BETTER-B Trial Results
We are delighted that the BETTER-B trial results are now published in the Lancet Respiratory Medicine.
Key finding: the antidepressant Mirtazapine does not alleviate severe breathlessness. Our findings raise questions about using medicines in a manner different from its licence.
Why was the research done?
Long-term lung diseases affect 454.6 million people worldwide, with numbers predicted to increase. Over 217 million people globally have Chronic Obstructive Pulmonary Disease (COPD) or Interstitial Lung Disease (ILD).
Severe breathlessness, becoming worse as the diseases progress, is very common in people with COPD and ILD as well as in other diseases such as cancer, heart disease and long COVID.
There are currently no licensed medicines for long-term or severe breathlessness globally, except in Australia, where morphine can be used for long-term breathlessness.
Given the lack of licensed medicines, clinicians often turn to 'off-label' prescribing, recommending a medicine in a manner different from its licence. The only licensed medicines for severe breathlessness in most countries treat the underlying illness.
A survey of lung and palliative care physicians, as part of the BETTER-B programme, found that 19% of lung and 11% of palliative care physicians already often or always recommended antidepressants for advanced COPD, even without signs of depression. For fibrotic ILD, the figures were 12% and 13%, respectively.
This demonstrated the vital need for proper evaluation of possible treatments, like antidepressants, which are sometimes being used off-label.
What did we do?
Mirtazapine, a widely used antidepressant, showed promise and so the BETTER-B research tested if it could relieve severe breathlessness in COPD and ILD compared with a dummy drug, known as a placebo. This was done through the international randomised trial, BETTER-B. Patients and carers affected by breathlessness were involved throughout the research processes.
We enrolled and randomly assigned 225 eligible adults with COPD or ILD and severe breathlessness across 16 centres in seven countries.
What were the results?
There was no difference in severe breathlessness between those people taking Mirtazapine and those taking placebo during the main period of the trial, of 56 days.
Similar results were found for other measures. This included a person’s quality of life, broader symptoms, anxiety and depression, and frequency of breathlessness episodes. There were no differences found up to six months after the start of the trial.
In contrast, some people treated with Mirtazapine experienced slightly more side effects and needed slightly more care from hospitals and from their family members than those receiving placebo during the first two months of treatment.
We also carried out in-depth interviews with people with severe breathlessness and their carers or family members to better understand their experiences. Many people did not notice any changes in their health, including sleep, appetite, mood, and drowsiness. Some experienced mild side effects like dizziness, memory problems, or dry mouth.
What wider questions were raised?
Mirtazapine was being used ‘off-label’, meaning it was not originally developed to treat breathlessness and had not, along with other off-label medicines, been tested through sufficient clinical trials to enable it to be licenced.
However, people with severe breathlessness and their carers should be aware and informed about the medicines they are being offered and the alternatives, including the non-pharmacological alternatives.
The following briefs contain information on the recommendations from this research:
Patient and carer brief (including translated versions on the European Lung Foundation website)
Policy brief (including translated versions on the European Lung Foundation website)
Clinician brief