Metformin in Chronic Obstructive Pulmonary Disease

Study Overview
=================
Brief Summary
-----------------
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.

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.

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

Conditions
-----------------
Chronic Obstructive Pulmonary Disease

Intervention / Treatment
-----------------
* Drug: Metformin
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 35 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

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) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Chronic obstructive pulmonary disease, COPD, metformin