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

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: NCT01491919
Recruitment Status : Completed
First Posted : December 14, 2011
Results First Posted : July 8, 2015
Last Update Posted : July 8, 2015
Sponsor:
Collaborators:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
The Emmes Company, LLC
University of Rochester
OpAns, LLC
Information provided by (Responsible Party):
Uptal Patel, Duke University

Tracking Information
First Submitted Date  ICMJE November 29, 2011
First Posted Date  ICMJE December 14, 2011
Results First Submitted Date  ICMJE April 27, 2015
Results First Posted Date  ICMJE July 8, 2015
Last Update Posted Date July 8, 2015
Study Start Date  ICMJE June 2012
Actual Primary Completion Date September 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 15, 2015)
  • 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 ]
    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 ]
    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 ]
    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 ]
    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. ]
    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 ]
    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
Original Primary Outcome Measures  ICMJE
 (submitted: December 12, 2011)
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 ]
  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).
Change History Complete list of historical versions of study NCT01491919 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 15, 2015)
  • Change in Potassium Level From Baseline in Lisinopril-naive Participants [ Time Frame: 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.
  • Worse Post-dose Decrease in Estimated Glomerular Filtration Rate (eGFR) From Baseline in Lisinopril-naive Participants [ Time Frame: 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.
  • Largest eGFR Percent Decrease From Baseline in Lisinopril-naive Participants [ Time Frame: 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.
  • Change in Urine Protein/Creatinine From Baseline in Lisinopril-naive Participants. [ Time Frame: 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.
  • Change in Diastolic Blood Pressure From Baseline in Lisinopril-naive Participants [ Time Frame: 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.
  • Change in Systolic Blood Pressure From Baseline in Lisinopril-naive Participants [ Time Frame: 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.
  • Change in Systolic Blood Pressure (BP) From Baseline in Lisinopril SOC Group [ Time Frame: 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.
  • Change in Diastolic Blood Pressure From Baseline in Lisinopril SOC Group [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 12, 2011)
  • Safety [ Time Frame: First dose of lisinopril to 30 days after last dose of study medication ]
    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 ]
    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 ]
    eGFR and iohexol GFR relationship
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety Study of Lisinopril in Children and Adolescents With a Kidney Transplant
Official Title  ICMJE Safety and Pharmacokinetics of Lisinopril in Pediatric Kidney Transplant Recipients
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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Hypertension
Intervention  ICMJE Drug: Lisinopril
Subjects will be randomized to Low, Medium, or High dose of Lisinopril
Study Arms  ICMJE
  • 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
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 18, 2013)
26
Original Estimated Enrollment  ICMJE
 (submitted: December 12, 2011)
28
Actual Study Completion Date  ICMJE September 2013
Actual Primary Completion Date September 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Years to 17 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01491919
Other Study ID Numbers  ICMJE Pro00029537
HHSN275201000003I ( Other Identifier: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Uptal Patel, Duke University
Study Sponsor  ICMJE Uptal Patel
Collaborators  ICMJE
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
  • The Emmes Company, LLC
  • University of Rochester
  • OpAns, LLC
Investigators  ICMJE
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
PRS Account Duke University
Verification Date June 2015

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