Cardiometabolic Disease and Pulmonary Hypertension
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
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
- 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)
- 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
- 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
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.- 2017P001020
- 1R01HL134893-01A1
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
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 |
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 |
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
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 |
jho@bidmc.harvard.edu |
- 2017P001020
- 1R01HL134893-01A1