The Effect of D-Cycloserine on Brain Processing of Breathlessness Over Pulmonary Rehabilitation - an Experimental Medicine Study

Background 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][1]) experimental medicine study running parallel to a pulmonary rehabilitation course. Participants were randomised to 250mg 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. Results No difference between D-cycloserine and placebo groups was observed across the primary or secondary outcome measures. Questionnaire and measures of respiratory function showed no group difference. Conclusions This is the first study testing brain-active drugs in pulmonary rehabilitation. Rigorous trial methodology and validated surrogate end-points maximised statistical power. 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. What is the key question? Does the partial NMDA-receptor agonist, D-cycloserine, augment the effects of pulmonary rehabilitation on breathlessness related brain activity? What is the bottom line? Rigorous trial methodology and validated surrogate end-points revealed no effect of D-cycloserine on breathlessness related brain activity across pulmonary rehabilitation. Why read on? This study highlights both the value of functional magnetic resonance imaging in “de-risking” expensive clinical trials and provides detailed investigation of brain-targeted points for pharmacological treatments of breathlessness. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT01985750 ### Funding Statement This work was supported by the Dunhill Medical Trust (Grant R333/0214) and the National Institute for Health Research Biomedical Research Centre (Grant RCF18/002) based at Oxford University Hospitals NHS Foundation Trust and The University of Oxford. This research was funded in whole or in part by the Wellcome Trust 203139/Z/16/Z. For the purpose of Open Access the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. OKH was supported via funding from the European Unions Horizon 2020 research and innovation programme under the Grant Agreement No 793580 and as a Rutherford Discovery Postdoctoral Fellow from the Royal Society of New Zealand. CJH is supported by the National Institute for Health Research Biomedical Research Centre based at Oxford Health NHS Foundation Trust and The University of Oxford and by the UK Medical Research Council. KTSP and NMR are supported by the National Institute for Health Research Biomedical Research Centre based at Oxford University Hospitals NHS Foundation Trust and the University of Oxford. AR is funded by a fellowship from MQ. Transforming mental health. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Study approval was granted by South Central Oxford REC B (Ref: 118784, Ethics number: 12/SC/0713). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The research materials supporting this publication can be accessed by contacting kyle.pattinson{at}ndcn.ox.ac.uk [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01985750&atom=%2Fmedrxiv%2Fearly%2F2021%2F11%2F26%2F2021.06.24.21259306.atom