Proteinuria
Conditions
Brief summary
The purpose of this study is to evaluate the effects of losartan on proteinuria in pediatric patients.
Detailed description
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.
Interventions
Enalapril 2.5-, 5-, 10-, and 20-mg tablets or enalapril suspension (1 mg/mL), oral administration, once daily for 36 months.
DRUGLosartan Potassium
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.
OTHERComparator: Placebo (Losartan)
Placebo (losartan suspension), administered orally, once daily for 12 weeks
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
OTHERComparator: Placebo (amlodipine besylate)
Liquid suspension, 1mg/mL, titrated to 0.2 mg/kg/day (5 mg maximum dose) once daily, for 12 weeks
OTHERPlacebo (Losartan)
Normotensive patients randomized to losartan placebo for 12 weeks.
Sponsors
Organon and Co
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Months to 17 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Double-Blind Treatment Phase: Percent Change From Baseline in Urinary Protein/Creatinine (Pr/Cr) Ratio (gm/gm) at Week 12 | Baseline and 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. |
| Open Label Extension: Percent Change From Baseline of Urinary Pr/Cr Ratio (gm/gm) at Month 36 | Baseline and 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. |
| Open Label Extension: Change From Baseline in Glomerular Filtration Rate (GFR) at Month 36 | Baseline and 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. |
Secondary
| Measure | 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 |
Participant flow
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.
Participants by arm
| Arm | Count |
|---|---|
| Losartan 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. | 152 |
| Amlodipine/Placebo 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. | 154 |
| Total | 306 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Double Blind Base Study | Adverse Event | 0 | 2 | 1 | 2 | 0 | 0 |
| Double Blind Base Study | Lost to Follow-up | 1 | 0 | 0 | 1 | 0 | 0 |
| Double Blind Base Study | Physician Decision | 1 | 1 | 0 | 1 | 0 | 0 |
| Double Blind Base Study | Progressive Disease | 0 | 0 | 0 | 1 | 0 | 0 |
| Double Blind Base Study | Protocol Violation | 3 | 2 | 0 | 0 | 0 | 0 |
| Double Blind Base Study | Withdrawal by Subject | 1 | 1 | 0 | 0 | 0 | 0 |
| Open Label Extension | Adverse Event | 0 | 0 | 0 | 0 | 11 | 8 |
| Open Label Extension | Lost to Follow-up | 0 | 0 | 0 | 0 | 6 | 11 |
| Open Label Extension | Physician Decision | 0 | 0 | 0 | 0 | 9 | 8 |
| Open Label Extension | Pregnancy | 0 | 0 | 0 | 0 | 0 | 1 |
| Open Label Extension | Progressive Disease | 0 | 0 | 0 | 0 | 3 | 1 |
| Open Label Extension | Protocol Violation | 0 | 0 | 0 | 0 | 1 | 0 |
| Open Label Extension | Termination of Trial | 0 | 0 | 0 | 0 | 45 | 47 |
| Open Label Extension | Withdrawal by Subject | 0 | 0 | 0 | 0 | 4 | 4 |
Baseline characteristics
| Characteristic | Losartan | Total | Amlodipine/Placebo |
|---|---|---|---|
| Age, Continuous | 10.4 years STANDARD_DEVIATION 4.7 | 10.1 years STANDARD_DEVIATION 4.7 | 9.7 years STANDARD_DEVIATION 4.6 |
| Age, Customized 13-17 Years of Age | 62 participants | 117 participants | 55 participants |
| Age, Customized ≤6 Years of Age | 33 participants | 75 participants | 42 participants |
| Age, Customized 7-12 Years of Age | 57 participants | 114 participants | 57 participants |
| Body Mass Index (BMI) | 19.8 kilograms per meter squared (kg/m2) STANDARD_DEVIATION 5.5 | 19.5 kilograms per meter squared (kg/m2) STANDARD_DEVIATION 4.9 | 19.2 kilograms per meter squared (kg/m2) STANDARD_DEVIATION 4.2 |
| Duration of Hypertension | 4.8 Years STANDARD_DEVIATION 4.1 | 5.5 Years STANDARD_DEVIATION 4.5 | 6.1 Years STANDARD_DEVIATION 4.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 79 Participants | 161 Participants | 82 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 73 Participants | 145 Participants | 72 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Height | 135.8 Centimeters (cm) STANDARD_DEVIATION 27.3 | 133.9 Centimeters (cm) STANDARD_DEVIATION 27.9 | 132.0 Centimeters (cm) STANDARD_DEVIATION 28.4 |
| Hypertensive No | 122 Participants | 246 Participants | 124 Participants |
| Hypertensive Yes | 30 Participants | 60 Participants | 30 Participants |
| Prior Angiotensin Converting Enzyme Inhibitor /Angiotensin II Type I Receptor Blocker (ACE-I/ARB)Use No | 69 Participants | 142 Participants | 73 Participants |
| Prior Angiotensin Converting Enzyme Inhibitor /Angiotensin II Type I Receptor Blocker (ACE-I/ARB)Use Yes | 83 Participants | 164 Participants | 81 Participants |
| Protein-to-Creatinine Ratio | 2.2 grams/grams STANDARD_DEVIATION 2.6 | 2.5 grams/grams STANDARD_DEVIATION 3.3 | 2.8 grams/grams STANDARD_DEVIATION 3.8 |
| Race Asian | 26 participants | 52 participants | 26 participants |
| Race Black | 5 participants | 10 participants | 5 participants |
| Race Multi-Racial | 36 participants | 70 participants | 34 participants |
| Race Other | 8 participants | 12 participants | 4 participants |
| Race White | 77 participants | 162 participants | 85 participants |
| Region Outside of United States | 137 Participants | 281 Participants | 144 Participants |
| Region United States | 15 Participants | 25 Participants | 10 Participants |
| Sex: Female, Male Female | 66 Participants | 130 Participants | 64 Participants |
| Sex: Female, Male Male | 86 Participants | 176 Participants | 90 Participants |
| Sitting Diastolic Blood Pressure | 66.8 millimeters of mercury (mm Hg) STANDARD_DEVIATION 10.7 | 67.3 millimeters of mercury (mm Hg) STANDARD_DEVIATION 11.2 | 67.8 millimeters of mercury (mm Hg) STANDARD_DEVIATION 11.6 |
| Sitting Systolic Blood Pressure | 106.0 mm Hg STANDARD_DEVIATION 13.4 | 106.6 mm Hg STANDARD_DEVIATION 13.6 | 107.2 mm Hg STANDARD_DEVIATION 13.8 |
| Tanner Stage Stage I | 69 Participants | 147 Participants | 78 Participants |
| Tanner Stage Stage II | 26 Participants | 47 Participants | 21 Participants |
| Tanner Stage Stage III | 22 Participants | 40 Participants | 18 Participants |
| Tanner Stage Stage IV | 23 Participants | 47 Participants | 24 Participants |
| Tanner Stage Stage V | 12 Participants | 25 Participants | 13 Participants |
| Weight | 39.6 Kilograms (kg) STANDARD_DEVIATION 21 | 38.0 Kilograms (kg) STANDARD_DEVIATION 20.3 | 36.4 Kilograms (kg) STANDARD_DEVIATION 19.5 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 71 / 152 | 66 / 154 | 83 / 134 | 78 / 134 |
| serious Total, serious adverse events | 8 / 152 | 5 / 154 | 27 / 134 | 25 / 134 |
Outcome results
Primary
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.
Time frame: Baseline and Week 12
Population: 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 | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Losartan | Double-Blind Treatment Phase: Percent Change From Baseline in Urinary Protein/Creatinine (Pr/Cr) Ratio (gm/gm) at Week 12 | -35.80 Percent Change in Pr/Cr |
| Amlodipine/Placebo | Double-Blind Treatment Phase: Percent Change From Baseline in Urinary Protein/Creatinine (Pr/Cr) Ratio (gm/gm) at Week 12 | 1.37 Percent Change in Pr/Cr |
p-value: 0.00195% CI: [0.54, 0.74]Mixed Models Analysis
Primary
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.
Time frame: Baseline and Month 36
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Losartan | Open Label Extension: Change From Baseline in Glomerular Filtration Rate (GFR) at Month 36 | 3.3 Change in GFR mL/min1.73m^2 | 95% Confidence Interval 66.3 |
| Amlodipine/Placebo | Open Label Extension: Change From Baseline in Glomerular Filtration Rate (GFR) at Month 36 | 7.0 Change in GFR mL/min1.73m^2 | 95% Confidence Interval 53.2 |
95% CI: [-15.2, 7.6]Mixed Models Analysis
Primary
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.
Time frame: Baseline and Month 36
Population: 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 | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Losartan | Open Label Extension: Percent Change From Baseline of Urinary Pr/Cr Ratio (gm/gm) at Month 36 | -30.01 Percent Change in Pr/Cr | 95% Confidence Interval 5.02 |
| Amlodipine/Placebo | Open Label Extension: Percent Change From Baseline of Urinary Pr/Cr Ratio (gm/gm) at Month 36 | -40.45 Percent Change in Pr/Cr | 95% Confidence Interval 2.1 |
95% CI: [0.86, 1.6]Mixed Models Analysis
Secondary
Double-Blind Treatment Phase: Change From Baseline in Diastolic Blood Pressure in Hypertensive Participants at Week 12
Time frame: Baseline and Week 12
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Losartan | Double-Blind Treatment Phase: Change From Baseline in Diastolic Blood Pressure in Hypertensive Participants at Week 12 | -3.8 mm Hg |
| Amlodipine/Placebo | Double-Blind Treatment Phase: Change From Baseline in Diastolic Blood Pressure in Hypertensive Participants at Week 12 | 0.8 mm Hg |
95% CI: [-9.2, -0.1]Mixed Models Analysis
Secondary
Double-Blind Treatment Phase: Change From Baseline in Systolic Blood Pressure in Hypertensive Participants at Week 12
Time frame: Baseline and Week 12
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Losartan | Double-Blind Treatment Phase: Change From Baseline in Systolic Blood Pressure in Hypertensive Participants at Week 12 | -5.5 mm Hg |
| Amlodipine/Placebo | Double-Blind Treatment Phase: Change From Baseline in Systolic Blood Pressure in Hypertensive Participants at Week 12 | -0.1 mm Hg |
95% CI: [-9.9, -1]Mixed Models Analysis