Metformin to Attenuate Progressive Respiratory Decline in Idiopathic Pulmonary Fibrosis

Phase 3Not Yet RecruitingNCT07520110

University of Massachusetts, Worcester800 enrolled

Overview

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.

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

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

Eligibility

Sex: ALLMin age: 40 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

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.

Time frame: Baseline (visit 1) to up to 24 months

Secondary Outcomes

Time to all-cause mortality

The time from randomization to death from any cause.

Time frame: 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

Time frame: 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

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Baseline (visit 1) to 12 months

Change in Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) corrected for hemoglobin.

Units - ml/(min\*mmHg)

Time frame: 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.

Time frame: 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.

Time frame: Baseline (visit 1) to 12 months

Change in patient reported outcomes scores for the Living with Pulmonary Fibrosis (L-PF) Impacts Questionnaire

Time frame: 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.

Time frame: Baseline (visit 1) to 12 months

Change in patient reported outcomes scores for the Living with Pulmonary Fibrosis (L-PF) Symptoms Questionnaire

Time frame: 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.

Time frame: Baseline (visit 1) to 12 months

Change in patient reported outcomes scores for the R-Scale-PF

Time frame: 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.

Time frame: From baseline (visit 1) to 12 months

Change in Fatigue Severity Scale Score

Time frame: Baseline (visit 1) to 24 months

Rate of non-elective hospitalization

The rate of all non-elective hospitalizations from baseline (visit 1) to 12 months (number of hospitalizations per year).

Time frame: 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).

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Baseline (visit 1) through final follow-up visit

Metformin to Attenuate Progressive Respiratory Decline in Idiopathic Pulmonary Fibrosis

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes