Study to Determine the Effects of Losartan on Proteinuria in Pediatric Patients (0954-326) - Study Results

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Investigator); Primary Purpose: Treatment
Condition:	Proteinuria
Interventions:	Drug: Comparator: losartan potassium Drug: Comparator: Placebo to amlodipine Drug: Comparator: amlodipine besylate Drug: Comparator: Placebo to losartan

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Phase III First Patient In: 21Jun07; Last Patient Last Visit (double-blind base study): 16Sep08 Open-label extension is ongoing. 52 centers (USA, Europe, Latin America, and Asia) Patients included children aged 6-17 (hypertensive) or 1-17 (normotensive) with proteinuria (mean urine protein/creatinine ratio ≥0.3 g/g from 3 measurements at baseline).

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
During 4-week, single-blind run-in patients received losartan placebo (normotensive) or amlodipine (hypertensive) and were washed off renin-angiotensin-aldosterone system and other anti-hypertensive agents. Patients had to have mean urine protein/creatinine ratio ≥0.3 gram/gram (g/g) from 3 measurements at baseline to be randomized.

Reporting Groups

	Description
Normotensive: Losartan	Group includes normotensive patients randomized to losartan. Losartan dispensed as tablets or suspension depending on patient weight and ability to swallow tablets. Losartan suspension dosing: 0.7 milligram/kilograms/day (mg/kg/day) titrated at 2 weeks to 1.4 mg/kg/day orally (maximum 50 mg if <50 kg or 100 mg if ≥50 kg) for 12 weeks. Losartan tablet dosing: 25 mg/day orally titrated to 50 mg/day (patients <50 kg) OR 50 mg/day orally titrated to 100 mg/day (patients ≥50 kg) for 12 weeks.
Normotensive: Placebo	Group includes normotensive patients randomized to losartan placebo. Losartan placebo dispensed as tablets or suspension depending on patient weight and ability to swallow tablets. Losartan placebo suspension dosing: 0.7 mg/kg/day titrated at 2 weeks to 1.4 mg/kg/day orally (maximum 50 mg if <50 kg or 100 mg if ≥50 kg) for 12 weeks. Losartan placebo tablet dosing: 25 mg/day orally titrated to 50 mg/day (patients <50 kg) OR 50 mg/day orally titrated to 100 mg/day (patients ≥50 kg) for 12 weeks.
Hypertensive: Losartan	Group includes hypertensive patients randomized to losartan and amlodipine placebo. Losartan dispensed as tablets or suspension depending on patient weight and ability to swallow tablets. Amlodipine placebo dispensed as suspension for duration of study. Losartan suspension dosing: 0.7 milligram/kilograms/day (mg/kg/day) titrated at 2 weeks to 1.4 mg/kg/day orally (maximum 50 mg if <50 kg or 100 mg if ≥50 kg) for 12 weeks. Amlodipine placebo suspension dosing: starting dose 0.05 or 0.1 titrated to 0.2 mg/kg/day orally (max 5 mg/day) after 2 weeks if necessary to control blood pressure for 12 weeks. Losartan tablet dosing: 25 mg/day orally titrated to 50 mg/day (patients <50 kg) OR 50 mg/day orally titrated to 100 mg/day (patients ≥50 kg) for 12 weeks.
Hypertensive: Amlodipine	Group includes hypertensive patients randomized to amlodipine and losartan placebo. Losartan placebo dispensed as tablets or suspension depending on patient weight and ability to swallow tablets. Amlodipine dispensed as suspension for duration of study. Losartan placebo suspension dosing: 0.7 mg/kg/day titrated at 2 weeks to 1.4 mg/kg/day orally (maximum 50 mg if <50 kg or 100 mg if ≥50 kg) for 12 weeks. Amlodipine suspension dosing: starting dose 0.05 or 0.1 titrated to 0.2 mg/kg/day orally (max 5 mg/day) after 2 weeks if necessary to control blood pressure for 12 weeks. Losartan placebo tablet dosing: 25 mg/day orally titrated to 50 mg/day (patients <50 kg) OR 50 mg/day orally titrated to 100 mg/day (patients ≥50 kg) for 12 weeks.

Participant Flow: Overall Study

	Normotensive: Losartan	Normotensive: Placebo	Hypertensive: Losartan	Hypertensive: Amlodipine
STARTED	122	124	30	30
COMPLETED	116	118	29	25
NOT COMPLETED	6	6	1	5
Adverse Event	0	2	1	2
Lost to Follow-up	1	0	0	1
Physician Decision	1	1	0	1
Protocol Violation	3	2	0	0
Withdrawal by Subject	1	1	0	0
Progressive Disease	0	0	0	1

Baseline Characteristics

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Reporting Groups

	Description
Losartan	Four arms combined to 2 groups (losartan & amlodipine/placebo) for reporting to compare patients who took losartan to patients who did not (i.e., patients took amlodipine and/or placebo). "Losartan" group: Normotensive patients randomized to losartan. Hypertensive patients randomized to losartan & amlodipine placebo. Losartan dispensed as tablets or suspension depending on patient weight and ability to swallow tablets. Amlodipine placebo dispensed as suspension for duration of study. Losartan suspension dosing: 0.7 milligram/kilograms/day (mg/kg/day) titrated at 2 weeks to 1.4 mg/kg/day orally (maximum 50 mg if <50 kg or 100 mg if ≥50 kg) for 12 weeks. Amlodipine placebo suspension dosing: starting dose 0.05 or 0.1 titrated to 0.2 mg/kg/day orally (max 5 mg/day) after 2 weeks if necessary to control blood pressure for 12 weeks. Losartan tablet dosing: 25 mg/day orally titrated to 50 mg/day (patients <50 kg) OR 50 mg/day orally titrated to 100 mg/day (patients ≥50 kg) for 12 weeks.
Amlodipine/Placebo	"Amlodipine/Placebo" group includes the following: Normotensive patients randomized to losartan placebo. Hypertensive patients randomized to amlodipine and losartan placebo. Losartan placebo dispensed as tablets or suspension depending on patient weight and ability to swallow tablets. Amlodipine dispensed as suspension for duration of study. Losartan placebo suspension dosing: 0.7 mg/kg/day titrated at 2 weeks to 1.4 mg/kg/day orally (maximum 50 mg if <50 kg or 100 mg if ≥50 kg) for 12 weeks. Amlodipine suspension dosing: starting dose 0.05 or 0.1 titrated to 0.2 mg/kg/day orally (max 5 mg/day) after 2 weeks if necessary to control blood pressure for 12 weeks. Losartan placebo tablet dosing: 25 mg/day orally titrated to 50 mg/day (patients <50 kg) OR 50 mg/day orally titrated to 100 mg/day (patients ≥50 kg) for 12 weeks.

Description

Losartan

Four arms combined to 2 groups (losartan & amlodipine/placebo) for reporting to compare patients who took losartan to patients who did not (i.e., patients took amlodipine and/or placebo).

"Losartan" group: Normotensive patients randomized to losartan. Hypertensive patients randomized to losartan & amlodipine placebo.

Losartan dispensed as tablets or suspension depending on patient weight and ability to swallow tablets. Amlodipine placebo dispensed as suspension for duration of study.

Losartan suspension dosing: 0.7 milligram/kilograms/day (mg/kg/day) titrated at 2 weeks to 1.4 mg/kg/day orally (maximum 50 mg if <50 kg or 100 mg if ≥50 kg) for 12 weeks. Amlodipine placebo suspension dosing: starting dose 0.05 or 0.1 titrated to 0.2 mg/kg/day orally (max 5 mg/day) after 2 weeks if necessary to control blood pressure for 12 weeks. Losartan tablet dosing: 25 mg/day orally titrated to 50 mg/day (patients <50 kg) OR 50 mg/day orally titrated to 100 mg/day (patients ≥50 kg) for 12 weeks.

Amlodipine/Placebo

"Amlodipine/Placebo" group includes the following: Normotensive patients randomized to losartan placebo. Hypertensive patients randomized to amlodipine and losartan placebo.

Losartan placebo dispensed as tablets or suspension depending on patient weight and ability to swallow tablets. Amlodipine dispensed as suspension for duration of study. Losartan placebo suspension dosing: 0.7 mg/kg/day titrated at 2 weeks to 1.4 mg/kg/day orally (maximum 50 mg if <50 kg or 100 mg if ≥50 kg) for 12 weeks.

Amlodipine suspension dosing: starting dose 0.05 or 0.1 titrated to 0.2 mg/kg/day orally (max 5 mg/day) after 2 weeks if necessary to control blood pressure for 12 weeks. Losartan placebo tablet dosing: 25 mg/day orally titrated to 50 mg/day (patients <50 kg) OR 50 mg/day orally titrated to 100 mg/day (patients ≥50 kg) for 12 weeks.

Baseline Measures

	Losartan	Amlodipine/Placebo	Total
Number of Participants [units: participants]	152	154	306
Age, Customized [units: participants]
≤6 Years of Age	33	42	75
7-12 Years of Age	57	57	114
13-17 Years of Age	62	55	117
Age [units: years] Mean ± Standard Deviation	10.4 ± 4.7	9.7 ± 4.6	10.1 ± 4.7
Gender [units: participants]
Female	66	64	130
Male	86	90	176
Ethnicity (NIH/OMB) [units: participants]
Hispanic or Latino	79	82	161
Not Hispanic or Latino	73	72	145
Unknown or Not Reported	0	0	0
Hypertensive ^[1] [units: Participants]
Yes	30	30	60
No	122	124	246
Prior Angiotensin Converting Enzyme Inhibitor /Angiotensin II Type I Receptor Blocker (ACE-I/ARB)Use [units: Participants]
Yes	83	81	164
No	69	73	142
Race [units: participants]
Asian	26	26	52
Black	5	5	10
Multi-Racial	36	34	70
White	77	85	162
Other	8	4	12
Region [units: Participants]
United States	15	10	25
Outside of United States	137	144	281
Tanner Stage ^[2] [units: Participants]
Stage I	69	78	147
Stage II	26	21	47
Stage III	22	18	40
Stage IV	23	24	47
Stage V	12	13	25
Body Mass Index (BMI) [units: kilograms per meter squared (kg/m2)] Mean ± Standard Deviation	19.8 ± 5.5	19.2 ± 4.2	19.5 ± 4.9
Duration of Hypertension [units: Years] Mean ± Standard Deviation	4.8 ± 4.1	6.1 ± 4.8	5.5 ± 4.5
Height [units: Centimeters (cm)] Mean ± Standard Deviation	135.8 ± 27.3	132.0 ± 28.4	133.9 ± 27.9
Protein-to-Creatinine Ratio [units: grams/grams] Mean ± Standard Deviation	2.2 ± 2.6	2.8 ± 3.8	2.5 ± 3.3
Sitting Diastolic Blood Pressure [units: millimeters of mercury (mm Hg)] Mean ± Standard Deviation	66.8 ± 10.7	67.8 ± 11.6	67.3 ± 11.2
Sitting Systolic Blood Pressure [units: mm Hg] Mean ± Standard Deviation	106.0 ± 13.4	107.2 ± 13.8	106.6 ± 13.6
Weight [units: Kilograms (kg)] Mean ± Standard Deviation	39.6 ± 21.0	36.4 ± 19.5	38.0 ± 20.3

[1]	Sitting systolic blood pressure (SiSBP) or diastolic blood pressure (SiDBP) ≥90th percentile AND patient on medication for proteinuria/hypertension OR SiSBP or SiDBP ≥95th percentile AND patient NOT on medication for proteinuria/hypertension OR documented hypertension and on anti-hypertensive medication, whether or not medicated for proteinuria.
[2]	A scale of physical development. The scale defines physical measurements of development based on external primary and secondary sex characteristics, such as the size of the breasts, genitalia, and development of pubic hair. Stages range from I to V with I being the least developed.

[1]

Sitting systolic blood pressure (SiSBP) or diastolic blood pressure (SiDBP) ≥90th percentile AND patient on medication for proteinuria/hypertension OR SiSBP or SiDBP ≥95th percentile AND patient NOT on medication for proteinuria/hypertension OR documented hypertension and on anti-hypertensive medication, whether or not medicated for proteinuria.

[2]

A scale of physical development. The scale defines physical measurements of development based on external primary and secondary sex characteristics, such as the size of the breasts, genitalia, and development of pubic hair.

Stages range from I to V with I being the least developed.

Outcome Measures

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1. Primary:

Percent Change From Baseline in Protein/Creatinine (Pr/Cr) Ratio at Week 12 [ Time Frame: Baseline and Week 12 ]

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2. Secondary:

Change From Baseline in Systolic Blood Pressure in Hypertensive Patients at Week 12 [ Time Frame: Baseline and Week 12 ]

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3. Secondary:

Change From Baseline in Diastolic Blood Pressure in Hypertensive Patients at Week 12 [ Time Frame: Baseline and Week 12 ]

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Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: Merck agreements may vary with individual investigators, but will not prohibit any investigator from publishing. Merck supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact:

Name/Title: Executive Vice President, Clinical and Quantitative Sciences
Organization: Merck Sharp & Dohme Corp
phone: 1-800-672-6372

No publications provided by Merck

Publications automatically indexed to this study:

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. Epub 2011 Feb 1.

Responsible Party:	Vice President, Late Stage Development Group Leader, Merck Sharp & Dohme Corp
ClinicalTrials.gov Identifier:	NCT00568178 History of Changes
Other Study ID Numbers:	2006_560, MK0954-326
Study First Received:	December 3, 2007
Results First Received:	August 11, 2009
Last Updated:	April 21, 2011
Health Authority:	United States: Food and Drug Administration