Metformin to Attenuate Progressive Respiratory Decline in Idiopathic Pulmonary Fibrosis (MAVRIC)

Metformin to Attenuate Progressive Respiratory Decline in Idiopathic Pulmonary Fibrosis (MAVRIC)

This is a randomized, placebo-controlled trial of metformin in 400 participants with idiopathic pulmonary fibrosis (IPF) who are at high risk of adverse clinical outcomes based on a proteomic classifier. The primary objective is to assess the safety and efficacy of metformin compared to placebo in participants with IPF who are at high-risk for adverse clinical events.

Approximately 800 participants with IPF will be screened. 400 participants who are at high risk for adverse clinical events (proteomic signature present) will be randomized into receiving metformin (n~200) or matching placebo (n~200). Participants that meet the eligibility criteria but do not have the proteomic signature (proteomic signature absent) will be contacted by phone at 12 and 24 months to review medical history.

Study Overview

• Status: Not yet recruiting
• Conditions: Idiopathic Pulmonary Fibrosis
• Intervention / Treatment: Drug: Metformin; Drug: Matching Placebo

Detailed Description

This is a multi-center, randomized, double-blind, placebo-controlled trial, of metformin or placebo in 400 participants with idiopathic pulmonary fibrosis (IPF) who are at high risk of adverse clinical outcomes based on a proteomic classifier.

Eligible participants will be placed into 2 groups depending on the results of their proteomic signature blood test done at the Screening Visit (Visit 0).

• Eligible participants who have the proteomic signature present will be randomized in a 1:1 fashion to either metformin at Visit 1 (Enrollment/Baseline) and attend follow-up visits at Months 1, 3, 6, 12, 18, 24, and a follow-up phone call at 25 months. Randomization will be stratified by background FDA-approved IPF therapy (yes/no) and DM status (yes/no).
• Eligible participants who are proteomic signature absent will be asked to complete 2 follow-up remote visits at Months 12 and 24.

The metformin starting dose will be 500 mg daily of extended-release formulation or matching placebo. The dose will be increased by 500 mg every 14 days to a total target daily dose of 1500 mg. Participants will be followed for a minimum of 12 months and a maximum of approximately 25 months, depending on the date of randomization.

• Study Type: Interventional
• Enrollment (Estimated): 800
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Chan Medical School
      • Contact: William M Whalen, MD; Email: william.whalen@umassmemorial.org
      • Contact: Rayaan Yunus; Phone Number: 508-856-2858; Email: rayaan.yunus@umassmed.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. IPF diagnosis by enrolling investigator (following the 2022 updated guidelines on diagnosis and management of IPF)
2. Age 40 years or older
3. HbA1c < 9% at screening
4. High risk by proteomic signature (proteomic signature present) for participants randomized only (for participants randomized only; participants that are proteomic signature absent will undergo remote study assessments at 12 and 24 months only).
5. If on FDA-approved treatment(s) for IPF, on a stable dose for at least 8 weeks prior to randomization
6. Ability to provide informed consent

Exclusion Criteria:

1. Taking metformin within 3 months of randomization
2. Allergy or intolerance to metformin
3. Use of insulin or insulin secretagogue(s) at randomization
4. Pregnancy, planning to become pregnant, or lactating
5. Women of childbearing potential not willing to remain abstinent (refrain from heterosexual intercourse) or use two adequate methods of contraception, including at least one method with a failure rate of <1% per year during study participation
6. History of biochemically-confirmed acidosis (lactate > 5.0 mmol/L)
7. Estimated glomerular filtration rate less than 45 mL/min/1.73 m2 at screening
8. Moderate-to-severe liver disease, decompensated heart failure, or any other condition that may make the participant unsuitable for inclusion as assessed by the study investigator at each site
9. Receipt of an investigational study agent as part of a therapeutic trial within 30 days of the Screening Visit (Visit 0)
10. Continuous supplemental oxygen use at rest greater than 2 L/min
11. Unable to swallow pills
12. Taking a medication that has a major interaction with metformin, including acetazolamide (Diamox), cimetidine (Tagamet), dolutegravir, gatifloxacin, levoketoconazole, ranolazine, or carbonic anhydrase inhibitors. Occasional use of carbonic anhydrase inhibitors for travel is permitted.
13. Current alcohol intake ≥ 15 drinks per week in men, ≥ 8 drinks per week in women or ≥ 5 drinks per occasion in men, ≥ 4 drinks per occasion in women
14. Listed for transplant at the time of randomization

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Proteomic Signature Present - Metformin; 200 participants who have a screening blood test result that is proteomic signature present will be randomized to oral metformin at a total target daily dose of 1500mg per day for 12 to 24 months depending on time of enrollment into the trial.	Drug: Metformin; Metformin or matching placebo over 12 to 24 months depending on time of enrollment into the trial. The dose will be increased by 500 mg every 14 days to a total target daily dose of 1500 mg.
Placebo Comparator: Proteomic Signature Present - Placebo; 200 participants who have a screening blood test result that is proteomic signature present will be randomized to matching placebo 12 to 24 months depending on time of enrollment into the trial.	Drug: Matching Placebo; Matching placebo over 12 to 24 months depending on time of enrollment into the trial.
No Intervention: Proteomic Signature Absent; Participants that meet the eligibility criteria but do have a screening blood test result that is proteomic signature absent (about 400 participants) will be asked to attend 2 follow-up remote visits at 12 and 24 months. This arm will be observational only.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to death, non-elective hospitalization, or lung transplantation	Clinical composite measure defined as the time from randomization to the first occurrence of any of its three components: all-cause mortality, first unplanned (non-elective) hospitalization, or lung transplantation.	Baseline (visit 1) to up to 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to all-cause mortality	The time from randomization to death from any cause.	Baseline (visit 1) to up to 24 months
Time to first non-elective hospitalization	The time from randomization to the first unplanned inpatient hospital admission	Baseline (visit 1) to up to 24 months
Time to lung transplantation	The time from randomization to the date of a participant's lung transplant	Baseline (visit 1) to up to 24 months
Time to respiratory hospitalization	The time from randomization to the first non-elective respiratory hospitalization. Non-elective respiratory hospitalizations specifically refer to unplanned admissions where the primary cause is a pulmonary condition, as determined by a blinded adjudication committee.	Baseline (visit 1) to up to 24 months
Change in Forced Vital Capacity (FVC)	The longitudinal change in forced vital capacity (measured in liters) based on spirometry from baseline (visit 1) to 12 months.	Baseline (visit 1) to 12 months
Change in Forced Vital Capacity (FVC) % Predicted	The longitudinal change in FVC% predicted based on spirometry from baseline (visit 1) to 12 months.	Baseline (visit 1) to 12 months
Change in Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) corrected for hemoglobin.	Units - ml/(min*mmHg)	Baseline (visit 1) to 12 months.
Change in Six-Minute Walk Distance (6MWD)	The longitudinal change in the maximum distance (in meters) a participant can walk on a flat surface in six minutes.	Baseline (visit 1) to 12 months
Change in patient reported outcomes scores for the Living with Pulmonary Fibrosis (L-PF) Impacts Questionnaire	The L-PF Impacts module contains 21 items (5-point Likert scale) that assesses the impact of disease on patients with pulmonary fibrosis. The range of the total score is 0-100, with higher scores indicating greater symptom severity.	Baseline (visit 1) to 12 months
Change in patient reported outcomes scores for the Living with Pulmonary Fibrosis (L-PF) Impacts Questionnaire	The L-PF Impacts module contains 21 items (5-point Likert scale) that assesses the impact of disease on patients with pulmonary fibrosis. The range of the total score is 0-100, with higher scores indicating greater symptom severity.	Baseline (visit 1) to 24 months
Change in patient reported outcomes scores for the Living with Pulmonary Fibrosis (L-PF) Symptoms Questionnaire	The L-PF Symptoms modules contains contains 23 items (5-point Likert scale) that assesses shortness of breath, cough, and fatigue within the last 24 hours. The range of the total score is 0-100, with higher scores indicating greater symptom severity.	Baseline (visit 1) to 12 months
Change in patient reported outcomes scores for the Living with Pulmonary Fibrosis (L-PF) Symptoms Questionnaire	The L-PF Symptoms modules contains contains 23 items (5-point Likert scale) that assesses shortness of breath, cough, and fatigue within the last 24 hours. The range of the total score is 0-100, with higher scores indicating greater symptom severity.	Baseline (visit 1) to 24 months
Change in patient reported outcomes scores for the R-Scale-PF	The R-Scale-PF is a 5-item numerical rating scale (NRS) to allow for rapid assessment of symptoms and health related quality of life (HRQoL). Scores range from 0 to 50, with lower scores indicating a better HRQoL.	Baseline (visit 1) to 12 months
Change in patient reported outcomes scores for the R-Scale-PF	The R-Scale-PF is a 5-item numerical rating scale (NRS) to allow for rapid assessment of symptoms and health related quality of life (HRQoL). Scores range from 0 to 50, with lower scores indicating a better HRQoL.	Baseline (visit 1) to 24 months
Change in Fatigue Severity Scale Score	The Fatigue Severity Scale (FSS) is a nine-item questionnaire used to assess the impact of fatigue on an individual's daily life. The FSS is a self-report measure about their level of fatigue on a scale of 1 to 7, with 7 indicating a higher level of fatigue.	From baseline (visit 1) to 12 months
Change in Fatigue Severity Scale Score	The Fatigue Severity Scale (FSS) is a nine-item questionnaire used to assess the impact of fatigue on an individual's daily life. The FSS is a self-report measure about their level of fatigue on a scale of 1 to 7, with 7 indicating a higher level of fatigue.	Baseline (visit 1) to 24 months
Incidence of Major Adverse Cardiac Events (MACE)	The incidence of major adverse cardiac events (MACE), recorded from baseline (visit 1) through the final follow-up visit. MACE will be determined by the site investigator and defined as a composite of acute myocardial infarction, stroke, or death due to a cardiovascular cause.	Baseline (visit 1) through final follow-up visit
Rate of non-elective hospitalization	The rate of all non-elective hospitalizations from baseline (visit 1) to 12 months (number of hospitalizations per year).	Baseline (visit 1) to 12 months
Rate of non-elective hospitalization from baseline to 24 months	The rate of all non-elective hospitalizations from baseline (visit 1) to 24 months (number of hospitalizations per year).	Baseline (visit 1) to 24 months
Rate of Respiratory Hospitalizations	The rate of all non-elective respiratory hospitalizations from baseline (visit 1) to 12 months (number of hospitalizations per year). Non-elective respiratory hospitalizations will be defined as any unplanned inpatient hospitalizations for which the primary cause was a pulmonary condition, in the opinion of the blinded adjudicators and based on all available clinical data.	Baseline (visit 1) to 12 months
Rate of Respiratory Hospitalizations	The rate of all non-elective respiratory hospitalizations from baseline (visit 1) to 24 months (number of hospitalizations per year) Non-elective respiratory hospitalizations will be defined as any unplanned inpatient hospitalizations for which the primary cause was a pulmonary condition, in the opinion of the blinded adjudicators and based on all available clinical data.	Baseline (visit 1) to 24 months

Collaborators and Investigators

• Sponsor: University of Massachusetts, Worcester
• Collaborators: United States Department of Defense
• Investigators: Principal Investigator: Sydney Montesi, MD, Massachusetts General Hospital; Principal Investigator: Fernando Martinez, MD, MS, UMass Chan Medical School; Principal Investigator: Bhavika Kaul, MD, MAS, Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC)

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): March 15, 2029
• Study Completion (Estimated): March 15, 2029

Study Registration Dates

• First Submitted: April 2, 2026
• First Submitted That Met QC Criteria: April 2, 2026
• First Posted (Actual): April 9, 2026

Study Record Updates

• Last Update Posted (Actual): April 14, 2026
• Last Update Submitted That Met QC Criteria: April 8, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: metformin; Idiopathic Pulmonary Fibrosis; IPF
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Interstitial; Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Organic Chemicals; Biguanides; Guanidines; Amidines; Metformin
• Other Study ID Numbers: STUDY00002828; PR241441 (Other Grant/Funding Number: Department of Defense)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

This study will be conducted in accordance with the publication and data sharing policies and regulations from the Department of Defense Research and Development General Terms and Conditions.

De-identified samples and data may be shared with other researchers, institutions, and collaborating for-profit companies within and outside of the United States upon approval of the Ancillary Committee. Data from this study may be requested after the completion of the primary endpoint by contacting the Collaborating Studies Coordinating Center (CSCC) at The University of North Carolina at Chapel Hill.

• IPD Sharing Time Frame: One year from the study completion date.
• IPD Sharing Access Criteria: Data will be made available by the University of North Carolina at Chapel Hill upon approval of the request by the MAVRIC-IPF Ancillary Committee.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• 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