Use of Metformin in Prevention and Treatment of Cardiac Fibrosis in PAI-1 Deficient Population

This study is a phase 4, prospective, open-label, US single center study to assess the efficacy and safety of metformin for prevention or stabilization or regression of cardiac fibrosis in individuals homozygous for PAI-1 deficiency. Approximately 15 patients 18-65 years of age are expected to be enrolled, due to the rarity of this blood disorder. The study will have one metformin Treatment group (daily metformin administered) and one Observation group (no study drug administered). Subjects will be consented and screened by Indiana Hemophilia and Thrombosis Center (IHTC) staff. Individuals will be eligible for study participation if they meet all inclusion criteria. Subjects will be excluded from the study if they meet any of the exclusion criteria. US-labeled oral metformin (extended release) will be administered using the FDA-approved dosing regimen for diabetes mellitus type II starting at a dose of 500 mg and escalating up to a maximum of 2000 mg. In the final assessment, subjects who receive metformin for at least 36 months (and up to a maximum of 60 months) will be considered part of the Treated population. Subjects who refuse treatment with metformin or complete <36 months of treatment on metformin either due to intolerance to the study drug or due to any other reason, will be considered part of the Comparison population and will be followed clinically. Females will be offered the option to temporarily discontinue metformin during pregnancy and/or lactation period; they will be considered part of the Treated population if they receive metformin for at least 36 months during the study (those 36 months need not be consecutive). If they receive metformin for 0 to <36 months, they will be considered part of the Comparison population. The study enrollment period will be 12 months. Every subject will be in the study for a period of 60 months from the point of enrollment. There is no minimum on-study period. The decision to continue metformin treatment beyond the study period in the metformin Treatment group, will be made based on drug efficacy, patient tolerability/preference, and provider discretion.

Basic laboratory parameters (serum chemistry and hematology), specific cardiac markers (NT-pro BNP, TGF-β1) cardiac imaging and electrocardiograms will be performed at baseline, at study close out/subject withdrawal, and as specified in the schedule of activities. Adverse events (AE) will be recorded on an ongoing basis as they occur during the study. During the study, annual cardiac consultation, New York Heart Association (NYHA) scale and as needed, the Kansas City Cardiomyopathy Questionnaire (KCCQ-12) will be completed by patients.

The primary analysis will be performed when the last patient has completed 60 months in the study, is lost to follow up or has withdrawn from the study treatment, whichever occurs first.

An interim analysis will be performed at 30 months. All patients will be included in the interim analysis. This interim analysis will be performed for safety.

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