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Metformin Use in Cardiac Fibrosis in PAI-1 Deficiency

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05317806
Recruitment Status : Not yet recruiting
First Posted : April 8, 2022
Last Update Posted : April 8, 2022
Sponsor:
Information provided by (Responsible Party):
Sweta Gupta, Indiana Hemophilia &Thrombosis Center, Inc.

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
Plasminogen Activator Inhibitor-1 Deficiency Cardiac Fibrosis Drug: Metformin Extended Release Oral Tablet Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated 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)
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Use of Metformin in Prevention and Treatment of Cardiac Fibrosis in PAI-1 Deficient Population
Estimated Study Start Date : May 2022
Estimated Primary Completion Date : May 2027
Estimated Study Completion Date : May 2027


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 Name: 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




Primary Outcome Measures :
  1. 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.

  2. 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.


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) [ 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 )

  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) [ 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.


  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) [ Time Frame: 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 [ Time Frame: 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) [ 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




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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05317806


Contacts
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Contact: Nicci Knipe 317-871-0011 ext 281 nknipe@ihtc.org
Contact: Meadow Heiman 317-871-0011 ext 242 mheiman@ihtc.org

Sponsors and Collaborators
Indiana Hemophilia &Thrombosis Center, Inc.
Investigators
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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:

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Responsible Party: Sweta Gupta, Pediatric Hematologist, Indiana Hemophilia &Thrombosis Center, Inc.
ClinicalTrials.gov Identifier: NCT05317806    
Other Study ID Numbers: R2O210069
First Posted: April 8, 2022    Key Record Dates
Last Update Posted: April 8, 2022
Last Verified: March 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: TBD based on analysis
Supporting Materials: Study Protocol
Informed Consent Form (ICF)
Time Frame: Post analysis

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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, Indiana Hemophilia &Thrombosis Center, Inc.:
PAI-1 deficiency
Amish
cardiac fibrosis
Metformin
Additional relevant MeSH terms:
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Fibrosis
Pathologic Processes
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs