Cardiometabolic Disease and Pulmonary Hypertension

Sponsor
Massachusetts General Hospital (Other)
Overall Status
Terminated
CT.gov ID
NCT03349775
Collaborator
National Heart, Lung, and Blood Institute (NHLBI) (NIH)
21
1
2
36.8
0.6

Study Details

Study Description

Brief Summary

This study will investigate if metformin can help people with obesity and high pressures inside their lung blood vessels. Metformin is approved by the U.S. Food and Drug Administration (FDA) to treat diabetes, but metformin is not approved by the FDA to treat pulmonary hypertension.

This study will examine whether Metformin will improve the high pressure inside lung blood vessels in people who are obese. The study will help understand the effect of metformin on pressures inside lung blood vessels.

Condition or Disease Intervention/Treatment Phase
Early Phase 1

Detailed Description

Obesity can predispose people to develop high pressures inside their lung blood vessels, a condition called pulmonary hypertension, Pulmonary hypertension in turn, can lead to shortness of breath and other health complications such as heart failure. In this study, we seek to identify individuals at risk for the development of high pressures inside lung vessels based on BMI and dyspnea grade 1.

Participants will be screened by echocardiography to estimate pulmonary pressures. Potential participants will undergo invasive cardiopulmonary exercise testing with hemodynamic monitoring, in order to identify individuals with abnormal pulmonary vascular function either at rest or during exercise. Patients who have undergone clinically-indicated cardiopulmonary exercise testing and meet inclusion/exclusion criteria will also be recruited. Those with abnormal pulmonary vascular function will be randomized to receive Metformin or placebo for a total of 3 months under an IND exemption. The primary outcomes include the effect on pulmonary vascular function at rest and during exercise. Secondary outcomes include change in pulmonary artery endothelial cell phenotypes.

Study Design

Study Type:
Interventional
Actual Enrollment :
21 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Other
Official Title:
Cardiometabolic Disease and Pulmonary Hypertension
Actual Study Start Date :
Nov 27, 2017
Actual Primary Completion Date :
Dec 22, 2020
Actual Study Completion Date :
Dec 22, 2020

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Metformin

Metformin: 500mg twice daily for 1 week, followed by 1g twice daily for a total of 3 months.

Drug: Metformin
One capsule by mouth twice a day, followed by an increase to two capsules by mouth twice a day for a total of 3 months

Placebo Comparator: Placebo

Placebo: 500 mgh twice daily for 1 week, followed by 1g twice daily for a total of 3 months.

Drug: Placebo
One capsule by mouth twice a day, followed by an increase to two capsules by mouth twice a day for a total of 3 months

Outcome Measures

Primary Outcome Measures

  1. Pulmonary Vascular Hemodynamics (Rest) [Baseline and 3 months]

    The metformin and placebo groups will be compared with respect to resting mean pulmonary artery pressure (mmHg)

  2. Pulmonary Vascular Hemodynamics (Exercise) [Baseline and 3 months]

    The metformin and placebo groups will be compared with respect to augmentation of mean pulmonary artery pressure divided by augmentation of cardiac output during cardiopulmonary exercise testing (change in mean PAP divided by change in cardiac output from rest to peak exercise)

Secondary Outcome Measures

  1. Effect on Pulmonary Artery Endothelial Cell Phenotypes [baseline and 3 months]

    We will compare the metformin and placebo groups. Specifically we will examine the following pulmonary artery endothelial cell phenotypes: (1) activation of phospho-eNOS as detected by immunofluorescence staining

Eligibility Criteria

Criteria

Ages Eligible for Study:
30 Years to 80 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
  • Age 30-80 years

  • History of obesity and current BMI ≥ 25 kg/ m2 for study volunteers or BMI ≥ 25 kg/ m2 for those with clinically indicated CPET or known HFpEF

  • History of Dyspnea (Grade 1 or more)

  • Able to provide informed consent and willing to comply with study

Exclusion Criteria:
  • History of diabetes mellitus

  • History of primary pulmonary arterial hypertension

  • History of moderate to severe COPD

  • History of severe Obstructive Sleep apnea

  • History of renal disease (eGFR< 45 mL/min/1.732)

  • History of severe liver disease

  • History of cardiovascular disease (recent heart attack or stroke) except known HFpEF

  • History of blood clot in lung

  • History of Splenectomy

  • History of Active Cancer

  • Platelets count of < 75,000

  • International normalized ration (INR) of > 1.5

  • History of recent anemia (HB < 9g/dL)

  • Current use of Metformin

  • Prior LVEF < 50% on echocardiogram

  • Indication of severe valvular disease on echo

  • Pregnant or planning to become pregnant in next 4 months

  • History of HIV infection

Contacts and Locations

Locations

Site City State Country Postal Code
1 Massachusetts General Hospital Boston Massachusetts United States 02114

Sponsors and Collaborators

  • Massachusetts General Hospital
  • National Heart, Lung, and Blood Institute (NHLBI)

Investigators

  • Principal Investigator: Jennifer E Ho, MD, Massachusetts General Hospital

Study Documents (Full-Text)

More Information

Publications

None provided.
Responsible Party:
Jennifer En-Sian Ho M.D., Assistant Physician in Medicine, Massachusetts General Hospital
ClinicalTrials.gov Identifier:
NCT03349775
Other Study ID Numbers:
  • 2017P001020
  • 1R01HL134893-01A1
First Posted:
Nov 22, 2017
Last Update Posted:
Jan 21, 2022
Last Verified:
Dec 1, 2021
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Jennifer En-Sian Ho M.D., Assistant Physician in Medicine, Massachusetts General Hospital
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail
Arm/Group Title Metformin Placebo
Arm/Group Description Metformin: 500mg tablet orally twice daily for 1 week, followed by two 500mg tablets orally twice daily for a total of 3 months. Placebo: 500 mg tablet orally twice daily for 1 week, followed by two 500 mg tablets orally twice daily for a total of 3 months.
Period Title: Overall Study
STARTED 10 11
COMPLETED 8 7
NOT COMPLETED 2 4

Baseline Characteristics

Arm/Group Title Metformin Placebo Total
Arm/Group Description Metformin: 500mg tablet orally twice daily for 1 week, followed by two 500mg tablets orally twice daily for a total of 3 months. Placebo: 500 mg tablet orally twice daily for 1 week, followed by two 500 mg tablets orally twice daily for a total of 3 months. Total of all reporting groups
Overall Participants 8 7 15
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
65
(10)
60
(10)
63
(10)
Sex: Female, Male (Count of Participants)
Female
5
62.5%
4
57.1%
9
60%
Male
3
37.5%
3
42.9%
6
40%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino
0
0%
0
0%
0
0%
Not Hispanic or Latino
8
100%
7
100%
15
100%
Unknown or Not Reported
0
0%
0
0%
0
0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
0
0%
0
0%
0
0%
Asian
0
0%
0
0%
0
0%
Native Hawaiian or Other Pacific Islander
0
0%
0
0%
0
0%
Black or African American
1
12.5%
0
0%
1
6.7%
White
7
87.5%
7
100%
14
93.3%
More than one race
0
0%
0
0%
0
0%
Unknown or Not Reported
0
0%
0
0%
0
0%
Height (inches) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [inches]
65.1
(2.9)
67.7
(4.2)
66.3
(3.7)
Weight (pounds) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [pounds]
212.9
(44.1)
224.0
(32.9)
218.1
(38.3)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]
35.3
(6.0)
34.4
(4.6)
34.9
(5.2)
Heart Rate (HR) (beats per minute (bpm)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [beats per minute (bpm)]
70
(13)
70
(15)
70
(14)
Systolic Blood Pressure (SBP) (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]
133
(18)
142
(14)
137
(17)
Diastolic Blood Pressure (DBP) (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]
80
(8)
86
(11)
83
(9)

Outcome Measures

1. Primary Outcome
Title Pulmonary Vascular Hemodynamics (Rest)
Description The metformin and placebo groups will be compared with respect to resting mean pulmonary artery pressure (mmHg)
Time Frame Baseline and 3 months

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Metformin Placebo
Arm/Group Description Metformin: 500mg tablet orally twice daily for 1 week, followed by two 500mg tablets orally twice daily for a total of 3 months. Placebo: 500 mg tablet orally twice daily for 1 week, followed by two 500 mg tablets orally twice daily for a total of 3 months.
Measure Participants 8 7
Mean (Standard Deviation) [mmHg]
-3.00
(5.35)
-0.43
(4.89)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Metformin, Placebo
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.35
Comments
Method t-test, 2 sided
Comments
Method of Estimation Estimation Parameter Median Difference (Final Values)
Estimated Value -2.57
Confidence Interval (2-Sided) 95%
-8.32 to 3.18
Parameter Dispersion Type: Standard Deviation
Value: 5.14
Estimation Comments
2. Primary Outcome
Title Pulmonary Vascular Hemodynamics (Exercise)
Description The metformin and placebo groups will be compared with respect to augmentation of mean pulmonary artery pressure divided by augmentation of cardiac output during cardiopulmonary exercise testing (change in mean PAP divided by change in cardiac output from rest to peak exercise)
Time Frame Baseline and 3 months

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Metformin Placebo
Arm/Group Description Metformin: 500mg tablet orally twice daily for 1 week, followed by two 500mg tablets orally twice daily for a total of 3 months. Placebo: 500 mg tablet orally twice daily for 1 week, followed by two 500 mg tablets orally twice daily for a total of 3 months.
Measure Participants 8 7
Mean (Standard Deviation) [mmHg/L/min]
-0.29
(0.83)
-1.42
(3.00)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Metformin, Placebo
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.37
Comments
Method t-test, 2 sided
Comments
Method of Estimation Estimation Parameter Median Difference (Final Values)
Estimated Value 1.13
Confidence Interval (2-Sided) 95%
-1.65 to 3.92
Parameter Dispersion Type: Standard Deviation
Value: 2.13
Estimation Comments
3. Secondary Outcome
Title Effect on Pulmonary Artery Endothelial Cell Phenotypes
Description We will compare the metformin and placebo groups. Specifically we will examine the following pulmonary artery endothelial cell phenotypes: (1) activation of phospho-eNOS as detected by immunofluorescence staining
Time Frame baseline and 3 months

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description

Adverse Events

Time Frame Adverse event data were collected for the metformin and placebo groups over the course of the 3 months on randomized assignment to study drug.
Adverse Event Reporting Description
Arm/Group Title Metformin Placebo
Arm/Group Description Metformin: 500mg tablet orally twice daily for 1 week, followed by two 500mg tablets orally twice daily for a total of 3 months. Placebo: 500 mg tablet orally twice daily for 1 week, followed by two 500 mg tablets orally twice daily for a total of 3 months.
All Cause Mortality
Metformin Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/10 (0%) 0/11 (0%)
Serious Adverse Events
Metformin Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/10 (0%) 1/11 (9.1%)
Cardiac disorders
Left arm numbness and chest pain 0/10 (0%) 1/11 (9.1%)
Other (Not Including Serious) Adverse Events
Metformin Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 8/10 (80%) 8/11 (72.7%)
Gastrointestinal disorders
Acid Reflux 1/10 (10%) 2 0/11 (0%) 2
GI upset (e.g. nausea, diarrhea, vomiting, abdominal discomfort, flatulence) 7/10 (70%) 11 4/11 (36.4%) 5
General disorders
Fatigue/Weakness 0/10 (0%) 2/11 (18.2%)
Non-Specific Symptoms 0/10 (0%) 1/11 (9.1%)
Musculoskeletal and connective tissue disorders
Muscle or joint soreness 0/10 (0%) 3/11 (27.3%)
Respiratory, thoracic and mediastinal disorders
Asthma Flare 0/10 (0%) 1/11 (9.1%)
Shortness of breath 0/10 (0%) 1/11 (9.1%)
Skin and subcutaneous tissue disorders
Itching and rash/hives 1/10 (10%) 2 1/11 (9.1%) 1

Limitations/Caveats

After discussion with the Data Safety Monitoring Board and NIH, the randomized clinical trial involving metformin vs. placebo was terminated due to slow enrollment in the setting of the COVID-19 pandemic, resulting in small numbers of subjects analyzed.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Name/Title Dr. Jennifer Ho
Organization Beth Israel Deaconness Medical Center
Phone 617-735-4102
Email jho@bidmc.harvard.edu
Responsible Party:
Jennifer En-Sian Ho M.D., Assistant Physician in Medicine, Massachusetts General Hospital
ClinicalTrials.gov Identifier:
NCT03349775
Other Study ID Numbers:
  • 2017P001020
  • 1R01HL134893-01A1
First Posted:
Nov 22, 2017
Last Update Posted:
Jan 21, 2022
Last Verified:
Dec 1, 2021