Interventions Against Insulin Resistance in Pulmonary Arterial Hypertension

NCT ID: NCT03617458

Last Updated: 2025-09-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 73 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-08-23
• Study Completion Date: 2025-08-19

Brief Summary

The primary objective of this study is to determine the impact of two interventions against insulin resistance on the composite endpoint of 10% improvement in baseline six minute walk distance or improvement in World Health Organization (WHO) functional class in humans with pulmonary artery hypertension (PAH).

Detailed Description

The investigators propose to test the hypothesis that interventions to improve insulin resistance will improve exercise capacity and World Health Organization (WHO) functional class in PAH. The investigators propose three specific aims to test this 1) A prospective 2x2 factorial design 12-week clinical trial of metformin or placebo and activity intervention or usual care to assess effect on six minute walk and WHO functional class, 2) Assessment of the interventions in Aim 1 in a subset of patients on right ventricle (RV) and peripheral muscle function and lipid content and markers of pulmonary vascular disease to define how these interventions may work in PAH and 3) Identify and prospectively test peripheral blood markers of metformin response in PAH. The broad goals of this work are to demonstrate the efficacy and mechanisms of interventions against insulin resistance in PAH and to identify which patients are most likely to benefit from these interventions, moving to precision medicine in PAH.

The investigators are planning a factorial design trial. Patients will be randomized twice. The first is metformin or placebo and is quadruple randomized. The second is mobile health (mHealth) intervention via texts or standard of care and is not blinded to the patients, but is to the investigator and thus is triple randomized.

Conditions

Pulmonary Artery Hypertension

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: FACTORIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Metformin + mHealth Intervention

Patients will receive active ingredient medicine with mHealth texting platform, which are messages designed to facilitate self-awareness, reinforce step targets, and link physical activity with a reward or memorable cue.

Subjects will receive metformin 500mg. Patients will titrate the medication as follows: 500mg po daily x 5 days, 500mg po twice a day (BID) x 5 days, 500mg by mouth (po) three times a day (TID) x 5 days,1000mg po BID x 69 days (12 weeks total).

Group Type: ACTIVE_COMPARATOR

Metformin

Intervention Type: DRUG

Metformin is a drug has been on the market for several decades and is considered first line therapy for diabetes mellitus type 2.

mHealth Intervention

Intervention Type: DEVICE

Our Health Insurance Portability and Accountability Act (HIPAA) compliant texting platform is linked to the Fitbit Application Program Interface. Real time activity data will be transmitted from the subject's smartphone to our mHealth platform via cellular network.Subjects assigned to the texting arm will receive 3 texts/day in sync with their preferred morning, lunch, and evening leisure schedule, which is defined at enrollment. These texts will use personal, disease-specific, and provider information to deliver 2 types of messages customized to the current step count and sent in equal proportion. Messages are designed to facilitate self-awareness, reinforce step targets, and link physical activity with a reward or memorable cue.

Placebo + Usual Care

Patient will receive non active medicine and routine medical care.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

A treatment with no active ingredients or therapeutic effect.

Usual Care

Intervention Type: DEVICE

Our HIPAA data will be transmitted from the subject's smartphone to our mHealth platform via cellular network.

Metformin + Usual Care

Patient will receive active ingredient medicine with routine medical care.

Subjects will receive metformin 500mg. Patients will titrate the medication as follows: 500mg po daily x 5 days, 500mg po BID x 5 days, 500mg po TID x 5 days,1000mg po BID x 69 days (12 weeks total).

Group Type: ACTIVE_COMPARATOR

Metformin

Intervention Type: DRUG

Metformin is a drug has been on the market for several decades and is considered first line therapy for diabetes mellitus type 2.

Usual Care

Intervention Type: DEVICE

Our HIPAA data will be transmitted from the subject's smartphone to our mHealth platform via cellular network.

Placebo + mHealth Intervention

Patient will receive non active medicine and the mHealth texting platform, which are messages designed to facilitate self-awareness, reinforce step targets, and link physical activity with a reward or memorable cue.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

A treatment with no active ingredients or therapeutic effect.

mHealth Intervention

Intervention Type: DEVICE

Our Health Insurance Portability and Accountability Act (HIPAA) compliant texting platform is linked to the Fitbit Application Program Interface. Real time activity data will be transmitted from the subject's smartphone to our mHealth platform via cellular network.Subjects assigned to the texting arm will receive 3 texts/day in sync with their preferred morning, lunch, and evening leisure schedule, which is defined at enrollment. These texts will use personal, disease-specific, and provider information to deliver 2 types of messages customized to the current step count and sent in equal proportion. Messages are designed to facilitate self-awareness, reinforce step targets, and link physical activity with a reward or memorable cue.

Interventions

Metformin

Metformin is a drug has been on the market for several decades and is considered first line therapy for diabetes mellitus type 2.

Intervention Type: DRUG

Placebo

A treatment with no active ingredients or therapeutic effect.

Intervention Type: DRUG

mHealth Intervention

Our Health Insurance Portability and Accountability Act (HIPAA) compliant texting platform is linked to the Fitbit Application Program Interface. Real time activity data will be transmitted from the subject's smartphone to our mHealth platform via cellular network.Subjects assigned to the texting arm will receive 3 texts/day in sync with their preferred morning, lunch, and evening leisure schedule, which is defined at enrollment. These texts will use personal, disease-specific, and provider information to deliver 2 types of messages customized to the current step count and sent in equal proportion. Messages are designed to facilitate self-awareness, reinforce step targets, and link physical activity with a reward or memorable cue.

Intervention Type: DEVICE

Usual Care

Our HIPAA data will be transmitted from the subject's smartphone to our mHealth platform via cellular network.

Intervention Type: DEVICE

Eligibility Criteria

Inclusion Criteria

• Diagnosed with idiopathic, heritable, or drug- or toxin-associated pulmonary arterial hypertension (PAH) according to World Health Organization consensus recommendations.
• Stable PAH-specific medication regimen for three months prior to enrollment. Subjects with only a single diuretic adjustment in the prior three months will be included. Adjustments in IV prostacyclin for side effect management are allowed.
• Subjects must own a Bluetooth capable modern smartphone capable of receiving and sending text messages and an active data plan.
• WHO Functional Class I-III
• Ambulatory

Exclusion Criteria

• Prohibited from normal activity due to wheelchair bound status, bed bound status, reliance on a cane/walker, activity-limiting angina, activity-limiting osteoarthritis, or other condition that limits activity
• Pregnancy
• Diagnosis of PAH etiology other than idiopathic, heritable, or associated with drugs or toxins
• FEV1> or = 65% predicted AND normal chest imaging
• WHO Functional class IV heart failure
• Requirement of > 1 diuretic adjustment in the prior 30 days
• Preferred form of activity is not measured by an activity tracker (swimming, ice skating, stair master, or activities on wheels such as bicycling or rollerblading)
• Type I diabetes mellitus
• Prior diagnosis of cirrhosis
• Untreated hypo- or hyper-thyroidism
• estimated glomerular filtration rate (eGFR) by modification of diet in renal disease (MDRD) <60 milliliters per minute (mL/min)

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Mayo Clinic

OTHER

Sponsor Role: collaborator

The Cleveland Clinic

OTHER

Sponsor Role: collaborator

Vanderbilt University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Anna Hemnes

Associate Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Anna R Hemnes, MD

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University Medical Center

Locations

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Countries

United States

References

D'Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Kernis JT, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med. 1991 Sep 1;115(5):343-9. doi: 10.7326/0003-4819-115-5-343.

Reference Type: BACKGROUND

PMID: 1863023 (View on PubMed)

Benza RL, Miller DP, Barst RJ, Badesch DB, Frost AE, McGoon MD. An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry. Chest. 2012 Aug;142(2):448-456. doi: 10.1378/chest.11-1460.

Reference Type: BACKGROUND

PMID: 22281797 (View on PubMed)

Mathai SC, Puhan MA, Lam D, Wise RA. The minimal important difference in the 6-minute walk test for patients with pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012 Sep 1;186(5):428-33. doi: 10.1164/rccm.201203-0480OC. Epub 2012 Jun 21.

Reference Type: BACKGROUND

PMID: 22723290 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

180198

Identifier Type: -

Identifier Source: org_study_id