Met-PEFpilot: Metformin for Older Patients With Heart Failure With Preserved Ejection Fraction Pilot Study
Study Details
Study Description
Brief Summary
Met-PEF will be a randomized, double-blind, placebo-controlled trial to examine the effects of 20 weeks of 1500 mg/day of metformin on physical function, quality of life (QOL), microbiome diversity, leaky gut, and systemic inflammation in patients with 20 older patients with heart failure with preserved ejection fraction (HFpEF).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
Enrollment of participants will be conducted at both Wake Forest and Atrium Health (approximately 10 participants at each site) following assessment of eligibility criteria and willingness to participate in the trial. Eligibility criteria are designed to target the population under study and exclude participants unable to safely take the study intervention or undergo study procedures. Informed consent will be obtained from qualified participants. Participants will complete baseline assessments before masked, random assignment to metformin or placebo. The assigned study medications will be dispensed by the research pharmacy. Participants will take assigned metformin or placebo for a treatment period of 20 weeks, starting at 500mg/day and escalating over the first 3 weeks to a target dose of 1500mg/day. Participants will be contacted every 2 weeks for assessment of adverse events, side effects, and adherence. At week 4, participants will be seen in clinic for safety laboratory assessments. At week 20, participants will complete follow-up assessments by an assessor blinded to treatment group.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: Metformin 20 weeks of metformin 1500 mg daily. Metformin is a widely used medication with an excellent safety profile. Dosing will be escalated during the first 3 weeks of treatment. Dosing will be initiated with 500 mg taken orally once daily in the evening for 1 week. After one week, the participant will be called to assess tolerance and will be asked to increase dose to two capsules per day for a total 1000 mg per day for one week. At the end of the second week, participants will be called again and if they tolerated the increased dose will be instructed to increase to three capsules (1500 mg/day) per day for the remainder of the 20 weeks. An extended release formulation will be used which improves compliance and reduces GI side effects. |
Drug: Metformin
An extended release formulation will be used which improves compliance and reduces GI side effects.
Other Names:
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| Placebo Comparator: Placebo 20 weeks of placebo 1500 mg daily. Placebo is a biologically inert substance placed in capsules to match appearance of active intervention (metformin). Dosing will be escalated during the first 3 weeks of treatment. Dosing will be initiated with 500 mg taken orally once daily in the evening for 1 week. After one week, the participant will be called to assess tolerance and will be asked to increase dose to two capsules per day for a total 1000 mg per day for one week. At the end of the second week, participants will be called again and if they tolerated the increased dose will be instructed to increase to three capsules (1500 mg/day) per day for the remainder of the 20 weeks. |
Drug: Placebo
Placebo is a biologically inert substance placed in capsules to match appearance of active intervention
|
Outcome Measures
Primary Outcome Measures
- Lipopolysaccharide binding protein (LBP) [Week 20]
LBP is a marker of microbial translocation, is increased in older persons and is related to their reduced physical function.
- Fecal Mucin [Week 20]
Fecal mucin (mg/g) is a protein that indicates the mucus barrier functions and mucin production, measured by ELISA assays in feces. The higher the fecal mucin, better the mucus barriers are, or vice-versa.
Other Outcome Measures
- C-reactive protein [Week 20]
Inflammatory marker in serum blood
- Interleukin-6 [Week 20]
Inflammatory marker in serum blood
- Tumor necrosis factor-alpha [Week 20]
Inflammatory marker in serum blood
- Peak VO2 [Week 20]
Peak VO2 (ml of O2 relative to kg of body weight per minute [ml/kg/min]) is a measure of peak oxygen capacity during exercise, is a standardized, objective, reproducible and valid measure of exercise capacity.
- Kansas City Cardiomyopathy (KCCQ) Overall Score [Week 20]
The KCCQ overall score is the main summary score of the KCCQ containing physical, symptom, quality of life, and social subdomains. It is measured on a scale of 0-100 units with higher score indicating better HF-disease-specific quality of life.
- Short Physical Performance Battery (SPPB) [Week 20]
The SPPB is a valid, clinically meaningful measure of physical function in older adults. The SPPB has 3 components: standing balance, 4-meter walk, and repeated chair rises, corresponding to balance, mobility, and functional strength. Each component is scored on a scale of 0-4 for a total score of 0-12 units with a higher score indicating better physical function.
- 6-minute walk distance (6MWD) [Week 20]
6MWD is the distance walked in 6 minutes, with higher distance indicating better function. The 6MWD test is a well-established outcome measure in heart failure. It is valid and reproducible in patients with a wide range of physical function, predicts clinical events, and responds to interventions.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Heart failure with preserved ejection fraction (HFpEF) will be defined in accord with the American College of Cardiology/American Heart Association 2013 guidelines statement on Management of heart failure and as previously described. The 4 key inclusion criteria for HFpEF include: 1) clinical signs and symptoms as scored by National Health and Nutrition Examination Survey (NHANES)-HF Clinical Score ≥3 and the Rich Criteria; 2) a normal left ventricular (LV) ejection fraction (≥50%) by echocardiography; 3) LV diastolic dysfunction > grade 1 (American Society of Echocardiography Recommendations); 4) no evidence of significant ischemic, valvular, pulmonary or other medical disorder to account for their symptoms.
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Age ≥60
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Stable HF symptoms and medications for ≥3 weeks
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Final eligibility will be based upon all information available at the conclusion of the baseline visits tests, including review of hospital and outpatient records, history, physical examination, echocardiogram, and familiarization/screening exercise test by a board-certified investigator cardiologist who have extensive experience in heart failure investigations in older persons with HFpEF
Exclusion Criteria:
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History of treatment with metformin or other anti-diabetic drug intended to treat diabetes
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Body mass index (BMI) <25.0
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Uncontrolled dysrhythmia
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Uncontrolled hypertension (systolic blood pressure [SPB]>200 mmHg or diastolic blood pressure [DBP]>100 mmHg at rest)
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Significant anemia (<9.5 g hemoglobin [Hb]) (eligibility will be determined by complete blood count)
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Significant renal insufficiency (estimated glomerular filtration rate [eGFR] <45 ml/min/1.73 m2) (eligibility will be determined by comprehensive metabolic panel)
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Acute or chronic metabolic acidosis
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Type 2 diabetes, or HbA1c>6.5
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Low vitamin B12 (<300 pg/mL)
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Known valvular heart disease, infiltrative cardiomyopathy, or hypertrophic obstructive cardiomyopathy with active obstruction as the primary etiology of HF
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Evidence of significant chronic obstructive pulmonary disease (COPD) defined as either: a. On continuous home oxygen therapy for COPD; b. Hospitalization for COPD in last 6 months
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Any condition that in the judgement of the investigator precludes participation in study or study procedures such as significant dementia, mobility impairment, uncontrolled psychiatric disease, etc.
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Alcohol abuse (>14 drinks/week)
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Current or recent cancer, or chemotherapy/radiation treatment
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Pregnancy-women of child-bearing potential are excluded from participation in this study.
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A treadmill exercise test revealing: a. Evidence of significant ischemia; b. Electrocardiogram: 1mm flat ST depression; c. Stopped exercising due to chest or leg claudication or any reason other than exhaustion/fatigue/dyspnea; d. Exercise SBP > 240 mmHg, DBP > 110 mmHg ; e. Unstable hemodynamics or rhythm; f. Unwilling or unable to complete adequate exercise test
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Exclusions for microbiome testing: a. Antibiotics use within last 30 days; b. Diarrhea and/or vomiting within last 30 days; c. Surgery related to gut in last 6 months; d. Inflammatory bowel disease (such as Crohn's disease or ulcerative colitis), or irritable bowel syndrome
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Plans to leave area within 1 year
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Currently participating in other investigational study
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Refuses informed consent
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Atrium Health Sanger Heart and Vascular Clinic Institute | Charlotte | North Carolina | United States | 28203 |
| 2 | Wake Forest School of Medicine | Winston-Salem | North Carolina | United States | 27157 |
Sponsors and Collaborators
- Wake Forest University Health Sciences
- University of South Florida
Investigators
- Principal Investigator: Dalane W. Kitzman, MD, Wake Forest University Health Sciences
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- IRB00076663