Pravastatin as a Prophylactic to Reduce Endothelial Injury in Pediatric Patients With Elevated Body Mass Index

Pilot Trial of Pravastatin as a Novel Prophylactic Medicine to Reduce Endothelial Injury in Pediatric Patients With Elevated Body Mass Index

Chemotherapy and radiation used in patients undergoing bone marrow transplant (BMT) disrupts the endothelial lining (a thin layer of cells inside the blood vessels) which is found all throughout the body including the kidney, heart, lungs, and intestines. Disruption of this endothelial lining can lead to complications such as graft-vs-host disease (GVHD), thrombotic microangiopathy (TMA) and veno-occlusive disease (VOD). The purpose of this research study is to help investigators see if pravastatin is safe and well tolerated in patients undergoing BMT to see if it will reduce endothelial injury after BMT.

The investigator hypothesizes that prophylactic pravastatin in pediatric allogeneic hematopoietic stem cell transplant recipients with elevated BMI is safe and feasible.

Study Overview

• Status: Recruiting
• Conditions: Hematopoietic Stem Cell Transplant (HSCT); Endothelial Injury
• Intervention / Treatment: Drug: Pravastatin

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Ormarie Vazquez Silva; Phone Number: 513-803-0183; Email: Ormarie.VazquezSilva@cchmc.org

Study Locations

• United States
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Recruiting
      • Cincinnati Children's Hospital Medical Center
      • Contact: Ormarie Vazquez Silva; Phone Number: 513-803-0183; Email: Ormarie.VazquezSilva@cchmc.org
      • Principal Investigator: Jane Koo, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 25 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Scheduled for allogeneic stem cell transplant
• Ages ≥ 2 - ≤ 25 years old
• Elevated BMI defined by the Center for Disease Control and Prevention definitions. Both overweight (BMI between 85th-94th percentile) and obese (BMI >95th percentile) patients are eligible
• All diagnoses are eligible

Exclusion Criteria:

• Patients with documented anaphylaxis to pravastatin
• Patients will be ineligible if they are unable to take medication orally or enterally (i.e. intestinal failure)
• Patients with elevations in ALT/AST levels 3x ULN at time of enrollment
• Patients with renal impairment as clinically measured (GFR <50 ml/min/1.73m2) at time of enrollment
• Patients with known neuromuscular and metabolic disorders associated with an increased risk of rhabdomyolysis (ie metabolic muscle disorders, mitochondrial disorders, and muscular dystrophies)
• Patients taking any drugs that are known substrates for OATP1B1 and OATP1B3 transporters

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pravastatin Prophylactic Treatment	Drug: Pravastatin; Participants will receive pravastatin orally once daily through the first 35 days after bone marrow transplant.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of participants who developed clinically significant transaminitis, renal dysfunction and rhabdomyolysis	Every enrolled patient will have routine liver function test (LFT) and renal function profile monitoring as part of their standardized transplant care. Transaminitis is expected and often multifactorial in the HSCT population, (i.e. preparative regimen, azole antifungal prophylaxis, or post-transplant complications such as infection and GVHD), therefore, we have determined modified parameters to hold or modify the dose of pravastatin. We will modify and/or hold pravastatin dosing at the time of transaminase elevations > 3X upper limit of normal unless a clear-cut alternative explanation can be provided. Additionally, we will also check creatinine kinase (CK) levels on admission and once weekly while the patient is actively taking pravastatin to monitor for rhabdomyolysis.	Until day 35 after bone marrow transplant when pravastatin is discontinued
Percentage of participants who adhered to the medication plan	Participants will be considered adhered to the medication plan if they took the study drug at least 70% of the time. Nursing documentation of pravastatin administration and drug diaries will be used as documentation of compliance.	Until day 35 after bone marrow transplant when pravastatin is discontinued

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with overall survival		100 days after bone marrow transplant
Number of participants with graft failure	Graft failure is defined as follows: Primary graft failure is defined as no evidence of engraftment or hematological recovery of donor cells, within the first month after transplant, without evidence of disease relapse. Secondary graft failure refers to the loss of a previously functioning graft, resulting in cytopenia involving at least two blood cell lineages.	100 days after bone marrow transplant
Number of participants with primary disease relapse	Primary disease relapse is defined as: The return of a disease or the signs and symptoms of a disease after a period of improvement.	100 days after bone marrow transplant
Median number of days until neutrophil engraftment	Neutrophil engraftment is defined as the first day of three consecutive days where the neutrophil count (absolute neutrophil count) is 500 cells/mm3 (0.5 x 10^9/L) or greater.	Through study completion, an average of up to 100 days
Median number of days until platelet engraftment	Platelet engraftment is usually defined as independence from platelet transfusion for at least 7 days with a platelet count of more than >20 × 10^9/L	Through study completion, an average of up to 100 days
Assessment of SLCO1B1 genotyping	The SLCO1B1 gene encodes for making the protein organic anion transporting polypeptide 1B1 (OATP1B1), which is the transporter for drugs, including statins, into the liver. Patients enrolled on study will have their SLCO1B1 genotyping performed from whole blood samples at baseline to determine how this affects their overall statin clearance.	Baseline
Measurement of sphingosine-1-phosphate (S1P) levels in plasma	S1P levels will be measured on weekly intervals using mass spectrometry	Weekly from admission until day 35 from bone marrow transplant
Number of participants who adhered to the medication plan	The lipid profile is a blood test that includes measurements of cholesterol, triglycerides, High-density lipoprotein (HDL) and Low-density lipoprotein (LDL). It is a routine test that monitors cholesterol levels. Pravastatin reduces cholesterol production. The lipid profile will be measured prior to the first dose of pravastatin. After the last dose of pravastatin the lipid profile will be measured. Any reduction in total cholesterol and LDL levels will be used as a surrogate marker for medication adherence.	Through study completion, an average of 35 days after bone marrow transplant

Collaborators and Investigators

• Sponsor: Children's Hospital Medical Center, Cincinnati
• Investigators: Principal Investigator: Jane Koo, MD, Children's Hospital Medical Center, Cincinnati

Study record dates

Study Major Dates

• Study Start (Actual): January 27, 2023
• Primary Completion (Estimated): September 1, 2025
• Study Completion (Estimated): September 1, 2025

Study Registration Dates

• First Submitted: August 24, 2022
• First Submitted That Met QC Criteria: August 29, 2022
• First Posted (Actual): September 1, 2022

Study Record Updates

• Last Update Posted (Estimated): January 15, 2024
• Last Update Submitted That Met QC Criteria: January 11, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Wounds and Injuries; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pravastatin
• Other Study ID Numbers: 2022-0308

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No