Metformin for Pulmonary Hypertension HFpEF

Study Overview
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Brief Summary
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The main objective of this study is to determine the clinical efficacy of metformin versus placebo and the therapeutic response with regards to functional capacity and hemodynamics in PH-HFpEF.

Detailed Description
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This is a 12-week blinded cross over trial of metformin in PH-HFpEF to improve exercise hemodynamics, functional capacity, and glucose metabolism. This phase II clinical trial will provide detailed phenotyping, physiological and mechanistic data on PH-HFpEF.

Official Title
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Phase II Trial of Metformin for Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction

Conditions
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Pulmonary Hypertension, Heart Failure

Intervention / Treatment
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* Drug: Metformin
* Drug: Placebo oral capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 2. PH-HFpEF Confirmed diagnosis by RHC within the past 6 months: Mean Pulmonary Arterial Pressure (mPAP) ≥ 25 mm Hg AND Pulmonary artery wedge pressure (PAWP) ≥ 15 mm Hg AND Transpulmonary Gradient (TPG) ≥ 12 mm Hg OR Exercise measurements Mean Pulmonary Arterial Pressure (mPAP) ≥ 30 mm Hg AND Pulmonary artery wedge pressure (PAWP) ≥ 20 mm Hg AND PA calculation (change in mPAP/change in cardiac output) = ≥3 mmHg/L/min 3. Three or more features of metabolic syndrome defined as: Body Mass Index (BMI) ≥ 30 kg/m² Systolic blood pressure (BP) ≥ 130 mm Hg and/or diastolic BP ≥ 85 mm Hg Elevated waist circumference > 102 cm in men and > 88 cm in women Fasting triglyceride (TG) level over 150 mg/dl High-density lipoprotein <40 mg/dL in men or < 50 mg/dL in women Exclusion Criteria: Age less than 18 years; Uncontrolled systemic hypertension based on repeated measurement of sitting systolic blood pressure >170 mm Hg or sitting diastolic blood pressure >95 mm Hg at Screening; Systemic sitting blood pressure < 110 mmHg systolic or < 60 mm Hg diastolic at Screening; Hemoglobin A1C > 10; Currently taking metformin or history of intolerance to metformin or contraindication to taking metformin; Known type 1 diabetes Positive urine pregnancy test or breastfeeding Ejection Fraction < 50% Dementia; 11. End-stage malignancy; 12. Major cardiovascular event or procedure within 6 weeks prior to enrollment; 13. Severe valvular disease; 14. Other severe acute or chronic medical, psychiatric or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study or would prevent completion of the study; 15. Current Smoker; 16. Hemoglobin <9 g/dL; 17. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2; 18. Receipt of an investigational product or device, or participation in a drug research study within a period of 15 days 19. <3 months of stable dose of PDE5i

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Drug: Metformin<br>500mg PO (by mouth) BID (two times daily) x 1 week then increase to 1000mg PO BID x 11 weeks | Drug: Metformin<br>* 500 mg PO BID x 1 week then increase to 1000 mg PO BID x 11 weeks<br>|
| Placebo Comparator: Placebo Oral Capsule<br>Placebo capsule that is of identical size, shape, and color to experimental drug capsule PO (by mouth) BID (two times each day) for 12 weeks | Drug: Placebo oral capsule<br>* Placebo capsule that is of identical size, shape, and color to experimental drug capsule PO (by mouth) BID (two times each day) for 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary endpoint of the trial will be mean pulmonary artery pressure (mPAP) during submaximal exercise as compared between placebo and metformin at 12 weeks (i.e. the week 12 RHC of placebo vs week 12 RHC of metformin). |  | 12 weeks (i.e. the 12th week of placebo vs 12th week of metformin) |