Metformin in Chronic Obstructive Pulmonary Disease

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

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.

Study Overview

• Status: Completed
• Conditions: Chronic Obstructive Pulmonary Disease
• Intervention / Treatment: Drug: Placebo; Drug: Metformin

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.

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 4

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, SW10 9NH
    • Chelsea and Westminster Hospital
  • London, United Kingdom, SW17 0QT
    • St George's Hospital
  • Newcastle, United Kingdom, NE7 7DN
    • Freeman Hospital
  • Cleveland
    • Hartlepool, Cleveland, United Kingdom, TS24 9AH
      • North Tees and Hartlepool NHS Trust
  • Cumbria
    • Lancaster, Cumbria, United Kingdom, LA9 7RG
      • University Hospitals of Morecambe Bay NHS Trust
  • East Sussex
    • Hastings, East Sussex, United Kingdom, TN37 7PT
      • East Sussex Healthcare NHS Trust
  • Lancashire
    • Blackpool, Lancashire, United Kingdom, FY3 8NR
      • Blackpool Teaching Hospitals NHS Trust
    • Preston, Lancashire, United Kingdom, PR2 9HT
      • Lancashire Teaching Hospitals NHS Trust
  • Nottinghamshire
    • Sutton-in-Ashfield, Nottinghamshire, United Kingdom, NG17 4JL
      • Sherwood Forest Hospitals NHS Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 31 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Metformin; Metformin 1 g twice daily for 28-35 days	Drug: Metformin; Metformin 1 g twice daily for 28-35 days
Placebo Comparator: Placebo; Matched placebo capsules	Drug: Placebo; Placebo

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: St George's, University of London
• Collaborators: British Lung Foundation; Medical Research Council
• Investigators: Study Chair: Emma H Baker, MBChB PhD, St George's, University of London; Principal Investigator: Andrew W Hitchings, BSc MBBS, St George's Healthcare NHS Trust

Publications and helpful links

General Publications

• Hitchings AW, Baker EH, Jones PW. Handling missing items in the Exacerbations of Chronic Pulmonary Disease Tool. Eur Respir J. 2016 Aug;48(2):564-6. doi: 10.1183/13993003.00269-2016. Epub 2016 May 12. No abstract available.
• Hitchings AW, Lai D, Jones PW, Baker EH; Metformin in COPD Trial Team. Metformin in severe exacerbations of chronic obstructive pulmonary disease: a randomised controlled trial. Thorax. 2016 Jul;71(7):587-93. doi: 10.1136/thoraxjnl-2015-208035. Epub 2016 Feb 25.

Study record dates

Study Major Dates

• Study Start: January 1, 2011
• Primary Completion (Actual): March 1, 2014
• Study Completion (Actual): May 1, 2014

Study Registration Dates

• First Submitted: November 23, 2010
• First Submitted That Met QC Criteria: November 23, 2010
• First Posted (Estimate): November 24, 2010

Study Record Updates

• Last Update Posted (Estimate): May 7, 2015
• Last Update Submitted That Met QC Criteria: May 6, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Keywords: Chronic obstructive pulmonary disease, COPD, metformin
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: 10.0086; 2010-020818-28 (EudraCT Number)