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

NCT01491919 | Completed Phase 1 Results DMC

• 2 other identifiers: Pro00029537HHSN275201000003I
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 7

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.

Conditions

Hypertension

Keywords

High Blood Pressure; Hypertension; Renal Transplantation; Kidney Transplantation

Outcome Measures

Primary Outcomes (6)

• Pharmacokinetics (PK) - Area Under the Plasma Concentration-time Curve (AUC)

  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.

  Day 14 (+/- 3 days) of lisinopril therapy at hours 0 (pre-dose) and 1,2,4,5,8,12 and 24 hrs after dose

• PK - Maximum Observed Concentration of Drug in Plasma (Cmax)

  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.

  Day14 (+/- 3 d) of dose at 0 hour and 1, 2, 4, 5, 8, 12, and 24 hrs after dose

• PK - Time of the Maximum Observed Concentration in Plasma (Tmax)

  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.

  Day 14 (+/- 3 d) of dose at 0 hour and 1, 2, 4, 5, 8, 12, and 24 hrs after dose

• PK - Oral Clearance (CL/F)

  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.

  Day 14 (+/- 3 d) of dose at 0 hour and at 1, 2, 4, 5, 8, 12, and 24 hrs after dose

• PK Renal Clearance (CLrenal)

  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.

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

• Number of Adverse Events (AEs) and Serious Adverse Events (SAEs) During/After Study Drug Administration

  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

  First dose of study drug to 30 days after final study visit for AEs and until resolution for SAEs

Secondary Outcomes (8)

• Change in Potassium Level From Baseline in Lisinopril-naive Participants

  At baseline visit and Day 14 prior to final study dose.

• Worse Post-dose Decrease in Estimated Glomerular Filtration Rate (eGFR) From Baseline in Lisinopril-naive Participants

  Baseline to Day 14 (+/- 3 days)

• Largest eGFR Percent Decrease From Baseline in Lisinopril-naive Participants

  Baseline to Day 14 (+/- 3 days)

• Change in Urine Protein/Creatinine From Baseline in Lisinopril-naive Participants.

  Baseline to worst post-dose before Day 14 (+/- 3 days)

• Change in Diastolic Blood Pressure From Baseline in Lisinopril-naive Participants

  Baseline to Day 14 (+/-3 days)

Study Arms (3)

Low Dose: Lisinopril

EXPERIMENTAL

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

Drug: Lisinopril

Medium Dose: Lisinopril

EXPERIMENTAL

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

Drug: Lisinopril

High Dose: Lisinopril

EXPERIMENTAL

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

Interventions

Lisinopril DRUG

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

High Dose: Lisinopril; Low Dose: Lisinopril; Medium Dose: Lisinopril

Eligibility Criteria

• Age: 2 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Kidney transplant recipient
• Age 2-17 years, inclusive, at the time of first study dose
• 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
• Stable immunosuppressive regimen, as indicated by \<10% change in dosage (in mg/kg) in these medications, within the 14 days prior to enrollment
• Systolic BP \>90th percentile for age, gender, and height, necessitating initiation or addition of an antihypertensive medication
• 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).

You may not qualify if:

• History of anaphylaxis attributable to lisinopril or other angiotensin-converting enzyme inhibitor (ACEI) agents (e.g.,enalapril, ramipril, quinapril)
• History of anaphylaxis attributable to iohexol or an iodine hypersensitivity
• Use of an angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker, or renin antagonist within 30 days prior to enrollment
• Stage 2 hypertension defined as the \>99th percentile for age, height and gender + 5 mm Hg
• Blood Potassium value \> 6.0 milliequivalent / liter (mEq/L) (as determined at the screening visit)
• Previous participation in this study
• Physician concern that the participant may not adhere to the study protocol, based on prior behavior
• Current plasmapheresis treatment
• History of angioedema
• Pregnancy

Sponsors & Collaborators

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

Study Sites (7)

University of Alabama

Birmingham, Alabama, 35233, United States

Location

Arkansas Children's Hospital

Little Rock, Arkansas, 72202, United States

Location

Emory University and Children's Healthcare of Atlanta

Atlanta, Georgia, 30322, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Children's Mercy Hospitals & Clinics

Kansas City, Missouri, 64108, United States

Location

New York University Langone Medical Center

New York, New York, 10016, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Related Publications (34)

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Related Links

• Pediatric Trials Network (PTN)
• The Eunice Kennedy Shriver National Institute of Child Health and Human
• Information about Lisinopril

MeSH Terms

Conditions

Hypertension

Interventions

Lisinopril

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Dipeptides; Oligopeptides; Peptides; Amino Acids, Peptides, and Proteins

Results Point of Contact

• Title: Uptal Patel, MD
• Organization: Duke Clinical Research Institute

uptal.patel@duke.edu

919-668-4601

Study Officials

• Daniel Benjamin, MD, PhD, MPH

  Duke University

  STUDY DIRECTOR

• Howard Trachtman, MD

  NYU Langone Health

  STUDY CHAIR

• Uptal D Patel, MD

  Duke University

  PRINCIPAL INVESTIGATOR

• Adam Frymoyer, MD

  Stanford University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assoc Professor of Medicine

Study Record Dates

• First Submitted: November 29, 2011
• First Posted: December 14, 2011
• Study Start: June 1, 2012
• Primary Completion: September 1, 2013
• Study Completion: September 1, 2013
• Last Updated: July 8, 2015
• Results First Posted: July 8, 2015

Record last verified: 2015-06

Locations

US (7)