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Metformin for Older Patients With Heart Failure With Preserved Ejection Fraction (Met-PEF)

Primary Purpose

Heart Failure With Preserved Ejection Fraction

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Metformin
Placebo
Sponsored by
Wake Forest University Health Sciences
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Heart Failure With Preserved Ejection Fraction focused on measuring heart failure, metformin, inflammation

Eligibility Criteria

60 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • 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.
  • Age ≥60
  • Stable HF symptoms and medications for ≥3 weeks
  • 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:

  • History of treatment with metformin or other anti-diabetic drug intended to treat diabetes
  • Body mass index (BMI) <25.0
  • Uncontrolled dysrhythmia
  • Uncontrolled hypertension (systolic blood pressure [SPB]>200 mmHg or diastolic blood pressure [DBP]>100 mmHg at rest)
  • Significant anemia (<9.5 g hemoglobin [Hb]) (eligibility will be determined by complete blood count)
  • Significant renal insufficiency (estimated glomerular filtration rate [eGFR] <45 ml/min/1.73 m2) (eligibility will be determined by comprehensive metabolic panel)
  • Acute or chronic metabolic acidosis
  • Type 2 diabetes, or HbA1c>6.5
  • Low vitamin B12 (<232 pg/mL)
  • Known valvular heart disease, infiltrative cardiomyopathy, or hypertrophic obstructive cardiomyopathy with active obstruction as the primary etiology of HF
  • 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
  • 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.
  • Alcohol abuse (>14 drinks/week)
  • Current or recent cancer, or chemotherapy/radiation treatment
  • Pregnancy-women of child-bearing potential are excluded from participation in this study.
  • 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
  • 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
  • Plans to leave area within 1 year
  • Currently participating in other investigational study
  • Refuses informed consent

Sites / Locations

  • Atrium Health Sanger Heart and Vascular Clinic Institute
  • Wake Forest School of MedicineRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Metformin

Placebo

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Peak VO2
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.

Secondary Outcome Measures

Full Information

First Posted
October 22, 2021
Last Updated
September 25, 2023
Sponsor
Wake Forest University Health Sciences
Collaborators
University of South Florida, National Institute on Aging (NIA)
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1. Study Identification

Unique Protocol Identification Number
NCT05093959
Brief Title
Metformin for Older Patients With Heart Failure With Preserved Ejection Fraction
Acronym
Met-PEF
Official Title
Metformin for Older Patients With Heart Failure With Preserved Ejection Fraction
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
January 4, 2022 (Actual)
Primary Completion Date
March 2025 (Anticipated)
Study Completion Date
September 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Wake Forest University Health Sciences
Collaborators
University of South Florida, National Institute on Aging (NIA)

4. Oversight

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
Data Monitoring Committee
Yes

5. 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 80 older patients with heart failure with preserved ejection fraction (HFpEF).
Detailed Description
Enrollment of participants will be conducted at both Wake Forest and Atrium Health (approximately 40 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Heart Failure With Preserved Ejection Fraction
Keywords
heart failure, metformin, inflammation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Participants, care providers, investigators, and outcomes assessors will be unmasked at the end of data collection of all participants.
Allocation
Randomized
Enrollment
80 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Metformin
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Metformin
Other Intervention Name(s)
metformin XR
Intervention Description
An extended release formulation will be used which improves compliance and reduces GI side effects.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo is a biologically inert substance placed in capsules to match appearance of active intervention
Primary Outcome Measure Information:
Title
Peak VO2
Description
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.
Time Frame
Week 20
Other Pre-specified Outcome Measures:
Title
C-reactive protein
Description
Inflammatory marker in serum blood
Time Frame
Week 20
Title
Interleukin-6
Description
Inflammatory marker in serum blood
Time Frame
Week 20
Title
Tumor necrosis factor-alpha
Description
Inflammatory marker in serum blood
Time Frame
Week 20
Title
Kansas City Cardiomyopathy (KCCQ) Overall Score
Description
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.
Time Frame
Week 20
Title
Short Physical Performance Battery (SPPB)
Description
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.
Time Frame
Week 20
Title
6-minute walk distance (6MWD)
Description
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.
Time Frame
Week 20
Title
Lipopolysaccharide binding protein (LBP)
Description
LBP is a marker of microbial translocation, is increased in older persons and is related to their reduced physical function.
Time Frame
Week 20
Title
Fecal Mucin
Description
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.
Time Frame
Week 20

10. Eligibility

Sex
All
Minimum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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. Age ≥60 Stable HF symptoms and medications for ≥3 weeks 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: History of treatment with metformin or other anti-diabetic drug intended to treat diabetes Body mass index (BMI) <25.0 Uncontrolled dysrhythmia Uncontrolled hypertension (systolic blood pressure [SPB]>200 mmHg or diastolic blood pressure [DBP]>100 mmHg at rest) Significant anemia (<9.5 g hemoglobin [Hb]) (eligibility will be determined by complete blood count) Significant renal insufficiency (estimated glomerular filtration rate [eGFR] <45 ml/min/1.73 m2) (eligibility will be determined by comprehensive metabolic panel) Acute or chronic metabolic acidosis Type 2 diabetes, or HbA1c>6.5 Low vitamin B12 (<232 pg/mL) Known valvular heart disease, infiltrative cardiomyopathy, or hypertrophic obstructive cardiomyopathy with active obstruction as the primary etiology of HF 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 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. Alcohol abuse (>14 drinks/week) Current or recent cancer, or chemotherapy/radiation treatment Pregnancy-women of child-bearing potential are excluded from participation in this study. 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 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 Plans to leave area within 1 year Currently participating in other investigational study Refuses informed consent
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Michael B Nelson
Phone
336-716-6789
Email
mbnelson@wakehealth.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Dalane W. Kitzman, MD
Organizational Affiliation
Wake Forest University Health Sciences
Official's Role
Principal Investigator
Facility Information:
Facility Name
Atrium Health Sanger Heart and Vascular Clinic Institute
City
Charlotte
State/Province
North Carolina
ZIP/Postal Code
28203
Country
United States
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Melissa Myers, RN
Phone
704-928-6588
Email
melissa.myers@atriumhealth.org
First Name & Middle Initial & Last Name & Degree
Nicole Cyrille-Superville, MD
Facility Name
Wake Forest School of Medicine
City
Winston-Salem
State/Province
North Carolina
ZIP/Postal Code
27157
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Michael Nelson, MS
Phone
336-716-6789
Email
mbnelson@wakehealth.edu
First Name & Middle Initial & Last Name & Degree
Dalane W. Kitzman, MD

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
No data are to be shared from this study.

Learn more about this trial

Metformin for Older Patients With Heart Failure With Preserved Ejection Fraction

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