* Normotensive patients randomized to losartan placebo for 12 weeks.<br>|
| Experimental: Losartan Open-Label Extension Phase (Month 36)<br>Participants were were carried over from the base study into the long-term safety extension. Participants in the extension were randomly assigned to either losartan or enalapril regardless of their previous randomized treatment. Dosing during the extension period (i.e. starting dose and any titration) was up to the investigator and varied by patient). | Drug: Losartan Potassium<br>* Losartan Use During the Double-Blind Treatment Phase: Losartan potassium was administered orally as tablets; 25 or 50 milligrams (mg); or as a liquid suspension 2.5 mg/mL prepared for participants who weighed less than 25 kilograms (kg) or for those participants unable to swallow tablets. During the double-blind period, participants were initially randomized to either a once-daily weight-dependent dose of approximately 0.7 mg/kg (25 mg tablet; up to 50 mg per day) and at 2-weeks the dose was increased to a once-daily maximum weight-dependent dose of 1.4 mg/kg. The maximum dose of losartan, as specified in the protocol, was 50 mg/day (if the patient weighed <50 kg) or 100 mg/day (if the patient weighed ≥50 kg). Losartan Use During the Treatment Extension Phase: Dose modifications of the drug were left up to the discretion of the Investigators based on each participant's level of tolerance.<br>* Other names: Cozaar®;|
| Active Comparator: Enalapril Open-Label Extension Phase (Month 36)<br>Participants were were carried over from the base study into the long-term safety extension. Participants in the extension were randomly assigned to either losartan or enalapril regardless of their previous randomized treatment. Dosing during the extension period (i.e. starting dose and any titration) was up to the investigator and varied by patient). | Drug: Enalapril Maleate<br>* Enalapril 2.5-, 5-, 10-, and 20-mg tablets or enalapril suspension (1 mg/mL), oral administration, once daily for 36 months.<br>* Other names: Renitec®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Double-Blind Treatment Phase: Percent Change From Baseline in Urinary Protein/Creatinine (Pr/Cr) Ratio (gm/gm) at Week 12 | Change in urinary protein excretion, determined as urinary Pr/Cr ratio compared to baseline*, after approximately twelve weeks of treatment. Baseline is defined as values obtained at Visit 3, Week (-1) during the Single Blind Run-in period. | Baseline and Week 12 | 
| Open Label Extension: Percent Change From Baseline of Urinary Pr/Cr Ratio (gm/gm) at Month 36 | Change in urinary protein excretion, determined as urinary Pr/Cr ratio compared to baseline*, after approximately three years of treatment. *The baseline for efficacy data in the extension was defined as the last value obtained in the double-blind treatment phase. | Baseline and Month 36 | 
| Open Label Extension: Change From Baseline in Glomerular Filtration Rate (GFR) at Month 36 | The outcome measure of glomerular filtration rate was based on mL/min/1.73m^2, as determined by the Schwartz formula: GFR = _____0.55 x height (cm)_______ divided by serum creatinine (mg/dL) GFR values were compared to the baseline GFR measure. [Note: For male participants, ages 13 to 17 years, 0.70 was used as the multiplier in place of 0.55] Baseline in regard to the extension is defined as the last value obtained in the double-blind treatment phase. | Baseline and Month 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Double-Blind Treatment Phase: Change From Baseline in Systolic Blood Pressure in Hypertensive Participants at Week 12 |  | Baseline and Week 12 | 
| Double-Blind Treatment Phase: Change From Baseline in Diastolic Blood Pressure in Hypertensive Participants at Week 12 |  | Baseline and Week 12 |