Metformin Use in Cardiac Fibrosis in PAI-1 Deficiency

NCT05317806 | Active Not Recruiting Phase 4 DMC FDA Drug

• 1 other identifier: R2O210069
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

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.

Conditions

Plasminogen Activator Inhibitor-1 Deficiency; Cardiac Fibrosis

Keywords

PAI-1 deficiency; Amish; cardiac fibrosis; Metformin

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (5)

• 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

• 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

• 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

• Number of individuals homozygous for PAI-1 deficiency with stable or improved ejection fraction on 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)

  6 months after study enrollment, through the study annually, up to 60 months

Study Arms (2)

Metformin Treatment Group

EXPERIMENTAL

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

Observation Group

NO INTERVENTION

Subjects with PAI-1 deficiency with or without cardiac fibrosis, not receiving treatment with metformin Subjects are allowed to switch between the two groups

Interventions

Metformin Extended Release Oral Tablet DRUG

daily metformin treatment vs. no treatment with metformin

Also known as: Glucophage XR

Metformin Treatment Group

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Indiana Hemophilia &Thrombosis Center, Inc.: lead

Study Sites (1)

Indiana Hemophilia and Thrombosis Center

Indianapolis, Indiana, 46260, United States

Location

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Related Links

• Gupta S, Sealls W, Shapiro A. Rare coagulation disorders resource room - plasminogen activator inbitor type 1 deficiency. Rare coagulation disorders resource room \[cited August 8, 2019\]

MeSH Terms

Conditions

Plasminogen Activator Inhibitor-1 Deficiency

Interventions

Metformin

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Study Officials

• Sweta Gupta, MD

  Indiana Hemophilia and Thrombosis Center, Inc

  PRINCIPAL INVESTIGATOR

• Magdalena Lewandowska, MD

  Indiana Hemophilia and Thrombosis Center, Inc

  PRINCIPAL INVESTIGATOR

• Amy D Shapiro, MD

  Indiana Hemophilia and Thrombosis Center, Inc

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Pediatric Hematologist

Model Details: The study will have one metformin Treatment group (daily metformin administered) and one Observation group (no study drug administered)

Study Record Dates

• First Submitted: March 8, 2022
• First Posted: April 8, 2022
• Study Start: October 10, 2022
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): October 1, 2027
• Last Updated: November 6, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF
• Time Frame: Post analysis

Locations

US (1)