Understanding the Importance of Plasticity in the Brain Mechanisms of Dyspnoea Perception

NCT01985750 | Unknown Early Phase 1

• 1 other identifier: OX-KP001
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 1

Brief Summary

Dyspnoea is the uncomfortable shortness of breath that debilitates millions of patients with lung disease, heart failure and cancer. It is often very difficult to treat. The sensations of dyspnoea are processed in the brain, and we believe that psychological factors modify and amplify these sensations, frequently exacerbating symptoms. This study aims to identify the importance of learning in the brain mechanisms of dyspnoea by investigating a cohort of patients with chronic breathlessness undergoing pulmonary rehabilitation . Pulmonary rehabilitation is a six-week course of exercise, education and group therapy that improves dyspnoea but does not improve lung function. This leads us to hypothesise that some of the beneficial effects of PR maybe due to changes in brain processing, potentially relating to a learning effect. Therefore to probe whether learning is important in the beneficial effects of pulmonary rehabilitation, we intend to modify learning with the drug d-cycloserine. D-cycloserine is an antibiotic that enhances learning due to its effects at N-methyl D-aspartate (NMDA) receptors in the hippocampus. Our previous study in a similar group of patients demonstrated the importance of the hippocampus in breathlessness perception, and we now wish to investigate this in more depth. The study involves collecting physiological, psychological and clinical measures on in conjunction with brain scanning, before, during and once after pulmonary rehabilitation. Subjects will either receive d-cyloserine or placebo before the first four pulmonary rehabilitation sessions.

Conditions

Chronic Obstructive Pulmonary Disease

Keywords

dyspnea; fmri; d-cycloserine

Outcome Measures

Primary Outcomes (1)

• BOLD signal changes

  Changes in FMRI BOLD signal in response to breathlessness cues, as a consequence of d-cycloserine administration during pulmonary rehabilitation.

  baseline, week 3, week 8, 3 months following treatment

Secondary Outcomes (1)

• Grey matter volume

  baseline, week 3, week 8, 3 months following treatment

Other Outcomes (2)

• Grey matter volume compared with healthy controls

  baseline, week 3, week 8, 3 months following treatment

• difference in BOLD signal compared with healthy controls

  baseline, week 3, week 8, 3 months following treatment

Study Arms (2)

Drug: d-cycloserine or placebo

PLACEBO COMPARATOR

Other Names: comparison of d-cycloserine or placebo on enhancing the beneficial effects of pulmonary rehabilitation on breathlessness perception 250mg d-cycloserine or identical placebo given immediately to the first 4 sessions of a 6-week course pulmonary rehabilitation

Drug: placebo

D-cycloserine

ACTIVE COMPARATOR

Placebo Comparator: Drug: d-cycloserine or placebo Other Names: comparison of d-cycloserine or placebo on enhancing the beneficial effects of pulmonary rehabilitation on breathlessness perception 250mg d-cycloserine or identical placebo given immediately to the first 4 sessions of a 6-week course pulmonary rehabilitation

Drug: d-cycloserine

Interventions

d-cycloserine DRUG

250mg d-cycloserine or identical placebo given immediately to the first 4 sessions of a 6-week course pulmonary rehabilitation.

Also known as: comparison of d-cycloserine or placebo on enhancing the beneficial effects of pulmonary rehabilitation on breathlessness perception

D-cycloserine

placebo DRUG

Other Names: comparison of d-cycloserine or placebo on enhancing the beneficial effects of pulmonary rehabilitation on breathlessness perception 250mg d-cycloserine or identical placebo given immediately to the first 4 sessions of a 6-week course pulmonary rehabilitation

Also known as: Placebo - identically matched to d-cycloserine containing carrier compound only

Drug: d-cycloserine or placebo

Eligibility Criteria

• Age: 45 Years - 85 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Males and females with chronic lung disease, aged between 45 and 85 years old who have been referred for pulmonary rehabilitation.
• The subject is able and willing to give fully informed consent.

You may not qualify if:

• Any of the commonly accepted contraindications to MRI scanning, for example, severe claustrophobia, presence of metallic implants, a pacemaker etc.
• Pregnancy. The risk to foetus of radiofrequency energy of the MRI scan is unknown.
• Inadequate understanding of verbal and written information in English, sufficient to complete an MRI safety screening.
• Unable to lie flat and still for 1/2 hour
• Requirements for oxygen therapy
• Significant cardiac, neurological, psychiatric or metabolic disease
• Contra-indications to d-cycloserine: Alcoholism, known hypersensitivity, severe renal failure
• Regular therapy with prescribed opioid analgesics
• Antidepressant therapy (this may alter hippocampal plasticity)
• Previous pulmonary rehabilitation (because the learning may be different on repeat pulmonary rehabilitation treatments)

Sponsors & Collaborators

• University of Oxford: lead
• National Health Service, United Kingdom: collaborator

Study Sites (1)

Oxford Centre for Clinical Magnetic Resonance Imaging

Oxford, Oxfordshire, OX3 9DU, United Kingdom

RECRUITING

Related Publications (3)

• Finnegan SL, Harrison OK, Ezra M, Harmer CJ, Nichols TE, Rahman NM, Reinecke A, Pattinson KTS. The effect of D-cycloserine on brain connectivity over a course of pulmonary rehabilitation - A randomised control trial with neuroimaging endpoints. PLoS One. 2025 Jun 2;20(6):e0323213. doi: 10.1371/journal.pone.0323213. eCollection 2025.

  PMID: 40455920 DERIVED

• Finnegan SL, Harrison OK, Booth S, Dennis A, Ezra M, Harmer CJ, Herigstad M, Guillaume B, Nichols TE, Rahman NM, Reinecke A, Renaud O, Pattinson KTS. The effect of d-cycloserine on brain processing of breathlessness over pulmonary rehabilitation: an experimental medicine study. ERJ Open Res. 2023 Apr 3;9(2):00479-2022. doi: 10.1183/23120541.00479-2022. eCollection 2023 Mar.

  PMID: 37020840 DERIVED

• Finnegan SL, Browning M, Duff E, Harmer CJ, Reinecke A, Rahman NM, Pattinson KTS. Brain activity measured by functional brain imaging predicts breathlessness improvement during pulmonary rehabilitation. Thorax. 2023 Sep;78(9):852-859. doi: 10.1136/thorax-2022-218754. Epub 2022 Dec 26.

  PMID: 36572534 DERIVED

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive; Dyspnea

Interventions

Cycloserine

Condition Hierarchy (Ancestors)

Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Respiration Disorders; Signs and Symptoms, Respiratory; Signs and Symptoms

Intervention Hierarchy (Ancestors)

Isoxazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Oxazolidinones; Oxazoles; Serine; Amino Acids, Neutral; Amino Acids; Amino Acids, Peptides, and Proteins

Study Officials

• Kyle TS Pattinson, BM DPhil FRCA

  University of Oxford

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Kyle TS Pattinson, BM DPhil FRCA

CONTACT

01865 231 509; kyle.pattinson@nda.ox.ac.uk

Sarah Finnegan, DPhil

CONTACT

01865 234 544; copd@fmrib.ox.ac.uk

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 29, 2013
• First Posted: November 15, 2013
• Study Start: November 1, 2013
• Primary Completion: December 1, 2018
• Study Completion: February 1, 2020
• Last Updated: October 12, 2018

Record last verified: 2018-10

Locations

GB (1)