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

This study has been completed.
Sponsor:
Collaborators:
The EMMES Corporation
University of Rochester
OpAns, LLC
Information provided by (Responsible Party):
Uptal Patel, Duke University Medical Center
ClinicalTrials.gov Identifier:
NCT01491919
First received: November 29, 2011
Last updated: June 15, 2015
Last verified: June 2015

November 29, 2011
June 15, 2015
June 2012
September 2013   (final data collection date for primary outcome measure)
  • Pharmacokinetics (PK) - Area Under the Plasma Concentration-time Curve (AUC) [ 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 ] [ Designated as safety issue: No ]
    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.
  • PK - Maximum Observed Concentration of Drug in Plasma (Cmax) [ Time Frame: Day14 (+/- 3 d) of dose at 0 hour and 1, 2, 4, 5, 8, 12, and 24 hrs after dose ] [ Designated as safety issue: No ]
    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.
  • PK - Time of the Maximum Observed Concentration in Plasma (Tmax) [ Time Frame: Day 14 (+/- 3 d) of dose at 0 hour and 1, 2, 4, 5, 8, 12, and 24 hrs after dose ] [ Designated as safety issue: No ]
    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.
  • PK - Oral Clearance (CL/F) [ Time Frame: Day 14 (+/- 3 d) of dose at 0 hour and at 1, 2, 4, 5, 8, 12, and 24 hrs after dose ] [ Designated as safety issue: No ]
    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.
  • PK Renal Clearance (CLrenal) [ Time Frame: Day 14 (+/- 3 d) of dose at 0 hour and 1, 2, 4, 5, 8, 12, and 24 hrs after dose. ] [ Designated as safety issue: No ]
    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.
  • Number of Adverse Events (AEs) and Serious Adverse Events (SAEs) During/After Study Drug Administration [ Time Frame: First dose of study drug to 30 days after final study visit for AEs and until resolution for SAEs ] [ Designated as safety issue: Yes ]
    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
Pharmacokinetics (PK) [ Time Frame: PK evaluations will be performed after 14 +/- 3 days of lisinopril therapy at 0 hour (pre-dose) 1, 2, 4, 5, 8, 12, and 24 hours post-lisinopril dose ] [ Designated as safety issue: No ]
  1. Area under the plasma concentration-time curve (AUC)
  2. Maximum observed concentration of drug in plasma (Cmax) and time of the maximum observed concentration in plasma (Tmax).
  3. Observed concentration prior to dose (C0h) and at the 24h post-dose pharmacokinetic sample (C24h).
  4. Apparent oral clearance (CL/F) and renal clearance (CLrenal).
Complete list of historical versions of study NCT01491919 on ClinicalTrials.gov Archive Site
  • Change in Potassium Level From Baseline in Lisinopril-naive Participants [ Time Frame: At baseline visit and Day 14 prior to final study dose. ] [ Designated as safety issue: Yes ]
    Potassium values will be obtained at Baseline and Day 14 prior to the final dose of study drug. Mean calculated from the two measurements.
  • Worse Post-dose Decrease in Estimated Glomerular Filtration Rate (eGFR) From Baseline in Lisinopril-naive Participants [ Time Frame: Baseline to Day 14 (+/- 3 days) ] [ Designated as safety issue: Yes ]
    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.
  • Largest eGFR Percent Decrease From Baseline in Lisinopril-naive Participants [ Time Frame: Baseline to Day 14 (+/- 3 days) ] [ Designated as safety issue: Yes ]

    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.

  • Change in Urine Protein/Creatinine From Baseline in Lisinopril-naive Participants. [ Time Frame: Baseline to worst post-dose before Day 14 (+/- 3 days) ] [ Designated as safety issue: No ]
    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.
  • Change in Diastolic Blood Pressure From Baseline in Lisinopril-naive Participants [ Time Frame: Baseline to Day 14 (+/-3 days) ] [ Designated as safety issue: Yes ]

    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.

  • Change in Systolic Blood Pressure From Baseline in Lisinopril-naive Participants [ Time Frame: Baseline to Day 14 (+/- 3 days) ] [ Designated as safety issue: Yes ]

    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.

  • Change in Systolic Blood Pressure (BP) From Baseline in Lisinopril SOC Group [ Time Frame: Screening to Day 14 to 40 ] [ Designated as safety issue: No ]
    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.
  • Change in Diastolic Blood Pressure From Baseline in Lisinopril SOC Group [ Time Frame: Screening to Day 14 to 40 ] [ Designated as safety issue: No ]
    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.
  • Safety [ Time Frame: First dose of lisinopril to 30 days after last dose of study medication ] [ Designated as safety issue: Yes ]
    1. Additional PK data: lisinopril absorption rate (ka), oral apparent volume of distribution (V/F), influence on PK by demographic/ clinical covariates
    2. AEs during/after study drug administration by organ system
    3. Additional BP data: control per protocol clinic BPs, 24h ABPM, need for additional BP medications
    4. Exposure-response relationship: lisinopril plasma concentrations and BP (PK-PD model)
    5. Estimated glomerular filtration rate (eGFR) change
  • Non-Safety Secondary Outcome [ Time Frame: Dried Blood Spot (DBS) samples will be collected after 14 +/- 3 days of lisinopril therapy at 0 hour (pre-dose) and at 1, 2, 4, 5, 8, 12 and 24 hours post-lisinopril dose ] [ Designated as safety issue: No ]
    Dried blood spot (DBS) sampling validity
  • Non-Safety Secondary Outcome [ Time Frame: Iohexol GFR samples will be collected after 14 +/- 3 days of lisinopril therapy at intervals of 0, 2, 4, and 5 hours post-iohexol infusion ] [ Designated as safety issue: No ]
    eGFR and iohexol GFR relationship
Not Provided
Not Provided
 
Safety Study of Lisinopril in Children and Adolescents With a Kidney Transplant
Safety and Pharmacokinetics of Lisinopril in Pediatric Kidney Transplant Recipients

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.

Not Provided
Interventional
Phase 1
Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Hypertension
Drug: Lisinopril
Subjects will be randomized to Low, Medium, or High dose of Lisinopril
  • Experimental: Low Dose: Lisinopril
    Participants will receive study medication for 14±3 days at a dose 0.1 mg/kg/day
    Intervention: Drug: Lisinopril
  • Experimental: Medium Dose: Lisinopril
    Participants will receive study medication for 14±3 days at a dose 0.2 mg/kg/day
    Intervention: Drug: 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.
    Intervention: Drug: Lisinopril

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
26
September 2013
September 2013   (final data collection date for primary outcome measure)

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
Both
2 Years to 17 Years
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT01491919
Pro00029537, HHSN275201000003I
Yes
Uptal Patel, Duke University Medical Center
Uptal Patel
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
  • The EMMES Corporation
  • University of Rochester
  • OpAns, LLC
Study Director: Daniel Benjamin, MD, PhD, MPH Duke University
Study Chair: Howard Trachtman, MD New York University Langone Medical Center
Principal Investigator: Uptal D Patel, MD Duke University
Principal Investigator: Adam Frymoyer, MD Stanford University
Duke University
June 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP