Abstract
Research Question Pulmonary rehabilitation is the best treatment for chronic breathlessness in COPD but there remains an unmet need to improve efficacy. Pulmonary rehabilitation has strong parallels with exposure-based cognitive behavioural therapies (CBT), both clinically and in terms of brain activity patterns. The partial NMDA-receptor agonist, D-cycloserine has shown promising results in enhancing efficacy of CBT, thus we hypothesised that it would similarly augment the effects of pulmonary rehabilitation in the brain. Positive findings would support further development in phase 3 clinical trials.
Methods 72 participants with mild-to-moderate COPD were recruited to a double-blind pre-registered (ID: NCT01985750) experimental medicine study running parallel to a pulmonary rehabilitation course. Participants were randomised to 250 mg D-cycloserine or placebo, administered immediately prior to the first four sessions of pulmonary rehabilitation. Primary outcome measures were differences between D-cycloserine and placebo in brain activity in the anterior insula, posterior insula, anterior cingulate cortices, amygdala and hippocampus following completion of pulmonary rehabilitation. Secondary outcomes included the same measures at an intermediate time point and voxel-wise difference across wider brain regions. An exploratory analysis determined the interaction with breathlessness-anxiety.
Results No difference between D-cycloserine and placebo groups was observed across the primary or secondary outcome measures. D-cycloserine was shown instead to interact with changes in breathlessness anxiety to dampen reactivity to breathlessness cues. Questionnaire and measures of respiratory function showed no group difference. This is the first study testing brain-active drugs in pulmonary rehabilitation. Rigorous trial methodology and validated surrogate end-points maximised statistical power.
Conclusion Although increasing evidence supports therapeutic modulation of NMDA pathways to treat symptoms, we conclude that a phase 3 clinical trial of D-cycloserine would not be worthwhile.
Footnotes
This manuscript has recently been accepted for publication in the ERJ Open Research. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJOR online. Please open or download the PDF to view this article.
Conflict of interest: Dr. Harmer has valueless shares in p1vital and serves on their advisory panel. She has received consultancy payments from p1vital, Zogenix, J&J, Pfizer, Servier, Eli-Lilly, Astra Zeneca, Lundbeck.
Conflict of interest: Dr. Pattinson and Dr Ezra are named as co-inventors on a provisional U.K. patent application titled “Use of cerebral nitric oxide donors in the assessment of the extent of brain dysfunction following injury.
Conflict of interest: Dr. Rahman, has received consulting fees from Rocket Medical U.K. Prof. Nichols has received consulting fees from Perspectum Diagnostics.
Conflict of interest: The remaining authors have no biomedical financial interests or potential conflicts of interest.
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- Received September 12, 2022.
- Accepted December 11, 2022.
- Copyright ©The authors 2023.
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