Evaluation of Metformin Hydrochloride on Pulmonary Function in Patients with Chronic Obstructive Pulmonary Disease: A Randomized, Placebo-Controlled Trial

The primary objective is to compare the change in FEV1 over a three‑year period between metformin and placebo in patients with Chronic Obstructive Pulmonary Disease (COPD), providing insight into the drug’s effect on long‑term lung function decline. Secondary objectives include:

• Evaluating whether metformin reduces the natural progression of emphysema as a percentage of lung volume affected.
• Assessing changes in the COPD assessment test (CAT), St. George's Respiratory Questionnaire (SGRQ), use of respiratory medications, annual exacerbation rate, physician visits, hospitalizations, and the BODE index over three years.
• Measuring functional outcomes such as 6-minute walking distance and hand grip strength at three‑year follow‑up.
• Determining the incidence of lung cancer and other solid tumours.
• Determining the incidence of myocardial infarction, new angina, stroke, and renal failure.
• Identifying biological changes associated with decreased lung function that respond to metformin treatment.

The sponsor did not provide information on the total number of participants. The trial enrolled adults aged 40 to 75 years, inclusive, of both sexes, who met a clinical diagnosis of Chronic Obstructive Pulmonary Disease (COPD) according to the GOLD 2022 criteria, specifically a post‑bronchodilator FEV1/FVC ratio < 0.7 and a post‑bronchodilator FEV1 between >40 % and ≤70 % of predicted value. Eligible individuals demonstrated a smoking history exceeding 10 pack‑years and radiologically confirmed emphysema (centrolobular or paraseptal). Additional requirements included a documented decline in lung function of >40 ml per year over the preceding three years, ability to comprehend and comply with study procedures, and, for women of childbearing potential, a negative pregnancy test. The population was selected based on these inclusion parameters, forming a single cohort of patients meeting the specified clinical and functional criteria.

The study is a randomized, double‑blind, placebo‑controlled trial comparing metformin 1700 mg daily with a matching placebo in participants with Chronic Obstructive Pulmonary Disease (COPD). Recruitment is planned to begin in September 2025 and the trial will conclude in May 2029, with each participant remaining in the study for approximately three years after the screening visit. After obtaining informed consent, eligible subjects attend a screening visit (Visit 1) to confirm diagnosis, lung‑function criteria (post‑bronchodilator FEV1/FVC < 0.7 and FEV1 > 40 % ≤ 70 % predicted), smoking history, emphysema status, and to perform baseline assessments. Subjects are then randomized to receive either metformin or placebo and begin the treatment phase. Follow‑up visits occur at 6‑month intervals for patient‑reported outcomes (CAT, SGRQ) and at annual intervals for spirometry, blood and urine tests, microbiota analysis, imaging, BODE index, 6‑minute walk test, hand‑grip strength, and safety monitoring. An end‑of‑study visit is performed at the three‑year mark to repeat all baseline assessments, including the primary endpoint of change in FEV1. Participants are expected to remain on study medication and attend all scheduled visits for the full three‑year duration; early termination may occur if a participant withdraws consent, experiences a serious adverse event, fails to meet compliance criteria, or violates major protocol requirements.

The experimental medication is metformin hydrochloride supplied as the product “Metformina Uxa 850 mg comprimidos recubiertos con película EFG”. It is a film‑coated tablet containing 850 mg of metformin per tablet. The prescribed regimen is two tablets taken orally each day, providing a total daily dose of 1700 mg. Administration is once in the morning and once in the evening with water, and tablets are to be swallowed whole without chewing.

The comparator is a matched placebo consisting of white film‑coated tablets containing microcrystalline cellulose (Ph Eur). The placebo tablets are identical in appearance to the active tablets and are packaged in PVC/PE/PVDC blisters with an aluminum overlay. The dosing schedule mirrors that of the active product: one tablet taken orally in the morning and one in the evening.

Dosing compliance is monitored by tablet count at each study visit and by patient diaries documenting the time of each ingestion. Any missed doses are recorded, and participants are instructed to report deviations promptly. The study evaluates the effect of the interventions on lung function over a three‑year period in subjects with COPD. Regular follow‑up visits include spirometric assessment, safety laboratory tests, and review of adherence data.

Efficacy will be evaluated primarily by measuring the change in FEV1 from baseline to the 3‑year follow‑up visit. Spirometric assessments will be performed at the initial screening visit and again at the end of the 3‑year observation period, and the difference between these two time points will be calculated for each participant.

Secondary efficacy parameters include demographic and clinical variables, pulmonary function and imaging measures, patient‑reported outcomes, and incidence of comorbid events. The following assessments will be collected according to the specified schedule:

• Age, sex at birth, height, baseline weight and annual weight measurements.
• Baseline smoking status.
• Blood tests and urinalysis, including renal function, performed at baseline and annually.
• Microbiota analysis of samples obtained at baseline and at the 3‑year visit.
• Percentage of lung volume affected by emphysema assessed at baseline and at 3 years.
• COPD assessment test (CAT) administered at baseline and every 6 months.
• Modified Medical Research Council (mMRC) dyspnea scale recorded at baseline and annually.
• St. George’s Respiratory Questionnaire (SGRQ) completed at baseline and every 6 months.
• Documentation of concomitant respiratory treatments at baseline and every 6 months.
• Recording of annual exacerbation frequency, physician visits, and hospitalisations.
• BODE index measured at baseline and annually.
• Six‑minute walking distance (6MWD) assessed at baseline and annually.
• Hand‑grip strength of the dominant hand measured at baseline and annually.
• Incidence of lung cancer, other solid tumours, myocardial infarction, new angina, stroke, and renal failure tracked throughout the follow‑up period.

All data will be entered into the study database according to the predefined case report form schedule. Changes from baseline for continuous variables will be analysed using appropriate comparative statistics between the metformin and placebo groups, while categorical outcomes will be evaluated with frequency analyses. The timing of each assessment follows the protocol‑specified intervals to ensure consistent longitudinal evaluation of efficacy.