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Metformin Use in Cardiac Fibrosis in PAI-1 Deficiency

Sponsor
Indiana Hemophilia &Thrombosis Center, Inc. (Other)
Overall Status
Not yet recruiting
CT.gov ID
NCT05317806
Collaborator
(none)
15
Enrollment
2
Arms
55
Anticipated Duration (Months)

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
  • Drug: Metformin Extended Release Oral Tablet
 Phase 4

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.

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 Design

Study Type:
Interventional
Anticipated Enrollment :
15 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
The study will have one metformin Treatment group (daily metformin administered) and one Observation group (no study drug administered)The study will have one metformin Treatment group (daily metformin administered) and one Observation group (no study drug administered)
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Use of Metformin in Prevention and Treatment of Cardiac Fibrosis in PAI-1 Deficient Population
Anticipated Study Start Date :
Oct 1, 2022
Anticipated Primary Completion Date :
May 1, 2027
Anticipated Study Completion Date :
May 1, 2027

Arms and Interventions

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

    Outcome Measures

    Primary Outcome Measures

    1. Number of individuals homozygous for PAI-1 deficiency with stable or improved cardiac fibrosis [through the study annually, up to 60 months]

      Measured using cardiac MRI to quantify the percentage cardiac fibrosis.

    2. Number of individuals homozygous for PAI-1 deficiency with stable or improved Transforming growth factor (TGF-β1) [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.

    Secondary Outcome Measures

    1. Number of individuals homozygous for PAI-1 deficiency with metformin related adverse events as assessed by grading of diarrhea (CTCAE v5.0) [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 )

    2. 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) [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.

    3. 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) [through the study annually, up to 60 months]

      Objective evaluation of heart failure using NT-proBNP value as stable, increasing or decreasing

    4. Number of individuals homozygous for PAI-1 deficiency with stable or improved ejection fraction on echocardiogram [through the study annually, up to 60 months]

      Evaluate changes in ejection fraction by standard transthoracic echocardiogram

    5. 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) [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

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 65 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    No locations specified.

    Sponsors and Collaborators

    • 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

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    Responsible Party:
    Sweta Gupta, Pediatric Hematologist, Indiana Hemophilia &Thrombosis Center, Inc.
    ClinicalTrials.gov Identifier:
    NCT05317806
    Other Study ID Numbers:
    • R2O210069
    First Posted:
    Apr 8, 2022
    Last Update Posted:
    Aug 3, 2022
    Last Verified:
    Aug 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    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
    Keywords provided by Sweta Gupta, Pediatric Hematologist, Indiana Hemophilia &Thrombosis Center, Inc.
    PAI-1 deficiency
    Amish
    cardiac fibrosis
    Metformin
    Additional relevant MeSH terms:
    Fibrosis
    Metformin

    Study Results

    No Results Posted as of Aug 3, 2022