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

Study Overview
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Brief Summary
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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.

Official Title
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Safety and Pharmacokinetics of Lisinopril in Pediatric Kidney Transplant Recipients

Conditions
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Hypertension

Intervention / Treatment
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* Drug: Lisinopril


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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). Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low Dose: Lisinopril<br>Participants will receive study medication for 14±3 days at a dose 0.1 mg/kg/day | Drug: Lisinopril<br>* Subjects will be randomized to Low, Medium, or High dose of Lisinopril<br>|
| Experimental: Medium Dose: Lisinopril<br>Participants will receive study medication for 14±3 days at a dose 0.2 mg/kg/day | Drug: Lisinopril<br>* Subjects will be randomized to Low, Medium, or High dose of Lisinopril<br>|
| Experimental: High Dose: Lisinopril<br>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<br>* Subjects will be randomized to Low, Medium, or High dose of Lisinopril<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Potassium Level From Baseline in Lisinopril-naive Participants | Potassium values will be obtained at Baseline and Day 14 prior to the final dose of study drug. Mean calculated from the two measurements. | 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 | 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. | Baseline to Day 14 (+/- 3 days) | 
| Largest eGFR Percent Decrease From Baseline in Lisinopril-naive Participants | 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. | Baseline to Day 14 (+/- 3 days) | 
| Change in Urine Protein/Creatinine From Baseline in Lisinopril-naive Participants. | 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. | Baseline to worst post-dose before Day 14 (+/- 3 days) | 
| Change in Diastolic Blood Pressure From Baseline in Lisinopril-naive Participants | 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. | Baseline to Day 14 (+/-3 days) | 
| Change in Systolic Blood Pressure From Baseline in Lisinopril-naive Participants | 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. | Baseline to Day 14 (+/- 3 days) | 
| Change in Systolic Blood Pressure (BP) From Baseline in Lisinopril SOC Group | 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. | Screening to Day 14 to 40 | 
| Change in Diastolic Blood Pressure From Baseline in Lisinopril SOC Group | 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. | Screening to Day 14 to 40 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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High Blood Pressure, Hypertension, Renal Transplantation, Kidney Transplantation