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

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

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

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

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.

Normotensive participants received losartan. Hypertensive participants received either active losartan (plus amlodipine placebo) OR active amlodipine (plus losartan placebo).

Hypertensive participants were randomized to receive either active losartan (plus amlodipine placebo) OR active amlodipine (plus losartan placebo) for 12 weeks.

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).

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).

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.

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

Enalapril 2.5-, 5-, 10-, and 20-mg tablets or enalapril suspension (1 mg/mL), oral administration, once daily for 36 months.

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.

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.

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.

Double-Blind Treatment Phase: Change From Baseline in Systolic Blood Pressure in Hypertensive Participants at Week 12

Double-Blind Treatment Phase: Change From Baseline in Diastolic Blood Pressure in Hypertensive Participants at Week 12

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)

http://www.merck.com/clinical-trials/pdf/Merck%20Procedure%20on%20Clinical%20Trial%20Data%20Access%20Final_Updated%20July_9_2014.pdf http://engagezone.msd.com/ds_documentation.php

Webb NJ, Shahinfar S, Wells TG, Massaad R, Gleim GW, McCrary Sisk C, Lam C. Losartan and enalapril are comparable in reducing proteinuria in children with Alport syndrome. Pediatr Nephrol. 2013 May;28(5):737-43. doi: 10.1007/s00467-012-2372-9. Epub 2012 Dec 4.

Webb NJ, Shahinfar S, Wells TG, Massaad R, Gleim GW, Santoro EP, Sisk CM, Lam C. Losartan and enalapril are comparable in reducing proteinuria in children. Kidney Int. 2012 Oct;82(7):819-26. doi: 10.1038/ki.2012.210. Epub 2012 Jun 27.

Webb NJ, Lam C, Shahinfar S, Strehlau J, Wells TG, Gleim GW, Le Bailly De Tilleghem C. Efficacy and safety of losartan in children with Alport syndrome--results from a subgroup analysis of a prospective, randomized, placebo- or amlodipine-controlled trial. Nephrol Dial Transplant. 2011 Aug;26(8):2521-6. doi: 10.1093/ndt/gfq797. Epub 2011 Feb 1.