Metformin to Attenuate Progressive Respiratory Decline in Idiopathic Pulmonary Fibrosis

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.

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 \ 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