Developmental Clinical Studies - A clinical trial of metformin in COPD exacerbations

CONTEXT
Chronic obstructive pulmonary disease (COPD) is a lung disease that is usually caused by smoking. People with COPD feel short of breath and have a chronic cough. The condition worsens steadily, limiting exercise and normal activities. These symptoms are caused by damage to the breathing tubes which carry air into the lungs and to the air sacs where oxygen crosses from the air into the blood. In the UK, COPD affects around 3.7 million people and causes over 30,000 deaths per year. It is the fourth most common cause of death worldwide.
From time to time, COPD patients experience attacks, where they feel more breathless or cough up more phlegm (sputum). These attacks are called exacerbations and are often set off by infection. Exacerbations are major events for people with COPD. During an exacerbation, COPD patients need more treatment and may require admission to hospital. It can take weeks to recover fully from an exacerbation and some people never get back to how they were before the exacerbation. Unfortunately, despite current best treatment, many people die during the weeks, months and years after an exacerbation. New treatments are required to prevent deaths and speed up recovery after exacerbations.

AIM
The overall aim of our research is to see whether a drug called metformin can help COPD patients recover more quickly or survive longer after an exacerbation.
Metformin is usually used to lower blood sugar in patients with diabetes. We have found that most patients admitted to hospital for COPD exacerbations have high blood sugar. The higher their blood sugar, the less well they recover from their exacerbation. We therefore think that using metformin to lower blood sugar in COPD patients during exacerbations could improve recovery. Metformin can also dampen down inflammation and mop-up harmful substances called free radicals. These effects could be beneficial for COPD patients with exacerbations. To test our theory we looked back at hospital records of COPD patients. We found that patients leaving hospital on metformin survived longer than those without metformin. This finding is encouraging, but must be interpreted cautiously, as there are several possible explanations. We now need to test the benefits of metformin in clinical trials.

THE STUDY
Patients admitted to hospital with COPD exacerbations will be invited to take part in the trial. Those who agree will receive all the usual treatments for COPD exacerbations. In addition, they will take a study treatment as a capsule twice daily for 1 month. Participants will be allocated by chance (randomisation) to receive metformin or no medicine (placebo) in the capsule. Neither we nor the participants will know who is taking what. This will allow us to make an unbiased assessment of the effects of metformin.
We will assess the benefits of metformin by comparing blood glucose between patients during hospital admission and over the whole study using a test called fructosamine. We will check that people taking metformin don't become more unwell or develop dangerous side effects and that they can tolerate the tablets. We will also get some idea of whether metformin helps them recover more quickly from their COPD exacerbations. However this will need to be tested more thoroughly in the future in a larger group of patients.

POTENTIAL BENEFITS
At the end of this trial we will know whether metformin can lower blood sugar safely in patients with COPD exacerbations. The next step will be to test metformin in a larger number of COPD patients to see if it can help them to recover more quickly from their exacerbations. Metformin is cheap and widely available. If it works it could quickly be adopted as a new treatment for these patients.

OBJECTIVE. To determine whether a rapid dose escalation regimen of metformin can lower blood glucose reliably and safely in individuals during acute exacerbations of COPD.

STUDY DESIGN A randomised, double-blind, placebo-controlled trial of metformin in patients hospitalised for COPD exacerbations. Other inclusion criteria: age 50-85yrs, study entry within 72 hours of admission. Exclusion criteria: pre-existing diabetes; increased risk of lactic acidosis or hypoglycaemia.

INTERVENTION Participants will be randomised 2:1 to receive metformin or placebo for 28-35 days. Metformin dose will escalated rapidly to 1g twice-daily (or placebo equivalent) on day 4. Study treatment will be in addition to standard care.

ENDPOINTS. Metformin will be considered effective for COPD exacerbations if (compared to placebo) it reduces mean hospitalisation blood glucose by 1.5mmol/L (primary endpoint). A reduction in 28 day fructosamine will confirm reduction in blood glucose over the whole study period. Metformin will be considered safe if there are no cases of lactic acidosis (increase in serum lactate with metabolic acidosis not attributable to other cause) or other protocol-defined severe adverse events. It will be considered tolerable if at least 75% of patients take at least 50% of their tablets and less than 30% patients taking metformin drop out of the study.

APPLICATION/EXPLOITATION. If metformin meets these criteria for reliable and safe blood glucose lowering during COPD exacerbations, this will provide clear justification for progression to a large multicentre randomised controlled trial, powered to detect an effect of metformin on clinical endpoints. Confidence for progression to this follow on study will be increased if there are trends in improvement in patient reported outcomes or increases in time to next exacerbation. Conversely, failure to meet these criteria will clearly indicate that there is no justification for progressing to such a trial.

WHO WILL BENEFIT?
Potential beneficiaries include: patients with COPD and their families; social services; the health service; employers and the economy both within and outside the UK. Other beneficiaries may include: NHS translational research capabilities; other researchers investigating COPD exacerbations or other uses of metformin.

HOW WILL THEY BENEFIT?
The most likely research beneficiaries will be COPD patients with exacerbations. In the UK, COPD exacerbations account for 100,000 hospital admissions and 1 million inpatient days annually. The prognosis following hospitalisation for a COPD exacerbation is presently abysmal. More than one in eight patients die within 90 days of admission, and fewer than half survive 5 years. This study is part of a developmental programme which will determine whether metformin can hasten recovery from exacerbations and prolong survival. If efficacious, metformin could improve health of COPD patients with benefits for individuals and their families and reduced need for social services.

This research has potential benefits for the health service. Much of the impact of COPD, both for patients and the health service, arises from hospital admissions for exacerbations. COPD is the second most common cause of emergency admission and fifth most common cause of readmission. The National COPD Strategy, published for consultation in 2010, identified a need to address prognosis following hospital admission for COPD and to reduce admission and re-admission rates. Our research will support this strategy by developing metformin as a treatment for severe exacerbations requiring hospitalisation. If this proof of context study shows that metformin can reliably and safely lower blood glucose in COPD exacerbations, the next step will be a large randomised placebo controlled trial to determine whether metformin can improve clinical outcomes such as health status and time between exacerbations.
If metformin hastens recovery from exacerbations and increases time to next exacerbation it could have considerable economic benefits. The direct cost of COPD to the UK healthcare system is around £810-930 million per year and rising. COPD causes more lost working days than any other respiratory condition with an estimated cost of £3.8 billion per year in lost productivity for employers and the economy. Generic metformin costs £1.57 for a 21 day course of 1g twice daily. If clinical benefit is proven, metformin, as a cheap and widely available drug, is likely to be a cost effective treatment for exacerbations.
This research will build on an existing collaboration between acute hospitals in South/West London. It will increase research capabilities within this network for the benefit of future studies. This will contribute to the national initiative to make the NHS an attractive environment for investigator-led and industry clinical trials. Research training will support development of translational research skills in the NHS.

TIMESCALE
The proposed study will commence July 2012 with early dissemination of results in March 2014. This will inform progression to and design of a large multicentre trial investigating the effect of metformin on clinical outcomes in COPD exacerbations. If justified, we will apply for funding for this large phase III trial in 2014 with trial results anticipated in 2018. Metformin is widely available and used extensively for diabetes mellitus. If efficacious and safe for COPD exacerbations, translation into clinical practice would be relatively rapid and straightforward.