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

• ClinicalTrials.gov Identifier: NCT01985750
• Recruitment Status: Unknown
• First Posted: November 15, 2013
• Last Update Posted: October 12, 2018
• Sponsor: University of Oxford
• Collaborator: National Health Service, United Kingdom
• Information provided by (Responsible Party): University of Oxford

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Chronic Obstructive Pulmonary Disease	Drug: d-cycloserine; Drug: placebo	Early Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 90 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: Understanding the Importance of Plasticity in the Brain Mechanisms of Dyspnoea Perception
• Study Start Date: November 2013
• Estimated Primary Completion Date: December 2018
• Estimated Study Completion Date: February 2020

Arms and Interventions

Arm	Intervention/treatment
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: 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; Other Name: Placebo - identically matched to d-cycloserine containing carrier compound only
Active Comparator: D-cycloserine; 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; 250mg d-cycloserine or identical placebo given immediately to the first 4 sessions of a 6-week course pulmonary rehabilitation.; Other Name: comparison of d-cycloserine or placebo on enhancing the beneficial effects of pulmonary rehabilitation on breathlessness perception

Outcome Measures

Primary Outcome Measures :

1. BOLD signal changes [ Time Frame: baseline, week 3, week 8, 3 months following treatment ]
   Changes in FMRI BOLD signal in response to breathlessness cues, as a consequence of d-cycloserine administration during pulmonary rehabilitation.

Secondary Outcome Measures :

1. Grey matter volume [ Time Frame: baseline, week 3, week 8, 3 months following treatment ]
   Change in regional brain volume related to changes in breathlessness as a consequence of d-cycloserine administration during pulmonary rehabilitation.

Other Outcome Measures:

1. Grey matter volume compared with healthy controls [ Time Frame: baseline, week 3, week 8, 3 months following treatment ]
   Difference in regional brain volume related to breathlessness in comparison with healthy controls.
2. difference in BOLD signal compared with healthy controls [ Time Frame: baseline, week 3, week 8, 3 months following treatment ]
   Difference in FMRI BOLD signal in response to breathlessness cues, in comparison with healthy controls.

Eligibility Criteria

• Ages Eligible for Study: 45 Years to 85 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• 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.

Exclusion Criteria:

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)

Contacts and Locations

Contacts

Contact: Kyle TS Pattinson, BM DPhil FRCA; 01865 231 509; kyle.pattinson@nda.ox.ac.uk

Contact: Sarah Finnegan, DPhil; 01865 234 544; copd@fmrib.ox.ac.uk

Locations

United Kingdom

Oxford Centre for Clinical Magnetic Resonance Imaging; Recruiting

Oxford, Oxfordshire, United Kingdom, OX3 9DU

Contact: Kyle Pattinson, BM DPhil FRCA +441865 231509 kyle.pattinson@nda.ox.ac.uk

Contact: Sarah Finnegan, DPhil +441865 234544 copd@fmrib.ox.ac.uk

Sponsors and Collaborators

University of Oxford

National Health Service, United Kingdom

Investigators

• Principal Investigator: Kyle TS Pattinson, BM DPhil FRCA; University of Oxford

More Information

• Responsible Party: University of Oxford
• ClinicalTrials.gov Identifier: NCT01985750
• Other Study ID Numbers: OX-KP001
• First Posted: November 15, 2013
• Last Update Posted: October 12, 2018
• Last Verified: October 2018

Keywords provided by University of Oxford:

dyspnea; fmri; d-cycloserine

Additional relevant MeSH terms:

Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Dyspnea; Lung Diseases; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Respiration Disorders; Signs and Symptoms, Respiratory; Cycloserine; Anti-Infective Agents, Urinary; Anti-Infective Agents; Antibiotics, Antitubercular; Antitubercular Agents; Anti-Bacterial Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action