A Phase 4 interventional study of Metformin Extended Release Oral Tablet in Plasminogen Activator Inhibitor-1 Deficiency and Cardiac Fibrosis, sponsored by Indiana Hemophilia &Thrombosis Center, Inc.. Active, not recruiting at 1 site in United States. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2024-11-06.
Sponsored by Indiana Hemophilia &Thrombosis Center, Inc. · Phase 4, Interventional, and Treatment
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.
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
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.
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.
3,255 studies on the registry are indexed under Fibrosis; 465 are open to participants now.
This study's planned enrollment of 15 is below the median of 50 across 2,130 interventional studies indexed under Fibrosis.
Browse Fibrosis studies →Indiana Hemophilia &Thrombosis Center, Inc. is the lead sponsor of 4 studies on the registry; 2 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
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
Subjects with PAI-1 deficiency with or without cardiac fibrosis, not receiving treatment with metformin Subjects are allowed to switch between the two groups
daily metformin treatment vs. no treatment with metformin
Also known as: Glucophage XR
Number of individuals homozygous for PAI-1 deficiency with stable or improved cardiac fibrosis
Measured using cardiac MRI to quantify the percentage cardiac fibrosis.
Time frame: 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.
Time frame: through the study annually, up to 60 months
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 )
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
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.
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 6 months after study enrollment, through the study annually, up to 60 months
Plan to share: Yes — TBD based on analysis
Supporting information: Study protocol, Icf
This study is active, not recruiting, as verified in Oct 2024. You cannot join it, but the record below documents what was studied.
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Indiana Hemophilia &Thrombosis Center, Inc.