Metformin Use in Cardiac Fibrosis in PAI-1 Deficiency

Study Overview
=================
Brief Summary
-----------------
This study will evaluate the efficacy and safety of metformin, in patients 18-65 years of age with homozygous plasminogen activator inhibitor-1 (PAI-1) deficiency, with or without cardiac fibrosis, for a period of 60 months. The starting dose of metformin will be 500 mg up to a maximum dose of 2000 mg for a period of 5 years with the aim to assess the safety and efficacy of metformin on prevention/stabilization or regression of cardiac fibrosis in a Treated population vs. a Comparison population.

Detailed Description
-----------------
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. Definitions • Complete PAI-1 deficiency defined as subjects with homozygous mutation in SERPINE 1. During the clinical trial, subjects will be grouped according to whether they are currently receiving study drug or not. This will affect the schedule of study visits and assays/procedures performed. Metformin Treatment group: The group of individuals who are currently receiving metformin Observation group: The group of individuals who are NOT currently receiving metformin (this includes those who opted to never receive metformin) Patients will be allowed to switch between metformin treatment group and observation group. Following the completion of the clinical trial, subjects will be grouped according to the total amount of time they received study drug. This grouping is for analytical/statistical purposes only. Treated population: Individuals who received at least 36 months of metformin treatment while on study Comparison population: Individuals who did not receive metformin treatment at any point during the study, or received metformin for a total less than 36 months of treatment while on study i.e. 0 to <36 months of treatment

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

Conditions
-----------------
Plasminogen Activator Inhibitor-1 Deficiency, Cardiac Fibrosis

Intervention / Treatment
-----------------
* Drug: Metformin Extended Release Oral Tablet


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Confirmed homozygosity for mutation in SERPINE-1 for PAI-1 deficiency Male or female Aged 18-65 years Willing and able to choose between being in a metformin Treatment group (daily metformin) or an Observation group (no study drug) at study entry Capable of understanding and willing to comply with the conditions of the study (in the opinion of the study investigator(s)) Have read, understood and be able to provide written informed consent Exclusion Criteria: Not homozygous for SERPINE-1 mutation for PAI-1 deficiency, based on genetic testing Ages <18 or >65 years Renal dysfunction (Cockcroft Gault CrCl < 30) History of hypersensitivity of metformin or any component in the extended release formulation Unwillingness to avoid alcohol Currently prescribed cimetidine, dolutegravir, patiromer, ranolazine, or tafenoquine and no alternate therapy is possible History of illicit drug or alcohol abuse within 48 weeks prior to screening, in the study investigators' judgment Concomitant disease, condition, significant abnormality on screening evaluations or laboratory tests, or treatment that could interfere with the conduct of the study, or that would, in the opinion of the study investigator(s), pose an additional unacceptable risk in administering study drug to the patient Receipt of any other investigational medicinal product currently being administered (or planned to be administered) Inability to comply with the study protocol (in the opinion of the study investigator(s)) Inability to understand and provide written informed consent

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study will have one metformin Treatment group (daily metformin administered) and one Observation group (no study drug administered)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin Treatment Group<br>Subjects with PAI-1 deficiency with or without cardiac fibrosis, receiving daily treatment with metformin for a daily range of 500-2000mg | Drug: Metformin Extended Release Oral Tablet<br>* daily metformin treatment vs. no treatment with metformin<br>* Other names: Glucophage XR;|
| No Intervention: Observation Group<br>Subjects with PAI-1 deficiency with or without cardiac fibrosis, not receiving treatment with metformin Subjects are allowed to switch between the two groups | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of individuals homozygous for PAI-1 deficiency with stable or improved cardiac fibrosis | Measured using cardiac MRI to quantify the percentage cardiac fibrosis. | through the study annually, up to 60 months | 
| Number of individuals homozygous for PAI-1 deficiency with stable or improved Transforming growth factor (TGF-β1) | Measured by a blood draw as a surrogate marker for status of cardiac fibrosis stability or reduction. | through the study annually, up to 60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of individuals homozygous for PAI-1 deficiency with metformin related adverse events as assessed by grading of diarrhea (CTCAE v5.0) | Safety and tolerability of metformin when administered to individuals homozygous for PAI-1 deficiency as assessed by side effect profile (as measured by the type and number of adverse drug reactions and serious adverse drug reactions ) | approximately monthly (±4 weeks) until maximum tolerated dose for metformin is achieved until 6 months (±4 weeks) and then every 3 months (±4 weeks) for the entire study period for the metformin group | 
| Number of individuals homozygous for PAI-1 deficiency with clinical symptoms of heart failure as measured by the New York Heart Association (NYHA) scale and as needed, the Kansas City Cardiomyopathy Questionnaire (KCCQ-12) | Objective evaluation of cardiac symptoms by using a scale and questionnaire. New York Heart Association (NYHA) scale: lowest scale is Functional capacity I, Objective assessment A; Highest scale is Functional capacity IV, Objective assessment D. Higher scores worst outcome. | 6 months after study enrollment, through the study annually, up to 60 months | 
| Number of individuals homozygous for PAI-1 deficiency with additional signs of heart failure assessed by measuring N- terminal prohormone beta natriuretic peptide (NT-pro BNP) | Objective evaluation of heart failure using NT-proBNP value as stable, increasing or decreasing | through the study annually, up to 60 months | 
| Number of individuals homozygous for PAI-1 deficiency with stable or improved ejection fraction on echocardiogram | Evaluate changes in ejection fraction by standard transthoracic echocardiogram | through the study annually, up to 60 months | 
| Number of individuals homozygous for PAI-1 deficiency with clinical symptoms of heart failure impacting their health as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ-12) | Objective evaluation of cardiac failure symptoms impact on health by using a questionnaire. Kansas City Cardiomyopathy Questionnaire (KCCQ-12): KCCQ scores are scaled from 0 to 100 and frequently summarized in 25-point ranges, where scores represent health status as follows: 0 to 24: very poor to poor; 25 to 49: poor to fair; 50 to 74: fair to good; and 75 to 100: good to excellent. Higher scores are better outcome | 6 months after study enrollment, through the study annually, up to 60 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
PAI-1 deficiency, Amish, cardiac fibrosis, Metformin