Metformin in Chronic Obstructive Pulmonary Disease

Overview

The purpose of this study is to determine the effect of a tablet medication, called metformin, in flare-ups (exacerbations) of chronic obstructive pulmonary disease. The investigators believe that metformin may effectively control the blood sugar level during COPD exacerbations. This is important because there is evidence that a high blood sugar level during exacerbations may be linked with a worse prognosis. The investigators also think that metformin may have other potentially useful effects on inflammation, antioxidant levels, the effectiveness of steroid treatment, and recovery.

Full Title of Study: “A Randomised, Double-blind, Placebo-controlled Trial of Metformin in Chronic Obstructive Pulmonary Disease (COPD) Exacerbations: a Pilot Study”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: March 2014

Detailed Description

Does metformin lower the blood sugar level in patients suffering from exacerbations of chronic obstructive pulmonary disease (COPD)?

COPD is the fourth leading cause of death worldwide, and a major cause of ill health. In the UK, it affects some 3.7 million people and causes over 30,000 deaths per year. It is usually, but not always, caused by smoking. Most people affected are over 65-years-old. Sufferers experience progressively worsening cough, sputum production, breathlessness and exercise limitation. This is punctuated by 'flare-ups' (exacerbations), when their symptoms worsen substantially. Approximately 25% of patients hospitalised for exacerbations die within a year, and over 50% within 5 years. There is a pressing need for new and improved treatments for COPD exacerbations.

This study will assess the effect of metformin, a tablet medication, in COPD exacerbations. Metformin has been in common use for over 50 years in patients with diabetes, to lower the blood sugar level. In COPD exacerbations, the blood sugar level is often high, and the higher it is, the more likely the patient will have a poor outcome. This led us to speculate that lowering the sugar level with metformin may improve outcomes from COPD exacerbations. However, COPD and diabetes are quite different diseases, and the investigators do not know whether metformin will work as a sugar-lowering medicine in COPD exacerbations. The investigators need to confirm this before the investigators can perform larger studies to assess its effect on outcomes such as readmission and mortality rates.

The investigators will test this medicine in a 1-month trial in patients hospitalised for COPD exacerbations. The target sample size is 69 patients, with a minimum of 48 patients required for primary endpoint analysis. Two-thirds of the patients will take metformin, and one-third a dummy (placebo) tablet. Neither the patients nor the researchers know who is taking which. The investigators will measure their sugar levels by regular finger-prick tests, and then compare the average readings in the two groups. The investigators will also assess the medicine's effects on other markers of blood sugar level, and carry out additional exploratory investigations on the effect of the medicine on clinical outcomes, markers of inflammation, and markers of oxidative/carbonyl stress and steroid responsiveness.

Interventions

  • Drug: Metformin
    • Metformin 1 g twice daily for 28-35 days
  • Drug: Placebo
    • Placebo

Arms, Groups and Cohorts

  • Experimental: Metformin
    • Metformin 1 g twice daily for 28-35 days
  • Placebo Comparator: Placebo
    • Matched placebo capsules

Clinical Trial Outcome Measures

Primary Measures

  • Capillary glucose concentration
    • Time Frame: During hospitalisation period
    • The mean capillary glucose concentration during hospitalisation period following study entry, as a measure of both efficacy and safety.

Secondary Measures

  • COPD Assessment Test score
    • Time Frame: Study entry, hospital discharge, and follow-up
  • Exacerbation of Chronic Pulmonary Disease Tool (EXACT) score
    • Time Frame: Days 5, 10 and 28
  • Time to discharge
    • Time Frame: Hospital discharge
    • Number of days from hospital admission to hospital discharge
  • Recurrent exacerbation, readmission, and death rate
    • Time Frame: 3 months
    • Rates of recurrent exacerbation (defined as treatment with antibiotics and/or systemic corticosteroids for breathlessness, cough or wheeze), readmission to hospital, or death
  • Insulin requirement during hospitalisation period
    • Time Frame: During hospitalisation period following study entry
    • Mean daily insulin use during hospitalisation period following study entry
  • Haemoglobin A1c
    • Time Frame: Follow-up (one month post study entry)
    • Mean haemoglobin A1c concentration
  • C-reactive protein concentration
    • Time Frame: Days 7 and follow-up (one month)
    • Mean concentration of C-reactive protein in the blood
  • Body mass index
    • Time Frame: Follow-up (one month)
  • Waist circumference
    • Time Frame: Follow-up (one month)
  • Forced expiratory volume in 1 second
    • Time Frame: At hospital discharge and follow-up (one month)
    • Mean forced expiratory volume in 1 second (FEV1) expressed as a percentage of predicted value
  • Fructosamine
    • Time Frame: At hospital discharge and follow-up (one month)
    • Mean serum fructosamine concentration
  • Interleukin 6
    • Time Frame: At hospital discharge and follow-up (one month)
    • Serum concentration of IL-6 (absolute value and change from baseline)
  • Interleukin 8
    • Time Frame: At hospital discharge and follow-up (one month)
    • Serum concentration of IL-8 (absolute value and change from baseline)
  • Tumor necrosis factor alpha
    • Time Frame: At hospital discharge and follow-up (one month)
    • Serum concentration of TNF-alpha (absolute value and change from baseline)
  • Interferon gamma
    • Time Frame: At hospital discharge and follow-up (one month)
    • Serum concentration of IFN-gamma (absolute value and change from baseline)
  • 8-isoprostane
    • Time Frame: At hospital discharge and follow-up (one month)
    • Serum concentration of 8-isoprostane (absolute value and change from baseline)
  • Total carbonyl stress
    • Time Frame: At hospital discharge and follow-up (one month)
    • Total carbonyl stress, measured in serum (absolute value and change from baseline)
  • Glutathione reduced vs oxidised
    • Time Frame: At hospital discharge and follow-up (one month)
    • Glutathione reduced vs oxidised, measured in serum (absolute value and change from baseline)

Participating in This Clinical Trial

Inclusion Criteria

  • Diagnosis of COPD
  • Hospitalisation for exacerbation of COPD
  • Age ≥35 years
  • Expected to remain in hospital for at least 48 hours

Exclusion Criteria

  • Prior diagnosis of diabetes mellitus requiring insulin or oral hypoglycaemic therapy
  • Hypersensitivity to metformin hydrochloride or to any of the excipients
  • Renal impairment
  • Severe sepsis
  • Metabolic acidosis
  • Decompensated type 2 respiratory failure
  • Severe congestive cardiac failure
  • Acute coronary syndrome
  • Hepatic insufficiency
  • Excessive alcohol consumption
  • Malnourished or at high risk for malnutrition
  • Moribund or not for active treatment
  • Admitted to critical care unit
  • Unable to give informed consent
  • Pregnancy or lactation

Gender Eligibility: All

Minimum Age: 35 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • St George’s, University of London
  • Collaborator
    • Medical Research Council
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Emma H Baker, MBChB PhD, Study Chair, St George’s, University of London
    • Andrew W Hitchings, BSc MBBS, Principal Investigator, St George’s Healthcare NHS Trust

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