Idiopathic Pulmonary Fibrosis
Conditions
Keywords
Idiopathic Pulmonary Fibrosis, IPF, metformin
Brief summary
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.
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.
Interventions
DRUGMetformin
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.
DRUGMatching Placebo
Matching placebo over 12 to 24 months depending on time of enrollment into the trial.
Sponsors
University of Massachusetts, Worcester
United States Department of Defense
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Participants with a proteomic signature present are randomized into two separate, concurrent groups-one receiving the active drug (metformin) and the other a matching placebo-and remain in their assigned arm for the entire 12-to-24-month duration.
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to death, non-elective hospitalization, or lung transplantation | Baseline (visit 1) to up to 24 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to all-cause mortality | Baseline (visit 1) to up to 24 months | The time from randomization to death from any cause. |
| Time to first non-elective hospitalization | Baseline (visit 1) to up to 24 months | The time from randomization to the first unplanned inpatient hospital admission |
| Time to lung transplantation | Baseline (visit 1) to up to 24 months | The time from randomization to the date of a participant's lung transplant |
| Time to respiratory hospitalization | Baseline (visit 1) to up to 24 months | 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. |
| Change in Forced Vital Capacity (FVC) | Baseline (visit 1) to 12 months | The longitudinal change in forced vital capacity (measured in liters) based on spirometry from baseline (visit 1) to 12 months. |
| Change in Forced Vital Capacity (FVC) % Predicted | Baseline (visit 1) to 12 months | The longitudinal change in FVC% predicted based on spirometry from baseline (visit 1) to 12 months. |
| Change in Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) corrected for hemoglobin. | Baseline (visit 1) to 12 months. | Units - ml/(min\*mmHg) |
| Change in Six-Minute Walk Distance (6MWD) | Baseline (visit 1) to 12 months | The longitudinal change in the maximum distance (in meters) a participant can walk on a flat surface in six minutes. |
| Change in patient reported outcomes scores for the Living with Pulmonary Fibrosis (L-PF) Impacts Questionnaire | Baseline (visit 1) to 12 months | 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. |
| Change in patient reported outcomes scores for the Living with Pulmonary Fibrosis (L-PF) Symptoms Questionnaire | Baseline (visit 1) to 12 months | 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. |
| Change in patient reported outcomes scores for the R-Scale-PF | Baseline (visit 1) to 12 months | 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. |
| Change in Fatigue Severity Scale Score | From baseline (visit 1) to 12 months | 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. |
| Rate of non-elective hospitalization | Baseline (visit 1) to 12 months | The rate of all non-elective hospitalizations from baseline (visit 1) to 12 months (number of hospitalizations per year). |
| Rate of non-elective hospitalization from baseline to 24 months | Baseline (visit 1) to 24 months | The rate of all non-elective hospitalizations from baseline (visit 1) to 24 months (number of hospitalizations per year). |
| Rate of Respiratory Hospitalizations | Baseline (visit 1) to 12 months | 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. |
| Incidence of Major Adverse Cardiac Events (MACE) | Baseline (visit 1) through final follow-up visit | 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. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORFernando Martinez, MD, MS
UMass Chan Medical School
PRINCIPAL_INVESTIGATORSydney Montesi, MD
Massachusetts General Hospital
PRINCIPAL_INVESTIGATORBhavika Kaul, MD, MAS
Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC)
Outcome results
None listed