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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00568178
Recruitment Status : Completed
First Posted : December 5, 2007
Results First Posted : October 30, 2009
Last Update Posted : October 17, 2017
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Proteinuria
Interventions Drug: Losartan Potassium
Other: Comparator: Placebo (Losartan)
Drug: Comparator: amlodipine besylate
Other: Comparator: Placebo (amlodipine besylate)
Other: Placebo (Losartan)
Drug: Enalapril Maleate
Enrollment 306
Recruitment Details

As of March 2011, the study was completed.

Phase III First Patient In: 21Jun07; Last Patient Last Visit (double-blind base study): 16Sep08; and (open-label extension): 31Mar11. The study included 52 centers (USA, Europe, Latin America, and Asia) and participants included children aged 6-17 (hypertensive) or 1-17 (normotensive) with proteinuria.

Pre-assignment Details During a 4-week, single-blind run-in participants received losartan placebo (normotensive) or amlodipine (hypertensive) and underwent wash-out of anti-hypertensive agents. To qualify for randomization, participants had to have a mean urine Pr/Cr ratio of ≥0.3 gram/gram (gm/gm) derived from baseline urine samples.
Arm/Group Title Losartan Double Blind Normortensive Placebo Double Blind Normotensive Losartan Double Blind Hypertensive Amlodipine Double Blind Hypertensive Losartan Open Label Extension Enalapril Open Label Extension
Hide Arm/Group Description

Normotensive participants who were randomized to losartan.

Losartan dispensed as tablets or suspension depending on participant 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 (participants <50 kg) OR 50 mg/day orally titrated to 100 mg/day (participants ≥50 kg) for 12 weeks; or losartan placebo.

Normotensive participants who were randomized to losartan placebo.

Losartan placebo dispensed as tablets or suspension depending on participant 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 (participants <50 kg) OR 50 mg/day orally titrated to 100 mg/day (participants ≥50 kg) for 12 weeks.

Hypertensive patients who were randomized to receive losartan and amlodipine placebo for 12 weeks.

Losartan dispensed as tablets or suspension depending on participant 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 (participants <50 kg) OR 50 mg/day orally titrated to 100 mg/day (participants ≥50 kg) for 12 weeks.

Hypertensive patients who were randomized to receive amlodipine and losartan placebo for 12 weeks.

Losartan placebo dispensed as tablets or suspension depending on participant 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.

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 (participants <50 kg) OR 50 mg/day orally titrated to 100 mg/day (participants ≥50 kg) for 12 weeks.

Participants were stratified based on assigned treatment in the double-blind treatment phase and were randomized in a 1:1 ratio to either losartan or enalapril.

Dosing of study medication during the extension phase of the study was at the investigator’s discretion.

Losartan 25-mg and 50-mg tablets were available for patients able to swallow tablets. For patients unable to swallow tablets, or who weighed <25 kg, losartan suspension (2.5 mg/ml) was prepared.

Participants were stratified based on assigned treatment in the double-blind treatment phase and were randomized in a 1:1 ratio to either losartan or enalapril.

Dosing of study medication during the extension phase of the study was at the investigator’s discretion.

Enalapril 2.5-, 5-, 10-, and 20-mg tablets were available for participants able to swallow tablets. For participants unable to swallow tablets, or who weighed <25 kg, enalapril suspension (1 mg/mL) was prepared.

Period Title: Double Blind Base Study
Started 122 124 30 30 0 0
Completed 116 118 29 25 0 0
Not Completed 6 6 1 5 0 0
Reason Not Completed
Adverse Event             0             2             1             2             0             0
Lost to Follow-up             1             0             0             1             0             0
Physician Decision             1             1             0             1             0             0
Protocol Violation             3             2             0             0             0             0
Withdrawal by Subject             1             1             0             0             0             0
Progressive Disease             0             0             0             1             0             0
Period Title: Open Label Extension
Started 0 0 0 0 134 134
Completed 0 0 0 0 55 54
Not Completed 0 0 0 0 79 80
Reason Not Completed
Adverse Event             0             0             0             0             11             8
Protocol Violation             0             0             0             0             1             0
Lost to Follow-up             0             0             0             0             6             11
Physician Decision             0             0             0             0             9             8
Pregnancy             0             0             0             0             0             1
Progressive Disease             0             0             0             0             3             1
Termination of Trial             0             0             0             0             45             47
Withdrawal by Subject             0             0             0             0             4             4
Arm/Group Title Losartan Amlodipine/Placebo Total
Hide Arm/Group Description

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

"Losartan" group: Normotensives were randomized to losartan and Hypertensives were 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 dosing: 25 mg/day orally titrated to 50 mg/day (participants <50 kg) OR 50 mg/day orally titrated to 100 mg/day (participants ≥50 kg) for 12 weeks.

"Amlodipine/Placebo" group includes the following: Normotensive patients randomized to losartan. 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.

Total of all reporting groups
Overall Number of Baseline Participants 152 154 306
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 152 participants 154 participants 306 participants
10.4  (4.7) 9.7  (4.6) 10.1  (4.7)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 152 participants 154 participants 306 participants
≤6 Years of Age 33 42 75
7-12 Years of Age 57 57 114
13-17 Years of Age 62 55 117
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 152 participants 154 participants 306 participants
Female
66
  43.4%
64
  41.6%
130
  42.5%
Male
86
  56.6%
90
  58.4%
176
  57.5%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 152 participants 154 participants 306 participants
Hispanic or Latino
79
  52.0%
82
  53.2%
161
  52.6%
Not Hispanic or Latino
73
  48.0%
72
  46.8%
145
  47.4%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Hypertensive   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 152 participants 154 participants 306 participants
Yes 30 30 60
No 122 124 246
[1]
Measure Description: Sitting systolic blood pressure (SiSBP) or diastolic blood pressure (SiDBP) ≥90th percentile AND participant on medication for proteinuria/hypertension OR SiSBP or SiDBP ≥95th percentile AND participant NOT on medication for proteinuria/hypertension OR documented hypertension and on anti-hypertensive medication, whether or not medicated for proteinuria.
Prior Angiotensin Converting Enzyme Inhibitor /Angiotensin II Type I Receptor Blocker (ACE-I/ARB)Use  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 152 participants 154 participants 306 participants
Yes 83 81 164
No 69 73 142
Race  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 152 participants 154 participants 306 participants
Asian 26 26 52
Black 5 5 10
Multi-Racial 36 34 70
White 77 85 162
Other 8 4 12
Region  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 152 participants 154 participants 306 participants
United States 15 10 25
Outside of United States 137 144 281
Tanner Stage   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 152 participants 154 participants 306 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
[1]
Measure Description:

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.

Body Mass Index (BMI)  
Mean (Standard Deviation)
Unit of measure:  Kilograms per meter squared (kg/m2)
Number Analyzed 152 participants 154 participants 306 participants
19.8  (5.5) 19.2  (4.2) 19.5  (4.9)
Duration of Hypertension  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 152 participants 154 participants 306 participants
4.8  (4.1) 6.1  (4.8) 5.5  (4.5)
Height  
Mean (Standard Deviation)
Unit of measure:  Centimeters (cm)
Number Analyzed 152 participants 154 participants 306 participants
135.8  (27.3) 132.0  (28.4) 133.9  (27.9)
Protein-to-Creatinine Ratio  
Mean (Standard Deviation)
Unit of measure:  Grams/grams
Number Analyzed 152 participants 154 participants 306 participants
2.2  (2.6) 2.8  (3.8) 2.5  (3.3)
Sitting Diastolic Blood Pressure  
Mean (Standard Deviation)
Unit of measure:  Millimeters of mercury (mm Hg)
Number Analyzed 152 participants 154 participants 306 participants
66.8  (10.7) 67.8  (11.6) 67.3  (11.2)
Sitting Systolic Blood Pressure  
Mean (Standard Deviation)
Unit of measure:  Mm Hg
Number Analyzed 152 participants 154 participants 306 participants
106.0  (13.4) 107.2  (13.8) 106.6  (13.6)
Weight  
Mean (Standard Deviation)
Unit of measure:  Kilograms (kg)
Number Analyzed 152 participants 154 participants 306 participants
39.6  (21.0) 36.4  (19.5) 38.0  (20.3)
1.Primary Outcome
Title Double-Blind Treatment Phase: Percent Change From Baseline in Urinary Protein/Creatinine (Pr/Cr) Ratio (gm/gm) at Week 12
Hide Description

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.

Time Frame Baseline and Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set included all randomized participants who took at least one dose of study drug and had baseline and post randomization measurements available
Arm/Group Title Losartan Amlodipine/Placebo
Hide Arm/Group Description:
Participants were randomized in a 1:1 ratio within each stratum: hypertensive patients (6 to 17 years of age) were randomized to either amlodipine or losartan; normotensive patients (1 to 17 years of age) were randomized to either placebo or losartan. Losartan (or placebo) therapy was administered orally, in tablet or suspension form, at an initial dose of approximately 0.7 mg/kg once daily (up to 50 or 100 mg total daily dose, weight-dependent). Participants who were randomized to losartan were assigned to a normotensive or hypertensive group, based on clinical profile.

"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.

Overall Number of Participants Analyzed 150 152
Geometric Mean (95% Confidence Interval)
Unit of Measure: Percent Change in Pr/Cr
-35.80
(-43.11 to -27.55)
1.37
(-10.27 to 14.51)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Losartan, Amlodipine/Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.001
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio in Geometric Mean
Estimated Value 0.63
Confidence Interval (2-Sided) 95%
0.54 to 0.74
Estimation Comments [Not Specified]
2.Primary Outcome
Title Open Label Extension: Percent Change From Baseline of Urinary Pr/Cr Ratio (gm/gm) at Month 36
Hide Description

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.

Time Frame Baseline and Month 36
Hide Outcome Measure Data
Hide Analysis Population Description
Data for analysis was obtained only from participants who had: 1) Baseline measure of Pr/Cr, 2) At least one dose of study drug, and 3) Post randomization measure of Pr/Cr. The number of participants was determined by including only the individuals who satisfied the criteria.
Arm/Group Title Losartan Open Label Extension Enalapril Open Label Extension
Hide Arm/Group Description:
All participants who completed the 12-week double-blind treatment phase (or discontinued early due to increased proteinuria) were invited to participate in the open-label extension. Participants were randomized in a 1:1 ratio to either losartan or enalapril therapy. The duration of the extension varied, depending on the time of enrollment. All participants who entered the extension could continue until the 100th participant completed approximately 3 years of follow-up.
All participants who completed the 12-week double-blind treatment phase (or discontinued early due to increased proteinuria) were invited to participate in the open-label extension. Participants were randomized in a 1:1 ratio to either losartan or enalapril therapy. The duration of the extension varied, depending on the time of enrollment. All participants who entered the extension could continue until the 100th participant completed approximately 3 years of follow-up.
Overall Number of Participants Analyzed 130 130
Geometric Mean (95% Confidence Interval)
Unit of Measure: Percent Change in Pr/Cr
-30.01
(-44.35 to -11.98)
-40.45
(-52.45 to -25.42)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Losartan Open Label Extension, Enalapril Open Label Extension
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments No P Value was calculated for this outcome.
Method Mixed Models Analysis
Comments An unstructured variance-covariance was used.
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 1.18
Confidence Interval (2-Sided) 95%
0.86 to 1.60
Estimation Comments [Not Specified]
3.Primary Outcome
Title Open Label Extension: Change From Baseline in Glomerular Filtration Rate (GFR) at Month 36
Hide Description

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.

Time Frame Baseline and Month 36
Hide Outcome Measure Data
Hide Analysis Population Description
Data for analysis was obtained only from participants who had: 1) Baseline measure of Pr/Cr, 2) At least one dose of study drug, and 3) Post randomization measure of Pr/Cr. The number of participants was determined by including only individuals who satisfied the criteria.
Arm/Group Title Losartan Open Label Extension Enalapril Open Label Extension
Hide Arm/Group Description:
All participants who completed the 12-week double-blind treatment phase (or discontinued early due to increased proteinuria) were invited to participate in the open-label extension and were randomly assigned using a 1:1 ratio to either losartan or enalapril therapy. The duration of the extension varied, depending on the time of enrollment. All patients who entered the extension continued until the 100th patient completed approximately 3 years of follow-up.
All participants who completed the 12-week double-blind treatment phase (or discontinued early due to increased proteinuria) were invited to participate in the open-label extension and were randomly assigned using a 1:1 ratio to either losartan or enalapril therapy. The duration of the extension varied, depending on the time of enrollment. All patients who entered the extension continued until the 100th patient completed approximately 3 years of follow-up.
Overall Number of Participants Analyzed 127 127
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Change in GFR mL/min1.73m^2
3.3
(-5.2 to 11.7)
7.0
(-1.4 to 15.4)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Losartan Open Label Extension, Enalapril Open Label Extension
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments A P-Value was not calculated for this outcome.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Square Mean
Estimated Value -3.8
Confidence Interval 95%
-15.2 to 7.6
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Double-Blind Treatment Phase: Change From Baseline in Systolic Blood Pressure in Hypertensive Participants at Week 12
Hide Description [Not Specified]
Time Frame Baseline and Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
All-Participants-As-Treated population which included all randomized participants who received at least 1 dose of study therapy, and each participant was counted in the treatment group of the drug they actually received.
Arm/Group Title Losartan-Hypertensive Participants Amlodipine-Hypertensive Participants
Hide Arm/Group Description:
Group includes hypertensive participants who were randomized to losartan and amlodipine placebo.
Group includes hypertensive participants who were randomized to amlodipine and losartan placebo.
Overall Number of Participants Analyzed 30 30
Least Squares Mean (95% Confidence Interval)
Unit of Measure: mm Hg
-5.5
(-8.6 to -2.4)
-0.1
(-3.3 to 3.1)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Losartan-Hypertensive Participants, Amlodipine-Hypertensive Participants
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -5.4
Confidence Interval 95%
-9.9 to -1.0
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Double-Blind Treatment Phase: Change From Baseline in Diastolic Blood Pressure in Hypertensive Participants at Week 12
Hide Description [Not Specified]
Time Frame Baseline and Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
All-Participants-As-Treated population which included all randomized participants who received at least 1 dose of study therapy, and each participant was counted in the treatment group of the drug they actually received
Arm/Group Title Losartan-Hypertensive Participants Amlodipine-Hypertensive Participants
Hide Arm/Group Description:
Group includes hypertensive participants who were randomized to losartan and amlodipine placebo.
Group includes hypertensive participants who were randomized to amlodipine and losartan placebo.
Overall Number of Participants Analyzed 30 30
Least Squares Mean (95% Confidence Interval)
Unit of Measure: mm Hg
-3.8
(-7.0 to -0.7)
0.8
(-2.5 to 4.1)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Losartan-Hypertensive Participants, Amlodipine-Hypertensive Participants
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -4.6
Confidence Interval 95%
-9.2 to -0.1
Estimation Comments [Not Specified]
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Losartan: Double-Blind Base Study Amlodipine/Placebo: Double-Blind Base Study Losartan Open-Label Extension Enalapril: Open-Label Extension
Hide Arm/Group Description

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

"Losartan" group: Normotensives were randomized to losartan and Hypertensives were 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 dosing: 25 mg/day orally titrated to 50 mg/day (participants <50 kg) OR 50 mg/day orally titrated to 100 mg/day (participants ≥50 kg) for 12 weeks.

"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.

Please note that the open label participant population was derived exclusively from the original base study population. There was no additional recruitment.

Participants were randomized to either losartan or enalapril, administered in an unblinded fashion (placebo was not used) for the duration of the study. The maximum dose of losartan was 50 mg/day (if the participant weighed <50 kg) or 100 mg/day (if the participant weighed ≥50 kg) Losartan 25-mg and 50-mg tablets were available for participants able to swallow tablets, and losartan suspension (2.5 mg/ml) was prepared for participants unable to swallow tablets, or for those who weighed <25 kg.

Please note that the open label participant population was derived exclusively from the original base study population. There was no additional recruitment.

Participants were randomized to either losartan or enalapril, administered in an unblinded fashion (placebo was not used) for the duration of the study. The maximum specified dose of enalapril was 40 mg/day. For participants unable to swallow tablets, or for those who weighed <25 kg, enalapril suspension (1 mg/mL) was prepared. The starting dose of drug and any adjustments during the open-label period were at the discretion of the investigator.

All-Cause Mortality
Losartan: Double-Blind Base Study Amlodipine/Placebo: Double-Blind Base Study Losartan Open-Label Extension Enalapril: Open-Label Extension
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Losartan: Double-Blind Base Study Amlodipine/Placebo: Double-Blind Base Study Losartan Open-Label Extension Enalapril: Open-Label Extension
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   8/152 (5.26%)      5/154 (3.25%)      27/134 (20.15%)      25/134 (18.66%)    
Blood and lymphatic system disorders         
Leukopenia  1  0/152 (0.00%)  0 0/154 (0.00%)  0 2/134 (1.49%)  2 0/134 (0.00%)  0
Thrombocytopenia  1  0/152 (0.00%)  0 0/154 (0.00%)  0 0/134 (0.00%)  0 1/134 (0.75%)  1
Congenital, familial and genetic disorders         
Lipomeningocele  1  0/152 (0.00%)  0 0/154 (0.00%)  0 0/134 (0.00%)  0 1/134 (0.75%)  1
Renal hypoplasia  1  0/152 (0.00%)  0 0/154 (0.00%)  0 0/134 (0.00%)  0 1/134 (0.75%)  1
Ear and labyrinth disorders         
Vertigo  1  0/152 (0.00%)  0 0/154 (0.00%)  0 0/134 (0.00%)  0 1/134 (0.75%)  1
Gastrointestinal disorders         
Abdominal pain  1  0/152 (0.00%)  0 0/154 (0.00%)  0 0/134 (0.00%)  0 1/134 (0.75%)  1
Diarrhoea  1  0/152 (0.00%)  0 0/154 (0.00%)  0 0/134 (0.00%)  0 2/134 (1.49%)  2
Gingival bleeding  1  0/152 (0.00%)  0 0/154 (0.00%)  0 0/134 (0.00%)  0 1/134 (0.75%)  1
Ileus  1  0/152 (0.00%)  0 0/154 (0.00%)  0 0/134 (0.00%)  0 1/134 (0.75%)  1
General disorders         
Pyrexia  1  0/152 (0.00%)  0 0/154 (0.00%)  0 1/134 (0.75%)  1 0/134 (0.00%)  0
Infections and infestations         
Appendicitis  1  0/152 (0.00%)  0 0/154 (0.00%)  0 1/134 (0.75%)  1 1/134 (0.75%)  1
Arthritis bacterial  1  0/152 (0.00%)  0 0/154 (0.00%)  0 1/134 (0.75%)  1 0/134 (0.00%)  0
Bronchitis  1  1/152 (0.66%)  1 1/154 (0.65%)  1 0/134 (0.00%)  0 0/134 (0.00%)  0
Gastroenteritis  1  1/152 (0.66%)  1 0/154 (0.00%)  0 1/134 (0.75%)  1 1/134 (0.75%)  1
Helicobacter infection  1  0/152 (0.00%)  0 0/154 (0.00%)  0 0/134 (0.00%)  0 1/134 (0.75%)  1
Herpangina  1  0/152 (0.00%)  0 0/154 (0.00%)  0 0/134 (0.00%)  0 1/134 (0.75%)  1
Nasopharyngitis  1  0/152 (0.00%)  0 0/154 (0.00%)  0 1/134 (0.75%)  1 0/134 (0.00%)  0
Peritonitis bacterial  1  1/152 (0.66%)  1 0/154 (0.00%)  0 0/134 (0.00%)  0 0/134 (0.00%)  0
Pneumonia  1  0/152 (0.00%)  0 0/154 (0.00%)  0 2/134 (1.49%)  2 3/134 (2.24%)  3
Pyelonephritis  1  0/152 (0.00%)  0 0/154 (0.00%)  0 3/134 (2.24%)  4 0/134 (0.00%)  0
Pyelonephritis acute  1  0/152 (0.00%)  0 0/154 (0.00%)  0 0/134 (0.00%)  0 1/134 (0.75%)  1
Respiratory tract infection  1  0/152 (0.00%)  0 0/154 (0.00%)  0 0/134 (0.00%)  0 1/134 (0.75%)  1
Sepsis  1  0/152 (0.00%)  0 0/154 (0.00%)  0 1/134 (0.75%)  1 0/134 (0.00%)  0
Sinusitis  1  0/152 (0.00%)  0 0/154 (0.00%)  0 1/134 (0.75%)  1 1/134 (0.75%)  1
Urinary tract infection  1  0/152 (0.00%)  0 2/154 (1.30%)  2 2/134 (1.49%)  2 1/134 (0.75%)  1
Varicella  1  1/152 (0.66%)  1 0/154 (0.00%)  0 0/134 (0.00%)  0 0/134 (0.00%)  0
Injury, poisoning and procedural complications         
Femur fracture  1  0/152 (0.00%)  0 0/154 (0.00%)  0 1/134 (0.75%)  1 0/134 (0.00%)  0
Humerus fracture  1  0/152 (0.00%)  0 0/154 (0.00%)  0 0/134 (0.00%)  0 1/134 (0.75%)  1
Lower limb fracture  1  0/152 (0.00%)  0 0/154 (0.00%)  0 0/134 (0.00%)  0 1/134 (0.75%)  1
Overdose  1  0/152 (0.00%)  0 0/154 (0.00%)  0 0/134 (0.00%)  0 1/134 (0.75%)  1
Post procedural haemorrhage  1  0/152 (0.00%)  0 0/154 (0.00%)  0 1/134 (0.75%)  1 0/134 (0.00%)  0
Radius fracture  1  0/152 (0.00%)  0 0/154 (0.00%)  0 0/134 (0.00%)  0 1/134 (0.75%)  1
Ulna fracture  1  0/152 (0.00%)  0 0/154 (0.00%)  0 0/134 (0.00%)  0 1/134 (0.75%)  1
Investigations         
Blood creatinine increased  1  0/152 (0.00%)  0 0/154 (0.00%)  0 1/134 (0.75%)  1 0/134 (0.00%)  0
Metabolism and nutrition disorders         
Dehydration  1  0/152 (0.00%)  0 0/154 (0.00%)  0 1/134 (0.75%)  1 1/134 (0.75%)  1
Diabetes mellitus  1  0/152 (0.00%)  0 0/154 (0.00%)  0 1/134 (0.75%)  1 0/134 (0.00%)  0
Obesity  1  0/152 (0.00%)  0 0/154 (0.00%)  0 1/134 (0.75%)  1 0/134 (0.00%)  0
Musculoskeletal and connective tissue disorders         
Arthralgia  1  0/152 (0.00%)  0 0/154 (0.00%)  0 1/134 (0.75%)  1 0/134 (0.00%)  0
Pain in extremity  1  0/152 (0.00%)  0 0/154 (0.00%)  0 1/134 (0.75%)  1 0/134 (0.00%)  0
Systemic lupus erythematosus  1  1/152 (0.66%)  1 0/154 (0.00%)  0 1/134 (0.75%)  1 3/134 (2.24%)  4
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Acute lymphocytic leukaemia  1  0/152 (0.00%)  0 0/154 (0.00%)  0 1/134 (0.75%)  1 0/134 (0.00%)  0
Lipoma  1  1/152 (0.66%)  1 0/154 (0.00%)  0 0/134 (0.00%)  0 0/134 (0.00%)  0
Lymphoma  1  1/152 (0.66%)  1 0/154 (0.00%)  0 0/134 (0.00%)  0 0/134 (0.00%)  0
Metastases to lung  1  1/152 (0.66%)  1 0/154 (0.00%)  0 0/134 (0.00%)  0 0/134 (0.00%)  0
Metastasis  1  0/152 (0.00%)  0 0/154 (0.00%)  0 1/134 (0.75%)  1 0/134 (0.00%)  0
Nervous system disorders         
Altered state of consciousness  1  0/152 (0.00%)  0 0/154 (0.00%)  0 0/134 (0.00%)  0 1/134 (0.75%)  1
Aphasia  1  0/152 (0.00%)  0 0/154 (0.00%)  0 1/134 (0.75%)  1 0/134 (0.00%)  0
Convulsion  1  0/152 (0.00%)  0 0/154 (0.00%)  0 1/134 (0.75%)  1 2/134 (1.49%)  2
Encephalitis  1  0/152 (0.00%)  0 0/154 (0.00%)  0 1/134 (0.75%)  1 0/134 (0.00%)  0
Epilepsy  1  0/152 (0.00%)  0 0/154 (0.00%)  0 0/134 (0.00%)  0 1/134 (0.75%)  1
Intracranial pressure increased  1  0/152 (0.00%)  0 0/154 (0.00%)  0 1/134 (0.75%)  1 0/134 (0.00%)  0
Psychiatric disorders         
Somatoform disorder neurologic  1  0/152 (0.00%)  0 0/154 (0.00%)  0 0/134 (0.00%)  0 1/134 (0.75%)  1
Renal and urinary disorders         
Glomerulonephritis  1  0/152 (0.00%)  0 0/154 (0.00%)  0 1/134 (0.75%)  1 0/134 (0.00%)  0
Glomerulonephritis membranoproliferative  1  0/152 (0.00%)  0 0/154 (0.00%)  0 1/134 (0.75%)  1 0/134 (0.00%)  0
Haematuria  1  0/152 (0.00%)  0 0/154 (0.00%)  0 2/134 (1.49%)  2 1/134 (0.75%)  1
Hydronephrosis  1  1/152 (0.66%)  1 0/154 (0.00%)  0 0/134 (0.00%)  0 0/134 (0.00%)  0
Lupus nephritis  1  0/152 (0.00%)  0 0/154 (0.00%)  0 0/134 (0.00%)  0 1/134 (0.75%)  1
Nephrotic syndrome  1  0/152 (0.00%)  0 0/154 (0.00%)  0 1/134 (0.75%)  1 0/134 (0.00%)  0
Proteinuria  1  0/152 (0.00%)  0 1/154 (0.65%)  1 1/134 (0.75%)  1 1/134 (0.75%)  1
Renal failure  1  0/152 (0.00%)  0 0/154 (0.00%)  0 1/134 (0.75%)  1 0/134 (0.00%)  0
Renal failure acute  1  0/152 (0.00%)  0 0/154 (0.00%)  0 3/134 (2.24%)  3 2/134 (1.49%)  2
Renal impairment  1  0/152 (0.00%)  0 0/154 (0.00%)  0 2/134 (1.49%)  2 1/134 (0.75%)  1
Urinary retention  1  0/152 (0.00%)  0 0/154 (0.00%)  0 0/134 (0.00%)  0 1/134 (0.75%)  1
Reproductive system and breast disorders         
Menorrhagia  1  0/152 (0.00%)  0 0/154 (0.00%)  0 0/134 (0.00%)  0 1/134 (0.75%)  1
Respiratory, thoracic and mediastinal disorders         
Asthma  1  0/152 (0.00%)  0 0/154 (0.00%)  0 0/134 (0.00%)  0 1/134 (0.75%)  1
Epistaxis  1  0/152 (0.00%)  0 0/154 (0.00%)  0 0/134 (0.00%)  0 1/134 (0.75%)  1
Skin and subcutaneous tissue disorders         
Erythema  1  0/152 (0.00%)  0 0/154 (0.00%)  0 1/134 (0.75%)  1 0/134 (0.00%)  0
Rash  1  0/152 (0.00%)  0 1/154 (0.65%)  1 0/134 (0.00%)  0 0/134 (0.00%)  0
Vascular disorders         
Hypotension  1  0/152 (0.00%)  0 0/154 (0.00%)  0 1/134 (0.75%)  1 0/134 (0.00%)  0
Hypovolaemic shock  1  0/152 (0.00%)  0 0/154 (0.00%)  0 0/134 (0.00%)  0 1/134 (0.75%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 13.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Losartan: Double-Blind Base Study Amlodipine/Placebo: Double-Blind Base Study Losartan Open-Label Extension Enalapril: Open-Label Extension
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   71/152 (46.71%)      66/154 (42.86%)      83/134 (61.94%)      78/134 (58.21%)    
Blood and lymphatic system disorders         
Anaemia  1  0/152 (0.00%)  0 0/154 (0.00%)  0 11/134 (8.21%)  12 8/134 (5.97%)  10
Gastrointestinal disorders         
Diarrhoea  1  8/152 (5.26%)  10 7/154 (4.55%)  7 12/134 (8.96%)  15 7/134 (5.22%)  9
Vomiting  1  6/152 (3.95%)  8 4/154 (2.60%)  4 16/134 (11.94%)  22 4/134 (2.99%)  4
General disorders         
Pyrexia  1  6/152 (3.95%)  6 2/154 (1.30%)  2 8/134 (5.97%)  10 7/134 (5.22%)  9
Infections and infestations         
Bronchitis  1  9/152 (5.92%)  10 8/154 (5.19%)  8 9/134 (6.72%)  13 9/134 (6.72%)  10
Gastroenteritis  1  3/152 (1.97%)  3 3/154 (1.95%)  3 9/134 (6.72%)  15 6/134 (4.48%)  10
Influenza  1  2/152 (1.32%)  2 1/154 (0.65%)  1 3/134 (2.24%)  4 7/134 (5.22%)  9
Nasopharyngitis  1  24/152 (15.79%)  28 19/154 (12.34%)  22 31/134 (23.13%)  40 20/134 (14.93%)  28
Pharyngitis  1  6/152 (3.95%)  6 6/154 (3.90%)  7 21/134 (15.67%)  44 20/134 (14.93%)  31
Pharyngotonsillitis  1  0/152 (0.00%)  0 1/154 (0.65%)  1 8/134 (5.97%)  11 6/134 (4.48%)  6
Upper respiratory tract infection  1  7/152 (4.61%)  8 9/154 (5.84%)  13 15/134 (11.19%)  50 9/134 (6.72%)  20
Urinary tract infection  1  2/152 (1.32%)  2 3/154 (1.95%)  3 10/134 (7.46%)  14 10/134 (7.46%)  15
Investigations         
Urine protein/creatinine ratio increased  1  0/152 (0.00%)  0 0/154 (0.00%)  0 8/134 (5.97%)  10 6/134 (4.48%)  8
Metabolism and nutrition disorders         
Hyperkalaemia  1  1/152 (0.66%)  1 0/154 (0.00%)  0 4/134 (2.99%)  5 9/134 (6.72%)  15
Nervous system disorders         
Dizziness  1  6/152 (3.95%)  6 3/154 (1.95%)  3 3/134 (2.24%)  3 7/134 (5.22%)  10
Headache  1  13/152 (8.55%)  24 20/154 (12.99%)  31 7/134 (5.22%)  19 12/134 (8.96%)  23
Renal and urinary disorders         
Proteinuria  1  0/152 (0.00%)  0 1/154 (0.65%)  1 8/134 (5.97%)  9 3/134 (2.24%)  3
Respiratory, thoracic and mediastinal disorders         
Cough  1  5/152 (3.29%)  6 6/154 (3.90%)  8 8/134 (5.97%)  9 11/134 (8.21%)  13
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 13.1
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.
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Senior Vice President, Global Clinical Development
Organization: Merck Sharp & Dohme Corp
Phone: 1-800-672-6372
EMail: ClinicalTrialsDisclosure@merck.com
Layout table for additonal information
Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT00568178     History of Changes
Other Study ID Numbers: 0954-326
2006-006415-74 ( EudraCT Number )
First Submitted: December 3, 2007
First Posted: December 5, 2007
Results First Submitted: August 11, 2009
Results First Posted: October 30, 2009
Last Update Posted: October 17, 2017