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PTN_LISINO: Safety Study of Lisinopril in Children and Adolescents With a Kidney Transplant

Sponsor
Uptal Patel (Other)
Overall Status
Completed
CT.gov ID
NCT01491919
Collaborator
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH), The Emmes Company, LLC (Industry), University of Rochester (Other), OpAns, LLC (Other)
26
Enrollment
7
Locations
3
Arms
15
Duration (Months)
3.7
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The drug lisinopril is approved by the U.S. Food and Drug Administration for the treatment of high blood pressure, heart failure, and acute heart attacks in adult patients. In children over 6 years of age, lisinopril is approved for the treatment of high blood pressure. Lisinopril is in a group of medications called angiotensin-converting enzyme inhibitors (ACE). ACE inhibitors such as lisinopril work by decreasing certain chemicals that tighten the blood vessels so blood flows more smoothly and the heart can pump blood more efficiently.

There is some information available about how children with high blood pressure absorb, distribute, metabolize, and eliminate lisinopril (this information about medication processing by the body is called pharmacokinetic data). However, there is no information about how children with high blood pressure who have received a kidney transplant process lisinopril. In addition to decreasing blood pressure, investigators believe that lisinopril may help kidney transplants work longer by reducing the activity of chemicals made by cells in kidney transplants that can lead to inflammation and injury. Such benefits have not been found with another group of blood pressure medications called calcium channel blockers, which are the most commonly used medication group to control high blood pressure in children after a kidney transplant. A clinical trial will be conducted in the future to compare which medication group helps kidney transplants in children last longer. To guide the selection of the best dose to test in future studies, investigators in this study will try to determine the safety profile, dose tolerability, and pharmacokinetics of lisinopril in children and adolescents (2-17 years of age) who have received a kidney transplant and have high blood pressure.

Condition or Disease Intervention/Treatment Phase
Phase 1

Study Design

Study Type:
Interventional
Actual Enrollment :
26 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Safety and Pharmacokinetics of Lisinopril in Pediatric Kidney Transplant Recipients
Study Start Date :
Jun 1, 2012
Actual Primary Completion Date :
Sep 1, 2013
Actual Study Completion Date :
Sep 1, 2013

Arms and Interventions

Arm Intervention/Treatment
Experimental: Low Dose: Lisinopril

Participants will receive study medication for 14±3 days at a dose 0.1 mg/kg/day

Drug: Lisinopril
Subjects will be randomized to Low, Medium, or High dose of Lisinopril
Experimental: Medium Dose: Lisinopril

Participants will receive study medication for 14±3 days at a dose 0.2 mg/kg/day

Drug: Lisinopril
Subjects will be randomized to Low, Medium, or High dose of Lisinopril
Experimental: High Dose: Lisinopril

Participants will initially receive study medication at 0.2 mg/kg/day for 5±2 days. If blood tests exclude drug-related toxicity, then the lisinopril dose will be increased to 0.4 mg/kg/day and participants will continue to complete the 14±3 day Treatment Period.

Drug: Lisinopril
Subjects will be randomized to Low, Medium, or High dose of Lisinopril

Outcome Measures

Primary Outcome Measures

  1. Pharmacokinetics (PK) - Area Under the Plasma Concentration-time Curve (AUC) [Day 14 (+/- 3 days) of lisinopril therapy at hours 0 (pre-dose) and 1,2,4,5,8,12 and 24 hrs after dose]

    At the Day 14 (±3 days) visit, blood (1 mL) will be collected at 0 hour (pre-dose) and at 1, 2, 4, 5, 8, 12 and 24 hours post-lisinopril dose for determination of AUC. Geometric mean was calculated from all measurements.

  2. PK - Maximum Observed Concentration of Drug in Plasma (Cmax) [Day14 (+/- 3 d) of dose at 0 hour and 1, 2, 4, 5, 8, 12, and 24 hrs after dose]

    At the Day 14 (±3 days) visit, blood (1 mL) will be collected at 0 hour (pre-dose) and at 1, 2, 4, 5, 8, 12 and 24 hours post-lisinopril dose for determination of Cmax. Geometric mean was calculated from all measurements.

  3. PK - Time of the Maximum Observed Concentration in Plasma (Tmax) [Day 14 (+/- 3 d) of dose at 0 hour and 1, 2, 4, 5, 8, 12, and 24 hrs after dose]

    At the Day 14 (±3 days) visit, blood (1 mL) will be collected at 0 hour (pre-dose) and at 1, 2, 4, 5, 8, 12 and 24 hours post-lisinopril dose for determination of plasma lisinopril concentration. Medium was calculated from all measurements.

  4. PK - Oral Clearance (CL/F) [Day 14 (+/- 3 d) of dose at 0 hour and at 1, 2, 4, 5, 8, 12, and 24 hrs after dose]

    At the Day 14 (±3 days) visit, blood (1 mL) will be collected at 0 hour (pre-dose) and at 1, 2, 4, 5, 8, 12 and 24 hours post-lisinopril dose for determination of CL/F. Geometric mean was calculated from all measurements.

  5. PK Renal Clearance (CLrenal) [Day 14 (+/- 3 d) of dose at 0 hour and 1, 2, 4, 5, 8, 12, and 24 hrs after dose.]

    At the Day 14 (±3 days) visit, blood (1 mL) will be collected at 0 hour (pre-dose) and at 1, 2, 4, 5, 8, 12 and 24 hours post-lisinopril dose for determination of CLrenal. Geometric mean was calculated from all measurements.

  6. Number of Adverse Events (AEs) and Serious Adverse Events (SAEs) During/After Study Drug Administration [First dose of study drug to 30 days after final study visit for AEs and until resolution for SAEs]

    Number of Adverse Events (AEs) related and not related to study drug; number of Serious Adverse Events (SAEs) related and not related to study drug

Secondary Outcome Measures

  1. Change in Potassium Level From Baseline in Lisinopril-naive Participants [At baseline visit and Day 14 prior to final study dose.]

    Potassium values will be obtained at Baseline and Day 14 prior to the final dose of study drug. Mean calculated from the two measurements.

  2. Worse Post-dose Decrease in Estimated Glomerular Filtration Rate (eGFR) From Baseline in Lisinopril-naive Participants [Baseline to Day 14 (+/- 3 days)]

    The eGFR at entry will need to be ≥ 30 ml/min/1.73m^2 to minimize concerns about an acute angiotensin-converting enzyme inhibitors (ACE-I)-mediated reduction in kidney function. eGFR ratio was computed from the worst post-dose value divided by the Baseline value.

  3. Largest eGFR Percent Decrease From Baseline in Lisinopril-naive Participants [Baseline to Day 14 (+/- 3 days)]

    The eGFR at entry will need to be ≥ 30 ml/min/1.73m^2 to minimize concerns about an acute angiotensin-converting enzyme inhibitor (ACEI) mediated reduction in kidney function. Largest eGFR percent decrease from baseline reported in results section.

  4. Change in Urine Protein/Creatinine From Baseline in Lisinopril-naive Participants. [Baseline to worst post-dose before Day 14 (+/- 3 days)]

    Change in urine protein/creatinine obtained as follows: Mean change (worst post-dose from baseline) presented for urine protein/creatinine ratio. Geometric mean of the ratio (worst post-dose / baseline with Geometric Coefficient of Variation percent (CV%) and greatest decrease presented for eGFR by dose group. Two patients in the high dose group had an evaluable urine protein/creatinine change.

  5. Change in Diastolic Blood Pressure From Baseline in Lisinopril-naive Participants [Baseline to Day 14 (+/-3 days)]

    Ambulatory blood pressure readings were measured during the baseline/pre-study dose period using a SpaceLabs (Redmond, WA) device at home to avoid the confounding effects of venipuncture and abnormal sleep pattern. Another blood pressure reading was performed at 1 day before the final dose of lisinopril (day before the last scheduled visit). The mean of these measurements was calculated.

  6. Change in Systolic Blood Pressure From Baseline in Lisinopril-naive Participants [Baseline to Day 14 (+/- 3 days)]

    Ambulatory blood pressure readings were measured during the baseline/pre-study dose period using a SpaceLabs (Redmond, WA) device at home to avoid the confounding effects of venipuncture and abnormal sleep pattern. Another blood pressure reading was performed at 1 day before the final dose of lisinopril (day before the last scheduled visit). The mean from these measurements was calculated.

  7. Change in Systolic Blood Pressure (BP) From Baseline in Lisinopril SOC Group [Screening to Day 14 to 40]

    Lisinopril SOC participants were not given the ambulatory blood pressure machine to obtain readings at home, as was the Lisinopril-naive participants. Instead BP measurements were obtained during screening visit and compared to the Day 14 to 40 visit measurements. Note: these participants were not required to attend a Day 14 (+/-3 day visit) but did need to attend sometime between Day 14 to Day 40 (inclusive). The mean of these blood pressure measurements was calculated.

  8. Change in Diastolic Blood Pressure From Baseline in Lisinopril SOC Group [Screening to Day 14 to 40]

    Lisinopril SOC participants were not given the ambulatory blood pressure machine to obtain readings at home, as was the Lisinopril-naive participants. Instead BP measurements were obtained during screening visit and compared to the Day 14 to 40 visit measurements (note: the participants were not required to attend a Day 14 (+/-3 day visit) but did need to attend sometime between Day 14 to Day 40. The mean from the blood pressure measurements was calculated.

Eligibility Criteria

Criteria

Ages Eligible for Study:
2 Years to 17 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:

  1. Kidney transplant recipient

  2. Age 2-17 years, inclusive, at the time of first study dose

  3. Estimated GFR (eGFR) ≥30 ml/min/1.73m2, with stable allograft function as indicated by <20% change in serum creatinine in the previous 30 days

  4. Stable immunosuppressive regimen, as indicated by <10% change in dosage (in mg/kg) in these medications, within the 14 days prior to enrollment

  5. Systolic BP >90th percentile for age, gender, and height, necessitating initiation or addition of an antihypertensive medication

  6. For females of child-bearing potential, a negative serum pregnancy test prior to initial dosing and agreement to practice appropriate contraceptive measures, including abstinence, from the time of the initial pregnancy testing through the remainder of the study (30 days after last administration of investigational agents).

Exclusion Criteria:

  1. History of anaphylaxis attributable to lisinopril or other angiotensin-converting enzyme inhibitor (ACEI) agents (e.g.,enalapril, ramipril, quinapril)

  2. History of anaphylaxis attributable to iohexol or an iodine hypersensitivity

  3. Use of an angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker, or renin antagonist within 30 days prior to enrollment

  4. Stage 2 hypertension defined as the >99th percentile for age, height and gender + 5 mm Hg

  5. Blood Potassium value > 6.0 milliequivalent / liter (mEq/L) (as determined at the screening visit)

  6. Previous participation in this study

  7. Physician concern that the participant may not adhere to the study protocol, based on prior behavior

  8. Current plasmapheresis treatment

  9. History of angioedema

  10. Pregnancy

Contacts and Locations

Locations

Site City State Country Postal Code
1 University of Alabama Birmingham Alabama United States 35233
2 Arkansas Children's Hospital Little Rock Arkansas United States 72202
3 Emory University and Children's Healthcare of Atlanta Atlanta Georgia United States 30322
4 University of Michigan Ann Arbor Michigan United States 48109
5 Children's Mercy Hospitals & Clinics Kansas City Missouri United States 64108
6 New York University Langone Medical Center New York New York United States 10016
7 Cincinnati Children's Hospital Medical Center Cincinnati Ohio United States 45229

Sponsors and Collaborators

  • Uptal Patel
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
  • The Emmes Company, LLC
  • University of Rochester
  • OpAns, LLC

Investigators

  • Study Director: Daniel Benjamin, MD, PhD, MPH, Duke University
  • Study Chair: Howard Trachtman, MD, NYU Langone Health
  • Principal Investigator: Uptal D Patel, MD, Duke University
  • Principal Investigator: Adam Frymoyer, MD, Stanford University

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

Publications

Responsible Party:
Uptal Patel, Assoc Professor of Medicine, Duke University
ClinicalTrials.gov Identifier:
NCT01491919
Other Study ID Numbers:
  • Pro00029537
  • HHSN275201000003I
First Posted:
Dec 14, 2011
Last Update Posted:
Jul 8, 2015
Last Verified:
Jun 1, 2015
Keywords provided by Uptal Patel, Assoc Professor of Medicine, Duke University
High Blood Pressure
Hypertension
Renal Transplantation
Kidney Transplantation
Additional relevant MeSH terms:
Hypertension
Lisinopril

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail
Arm/Group Title Low Dose: Lisinopril Medium Dose: Lisinopril High Dose: Lisinopril
Arm/Group Description Participants will receive study medication for 14±3 days at a dose 0.1 mg/kg/day Participants will receive study medication for 14±3 days at a dose 0.2 mg/kg/day Participants will initially receive study medication at 0.2 mg/kg/day for 5±2 days. If blood tests exclude drug-related toxicity, then the lisinopril dose will be increased to 0.4 mg/kg/day and participants will continue to complete the 14±3 day Treatment Period.
Period Title: Overall Study
STARTED 13 10 3
COMPLETED 12 8 2
NOT COMPLETED 1 2 1

Baseline Characteristics

Arm/Group Title Low Dose: Lisinopril Medium Dose: Lisinopril High Dose: Lisinopril Total
Arm/Group Description Participants will receive study medication for 14±3 days at a dose 0.1 mg/kg/day Participants will receive study medication for 14±3 days at a dose 0.2 mg/kg/day Participants will initially receive study medication at 0.2 mg/kg/day for 5±2 days. If blood tests exclude drug-related toxicity, then the lisinopril dose will be increased to 0.4 mg/kg/day and participants will continue to complete the 14±3 day Treatment Period. Total of all reporting groups
Overall Participants 12 8 2 22
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
14.9
(2.3)
13.0
(3)
9.5
(3.5)
13.8
(3)
Sex: Female, Male (Count of Participants)
Female
4
33.3%
2
25%
1
50%
7
31.8%
Male
8
66.7%
6
75%
1
50%
15
68.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
0
0%
1
12.5%
0
0%
1
4.5%
Asian
0
0%
0
0%
0
0%
0
0%
Native Hawaiian or Other Pacific Islander
0
0%
0
0%
0
0%
0
0%
Black or African American
3
25%
4
50%
0
0%
7
31.8%
White
7
58.3%
2
25%
2
100%
11
50%
More than one race
0
0%
0
0%
0
0%
0
0%
Unknown or Not Reported
2
16.7%
1
12.5%
0
0%
3
13.6%
Region of Enrollment (participants) [Number]
United States
12
100%
8
100%
2
100%
22
100%
Estimated glomerular filtration rate (eGFR) (ml/min per 1.73m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ml/min per 1.73m^2]
72.5
(25.7)
62
(16.7)
89.3
(44.4)
70.2
(24.4)
Time since transplant (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
4.8
(4.7)
4.9
(3.4)
0.9
(0.4)
4.5
(4.1)
Ethnicity (participants) [Number]
Hispanic/Latino
2
16.7%
2
25%
0
0%
4
18.2%
Non-hispanic/non-latino
10
83.3%
6
75%
2
100%
18
81.8%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]
56.8
(19.4)
50.2
(28.7)
23.1
(3.0)
51.3
(23.8)

Outcome Measures

1. Primary Outcome
Title Pharmacokinetics (PK) - Area Under the Plasma Concentration-time Curve (AUC)
Description At the Day 14 (±3 days) visit, blood (1 mL) will be collected at 0 hour (pre-dose) and at 1, 2, 4, 5, 8, 12 and 24 hours post-lisinopril dose for determination of AUC. Geometric mean was calculated from all measurements.
Time Frame Day 14 (+/- 3 days) of lisinopril therapy at hours 0 (pre-dose) and 1,2,4,5,8,12 and 24 hrs after dose

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Low Dose: Lisinopril Medium Dose: Lisinopril High Dose: Lisinopril
Arm/Group Description Participants will receive study medication for 14±3 days at a dose 0.1 mg/kg/day Participants will receive study medication for 14±3 days at a dose 0.2 mg/kg/day Participants will initially receive study medication at 0.2 mg/kg/day for 5±2 days. If blood tests exclude drug-related toxicity, then the lisinopril dose will be increased to 0.4 mg/kg/day and participants will continue to complete the 14±3 day Treatment Period.
Measure Participants 12 8 2
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]
298
(46.5)
640
(28.6)
702
(66.4)
2. Primary Outcome
Title PK - Maximum Observed Concentration of Drug in Plasma (Cmax)
Description At the Day 14 (±3 days) visit, blood (1 mL) will be collected at 0 hour (pre-dose) and at 1, 2, 4, 5, 8, 12 and 24 hours post-lisinopril dose for determination of Cmax. Geometric mean was calculated from all measurements.
Time Frame Day14 (+/- 3 d) of dose at 0 hour and 1, 2, 4, 5, 8, 12, and 24 hrs after dose

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Low Dose: Lisinopril Medium Dose: Lisinopril High Dose: Lisinopril
Arm/Group Description Participants will receive study medication for 14±3 days at a dose 0.1 mg/kg/day Participants will receive study medication for 14±3 days at a dose 0.2 mg/kg/day Participants will initially receive study medication at 0.2 mg/kg/day for 5±2 days. If blood tests exclude drug-related toxicity, then the lisinopril dose will be increased to 0.4 mg/kg/day and participants will continue to complete the 14±3 day Treatment Period.
Measure Participants 12 8 2
Geometric Mean (Geometric Coefficient of Variation) [ng/ml]
20.9
(41.2)
47.7
(25.1)
58.0
(41.2)
3. Secondary Outcome
Title Change in Potassium Level From Baseline in Lisinopril-naive Participants
Description Potassium values will be obtained at Baseline and Day 14 prior to the final dose of study drug. Mean calculated from the two measurements.
Time Frame At baseline visit and Day 14 prior to final study dose.

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Low Dose: Lisinopril Medium Dose: Lisinopril High Dose: Lisinopril
Arm/Group Description Participants will receive study medication for 14±3 days at a dose 0.1 mg/kg/day Participants will receive study medication for 14±3 days at a dose 0.2 mg/kg/day Participants will initially receive study medication at 0.2 mg/kg/day for 5±2 days. If blood tests exclude drug-related toxicity, then the lisinopril dose will be increased to 0.4 mg/kg/day and participants will continue to complete the 14±3 day Treatment Period.
Measure Participants 6 6 3
Mean (Standard Deviation) [mEq/L]
0.1
(0.3)
-0.3
(0.6)
0.3
(0.5)
4. Secondary Outcome
Title Worse Post-dose Decrease in Estimated Glomerular Filtration Rate (eGFR) From Baseline in Lisinopril-naive Participants
Description The eGFR at entry will need to be ≥ 30 ml/min/1.73m^2 to minimize concerns about an acute angiotensin-converting enzyme inhibitors (ACE-I)-mediated reduction in kidney function. eGFR ratio was computed from the worst post-dose value divided by the Baseline value.
Time Frame Baseline to Day 14 (+/- 3 days)

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Low Dose: Lisinopril Medium Dose: Lisinopril High Dose: Lisinopril
Arm/Group Description Participants will receive study medication for 14±3 days at a dose 0.1 mg/kg/day Participants will receive study medication for 14±3 days at a dose 0.2 mg/kg/day Participants will initially receive study medication at 0.2 mg/kg/day for 5±2 days. If blood tests exclude drug-related toxicity, then the lisinopril dose will be increased to 0.4 mg/kg/day and participants will continue to complete the 14±3 day Treatment Period.
Measure Participants 6 6 3
Geometric Mean (Geometric Coefficient of Variation) [ratio]
1
(14)
1.02
(10)
0.89
(14)
5. Primary Outcome
Title PK - Time of the Maximum Observed Concentration in Plasma (Tmax)
Description At the Day 14 (±3 days) visit, blood (1 mL) will be collected at 0 hour (pre-dose) and at 1, 2, 4, 5, 8, 12 and 24 hours post-lisinopril dose for determination of plasma lisinopril concentration. Medium was calculated from all measurements.
Time Frame Day 14 (+/- 3 d) of dose at 0 hour and 1, 2, 4, 5, 8, 12, and 24 hrs after dose

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Low Dose: Lisinopril Medium Dose: Lisinopril High Dose: Lisinopril
Arm/Group Description Participants will receive study medication for 14±3 days at a dose 0.1 mg/kg/day Participants will receive study medication for 14±3 days at a dose 0.2 mg/kg/day Participants will initially receive study medication at 0.2 mg/kg/day for 5±2 days. If blood tests exclude drug-related toxicity, then the lisinopril dose will be increased to 0.4 mg/kg/day and participants will continue to complete the 14±3 day Treatment Period.
Measure Participants 12 8 2
Median (Full Range) [hours]
5.0
5.0
4.5
6. Primary Outcome
Title PK - Oral Clearance (CL/F)
Description At the Day 14 (±3 days) visit, blood (1 mL) will be collected at 0 hour (pre-dose) and at 1, 2, 4, 5, 8, 12 and 24 hours post-lisinopril dose for determination of CL/F. Geometric mean was calculated from all measurements.
Time Frame Day 14 (+/- 3 d) of dose at 0 hour and at 1, 2, 4, 5, 8, 12, and 24 hrs after dose

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Low Dose: Lisinopril Medium Dose: Lisinopril High Dose: Lisinopril
Arm/Group Description Participants will receive study medication for 14±3 days at a dose 0.1 mg/kg/day Participants will receive study medication for 14±3 days at a dose 0.2 mg/kg/day Participants will initially receive study medication at 0.2 mg/kg/day for 5±2 days. If blood tests exclude drug-related toxicity, then the lisinopril dose will be increased to 0.4 mg/kg/day and participants will continue to complete the 14±3 day Treatment Period.
Measure Participants 12 8 2
Geometric Mean (Geometric Coefficient of Variation) [L/h/70 kg]
17.9
(61.2)
18.6
(34.4)
32.8
(54.1)
7. Primary Outcome
Title PK Renal Clearance (CLrenal)
Description At the Day 14 (±3 days) visit, blood (1 mL) will be collected at 0 hour (pre-dose) and at 1, 2, 4, 5, 8, 12 and 24 hours post-lisinopril dose for determination of CLrenal. Geometric mean was calculated from all measurements.
Time Frame Day 14 (+/- 3 d) of dose at 0 hour and 1, 2, 4, 5, 8, 12, and 24 hrs after dose.

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Low Dose: Lisinopril Medium Dose: Lisinopril High Dose: Lisinopril
Arm/Group Description Participants will receive study medication for 14±3 days at a dose 0.1 mg/kg/day Participants will receive study medication for 14±3 days at a dose 0.2 mg/kg/day Participants will initially receive study medication at 0.2 mg/kg/day for 5±2 days. If blood tests exclude drug-related toxicity, then the lisinopril dose will be increased to 0.4 mg/kg/day and participants will continue to complete the 14±3 day Treatment Period.
Measure Participants 12 8 2
Geometric Mean (Geometric Coefficient of Variation) [L/h/70 kg]
3.4
(60.4)
3.4
(46.0)
6.8
(94.4)
8. Primary Outcome
Title Number of Adverse Events (AEs) and Serious Adverse Events (SAEs) During/After Study Drug Administration
Description Number of Adverse Events (AEs) related and not related to study drug; number of Serious Adverse Events (SAEs) related and not related to study drug
Time Frame First dose of study drug to 30 days after final study visit for AEs and until resolution for SAEs

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Lisinopril-naive Lisinopril Standard of Care (SOC)
Arm/Group Description These protocol participants were not randomized. Instead, the older age group (7-17 years) were first enrolled consecutively into each dose level, starting with the lowest dose level (0.1 mg/kg per day). After enrollment is complete in the low dose level for an eGFR strata, enrollment will commence for the intermediate (0.2 mg/kg per day) dosage in that strata, followed by the high (0.4 mg/kg per day) dosage level. Enrollment for the 2-6 years age group did not begin until enrollment in the older age group (7-17 years) for the low and intermediate dosage level at each eGFR strata is complete. These protocol participants were enrolled and continued on the lisinopril dose prescribed as standard of care. They were assigned to the appropriate eGFR and dose level stratum (rounding to the closest dose level). Since the lisinopril dose was assigned based on standard of care, a patient was enrolled without regard to open/closed status of the dose stratum in this group. Therefore, over enrollment of a specific dose and eGFR stratum was allowed for participants enrolled he the Lisinopril-naive group to accommodate these valuable low-risk participants already taking lisinopril.
Measure Participants 15 11
AEs
12
12
AE related to study drug
5
0
AEs not related to study drug
7
12
SAE
1
0
SAE not related to study drug
1
0
9. Secondary Outcome
Title Largest eGFR Percent Decrease From Baseline in Lisinopril-naive Participants
Description The eGFR at entry will need to be ≥ 30 ml/min/1.73m^2 to minimize concerns about an acute angiotensin-converting enzyme inhibitor (ACEI) mediated reduction in kidney function. Largest eGFR percent decrease from baseline reported in results section.
Time Frame Baseline to Day 14 (+/- 3 days)

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Low Dose: Lisinopril Medium Dose: Lisinopril High Dose: Lisinopril
Arm/Group Description Participants will receive study medication for 14±3 days at a dose 0.1 mg/kg/day Participants will receive study medication for 14±3 days at a dose 0.2 mg/kg/day Participants will initially receive study medication at 0.2 mg/kg/day for 5±2 days. If blood tests exclude drug-related toxicity, then the lisinopril dose will be increased to 0.4 mg/kg/day and participants will continue to complete the 14±3 day Treatment Period.
Measure Participants 6 6 3
Number [percentage]
15
12
21
10. Secondary Outcome
Title Change in Urine Protein/Creatinine From Baseline in Lisinopril-naive Participants.
Description Change in urine protein/creatinine obtained as follows: Mean change (worst post-dose from baseline) presented for urine protein/creatinine ratio. Geometric mean of the ratio (worst post-dose / baseline with Geometric Coefficient of Variation percent (CV%) and greatest decrease presented for eGFR by dose group. Two patients in the high dose group had an evaluable urine protein/creatinine change.
Time Frame Baseline to worst post-dose before Day 14 (+/- 3 days)

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Low Dose: Lisinopril Medium Dose: Lisinopril High Dose: Lisinopril
Arm/Group Description Participants will receive study medication for 14±3 days at a dose 0.1 mg/kg/day Participants will receive study medication for 14±3 days at a dose 0.2 mg/kg/day Participants will initially receive study medication at 0.2 mg/kg/day for 5±2 days. If blood tests exclude drug-related toxicity, then the lisinopril dose will be increased to 0.4 mg/kg/day and participants will continue to complete the 14±3 day Treatment Period.
Measure Participants 6 6 3
Geometric Mean (Geometric Coefficient of Variation) [mg/mg]
-0.45
(0.6)
-0.08
(0.15)
-0.74
(1.37)
11. Secondary Outcome
Title Change in Diastolic Blood Pressure From Baseline in Lisinopril-naive Participants
Description Ambulatory blood pressure readings were measured during the baseline/pre-study dose period using a SpaceLabs (Redmond, WA) device at home to avoid the confounding effects of venipuncture and abnormal sleep pattern. Another blood pressure reading was performed at 1 day before the final dose of lisinopril (day before the last scheduled visit). The mean of these measurements was calculated.
Time Frame Baseline to Day 14 (+/-3 days)

Outcome Measure Data

Analysis Population Description
Change in diastolic blood pressure from baseline is reported here for lisinopril-naive participants (not the standard of care group which are reported separately).
Arm/Group Title Low Dose: Lisinopril Medium Dose: Lisinopril High Dose: Lisinopril
Arm/Group Description Participants will receive study medication for 14±3 days at a dose 0.1 mg/kg/day Participants will receive study medication for 14±3 days at a dose 0.2 mg/kg/day Participants will initially receive study medication at 0.2 mg/kg/day for 5±2 days. If blood tests exclude drug-related toxicity, then the lisinopril dose will be increased to 0.4 mg/kg/day and participants will continue to complete the 14±3 day Treatment Period.
Measure Participants 6 6 3
eGFR 30-59 ml/min per 1.73m^2 (n=3, 1, 0)
-4.0
(20)
7.0
(0)
NA
(NA)
eGFR >=60 ml/min per 1.73m^2 (n=3, 5, 3)
-9.0
(7.5)
-6.0
(6.7)
-4.0
(5.3)
12. Secondary Outcome
Title Change in Systolic Blood Pressure From Baseline in Lisinopril-naive Participants
Description Ambulatory blood pressure readings were measured during the baseline/pre-study dose period using a SpaceLabs (Redmond, WA) device at home to avoid the confounding effects of venipuncture and abnormal sleep pattern. Another blood pressure reading was performed at 1 day before the final dose of lisinopril (day before the last scheduled visit). The mean from these measurements was calculated.
Time Frame Baseline to Day 14 (+/- 3 days)

Outcome Measure Data

Analysis Population Description
Change in systolic blood pressure from baseline is reported here for lisinopril-naive participants (not the standard of care (SOC) group which are reported separately).
Arm/Group Title Low Dose: Lisinopril Medium Dose: Lisinopril High Dose: Lisinopril
Arm/Group Description Participants will receive study medication for 14±3 days at a dose 0.1 mg/kg/day Participants will receive study medication for 14±3 days at a dose 0.2 mg/kg/day Participants will initially receive study medication at 0.2 mg/kg/day for 5±2 days. If blood tests exclude drug-related toxicity, then the lisinopril dose will be increased to 0.4 mg/kg/day and participants will continue to complete the 14±3 day Treatment Period.
Measure Participants 6 6 3
eGFR 30-59 ml/min per 1.73m2 (n=3, 1, 0)
-5.0
(11.4)
-6.0
(0)
NA
(NA)
eGFR >+60 ml/min per 1.732 (n=3, 5, 3)
-6.7
(4.0)
-8.8
(11.7)
-11.3
(2.1)
13. Secondary Outcome
Title Change in Systolic Blood Pressure (BP) From Baseline in Lisinopril SOC Group
Description Lisinopril SOC participants were not given the ambulatory blood pressure machine to obtain readings at home, as was the Lisinopril-naive participants. Instead BP measurements were obtained during screening visit and compared to the Day 14 to 40 visit measurements. Note: these participants were not required to attend a Day 14 (+/-3 day visit) but did need to attend sometime between Day 14 to Day 40 (inclusive). The mean of these blood pressure measurements was calculated.
Time Frame Screening to Day 14 to 40

Outcome Measure Data

Analysis Population Description
Change in systolic blood pressure from baseline is reported here for lisinopril SOCparticipants (not the Lisinopril-naive group which are reported separately).
Arm/Group Title Low Dose: Lisinopril Medium Dose: Lisinopril High Dose: Lisinopril
Arm/Group Description Participants will receive study medication for 14±3 days at a dose 0.1 mg/kg/day Participants will receive study medication for 14±3 days at a dose 0.2 mg/kg/day Participants will initially receive study medication at 0.2 mg/kg/day for 5±2 days. If blood tests exclude drug-related toxicity, then the lisinopril dose will be increased to 0.4 mg/kg/day and participants will continue to complete the 14±3 day Treatment Period.
Measure Participants 7 4 0
eGFR 30-59 ml/min per 1.73m2 (n=2, 2, 0)
-6.0
(17)
-1.0
(4.2)
eGFR >=60 ml/min per 1.73m2 (n=5, 2, 0)
6.4
(6.9)
-1.0
(0)
14. Secondary Outcome
Title Change in Diastolic Blood Pressure From Baseline in Lisinopril SOC Group
Description Lisinopril SOC participants were not given the ambulatory blood pressure machine to obtain readings at home, as was the Lisinopril-naive participants. Instead BP measurements were obtained during screening visit and compared to the Day 14 to 40 visit measurements (note: the participants were not required to attend a Day 14 (+/-3 day visit) but did need to attend sometime between Day 14 to Day 40. The mean from the blood pressure measurements was calculated.
Time Frame Screening to Day 14 to 40

Outcome Measure Data

Analysis Population Description
Change in diastolic blood pressure from baseline is reported here for lisinopril SOCparticipants (not the Lisinopril-naive group which are reported separately).
Arm/Group Title Low Dose: Lisinopril Medium Dose: Lisinopril High Dose: Lisinopril
Arm/Group Description Participants will receive study medication for 14±3 days at a dose 0.1 mg/kg/day Participants will receive study medication for 14±3 days at a dose 0.2 mg/kg/day Participants will initially receive study medication at 0.2 mg/kg/day for 5±2 days. If blood tests exclude drug-related toxicity, then the lisinopril dose will be increased to 0.4 mg/kg/day and participants will continue to complete the 14±3 day Treatment Period.
Measure Participants 7 4 0
eGFR 30-59 ml/min per 1.73m2 (n=2, 2, 0)
-6.0
(5.7)
-6.5
(9.2)
eGFR >=60 ml/min per 1.73m2 (n=5, 2, 0)
3.4
(14.0)
-3.0
(0)

Adverse Events

Time Frame
Adverse Event Reporting Description
Arm/Group Title Low Dose: Lisinopril Medium Dose: Lisinopril High Dose: Lisinopril
Arm/Group Description Participants will receive study medication for 14±3 days at a dose 0.1 mg/kg/day Participants will receive study medication for 14±3 days at a dose 0.2 mg/kg/day Participants will initially receive study medication at 0.2 mg/kg/day for 5±2 days. If blood tests exclude drug-related toxicity, then the lisinopril dose will be increased to 0.4 mg/kg/day and participants will continue to complete the 14±3 day Treatment Period.
All Cause Mortality
Low Dose: Lisinopril Medium Dose: Lisinopril High Dose: Lisinopril
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total / (NaN) / (NaN) / (NaN)
Serious Adverse Events
Low Dose: Lisinopril Medium Dose: Lisinopril High Dose: Lisinopril
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/12 (0%) 1/8 (12.5%) 0/2 (0%)
Infections and infestations
Gastroenteritis 0/12 (0%) 1/8 (12.5%) 0/2 (0%)
Other (Not Including Serious) Adverse Events
Low Dose: Lisinopril Medium Dose: Lisinopril High Dose: Lisinopril
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 5/12 (41.7%) 4/8 (50%) 2/2 (100%)
Blood and lymphatic system disorders
Anaemia 1/12 (8.3%) 0/8 (0%) 0/2 (0%)
Gastrointestinal disorders
Abdominal pain upper 1/12 (8.3%) 2/8 (25%) 0/2 (0%)
Diarrhea 0/12 (0%) 2/8 (25%) 0/2 (0%)
Nausea 1/12 (8.3%) 1/8 (12.5%) 0/2 (0%)
Retching 0/12 (0%) 2/8 (25%) 0/2 (0%)
Vomiting 0/12 (0%) 0/8 (0%) 1/2 (50%)
General disorders
Infusion site extravasation 1/12 (8.3%) 0/8 (0%) 0/2 (0%)
Infusion site pain 1/12 (8.3%) 0/8 (0%) 0/2 (0%)
Infusion site pruritus 1/12 (8.3%) 0/8 (0%) 0/2 (0%)
Infections and infestations
Otitis externa 0/12 (0%) 1/8 (12.5%) 0/2 (0%)
Injury, poisoning and procedural complications
Upper limb fracture 0/12 (0%) 0/8 (0%) 1/2 (50%)
Investigations
Glomerular filtration rate decreased 0/12 (0%) 0/8 (0%) 1/2 (50%)
Hemoglobin decreased 0/12 (0%) 0/8 (0%) 1/2 (50%)
Nervous system disorders
Dizziness 0/12 (0%) 2/8 (25%) 0/2 (0%)
Headache 1/12 (8.3%) 1/8 (12.5%) 0/2 (0%)
Skin and subcutaneous tissue disorders
Rash 1/12 (8.3%) 0/8 (0%) 0/2 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT 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.

Results Point of Contact

Name/Title Uptal Patel, MD
Organization Duke Clinical Research Institute
Phone 919-668-4601
Email uptal.patel@duke.edu
Responsible Party:
Uptal Patel, Assoc Professor of Medicine, Duke University
ClinicalTrials.gov Identifier:
NCT01491919
Other Study ID Numbers:
  • Pro00029537
  • HHSN275201000003I
First Posted:
Dec 14, 2011
Last Update Posted:
Jul 8, 2015
Last Verified:
Jun 1, 2015