Metformin Use in Cardiac Fibrosis in PAI-1 Deficiency

September 28, 2023 updated by: Sweta Gupta, Indiana Hemophilia &Thrombosis Center, Inc.

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

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.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

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

Study Type

Interventional

Enrollment (Estimated)

15

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Indiana
      • Indianapolis, Indiana, United States, 46260
        • Indiana Hemophilia and Thrombosis Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Metformin Treatment Group
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
daily metformin treatment vs. no treatment with metformin
Other Names:
  • Glucophage XR
No Intervention: Observation Group

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
Time Frame: through the study annually, up to 60 months
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)
Time Frame: through the study annually, up to 60 months
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)
Time Frame: 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
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)
Time Frame: 6 months after study enrollment, through the study annually, up to 60 months

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)
Time Frame: through the study annually, up to 60 months
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
Time Frame: through the study annually, up to 60 months
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)
Time Frame: 6 months after study enrollment, through the study annually, up to 60 months

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Indiana Hemophilia &Thrombosis Center, Inc.

Investigators

  • Principal Investigator: Sweta Gupta, MD, Indiana Hemophilia and Thrombosis Center, Inc
  • Principal Investigator: Magdalena Lewandowska, MD, Indiana Hemophilia and Thrombosis Center, Inc
  • Study Director: Amy D Shapiro, MD, Indiana Hemophilia and Thrombosis Center, Inc

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 10, 2022

Primary Completion (Estimated)

October 1, 2027

Study Completion (Estimated)

October 1, 2027

Study Registration Dates

First Submitted

March 8, 2022

First Submitted That Met QC Criteria

March 31, 2022

First Posted (Actual)

April 8, 2022

Study Record Updates

Last Update Posted (Actual)

September 29, 2023

Last Update Submitted That Met QC Criteria

September 28, 2023

Last Verified

September 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • R2O210069

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

TBD based on analysis

IPD Sharing Time Frame

Post analysis

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • ICF

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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