The Role of Ambulatory Oxygen in Improving the Effectiveness of Pulmonary Rehabilitation for Chronic Obstructive Pulmonary Diseases Patients
Phase: NA
Conditions: Chronic Obstructive Pulmonary Diseases
Sponsor: Imperial College Healthcare NHS Trust

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The Role of Ambulatory Oxygen in Improving the Effectiveness of 
Pulmonary Rehabilitation for COPD patients 
 
 
 
Version 3  
04/04/2016 
 
 
 
MAIN SPONSOR: Imperial College Healthcare NHS Trust  
FUNDERS: NIHR Imperial BRC and Imperial Charity 
STUDY COORDINATION CENTRE: St Marys Hospital 
NRES reference: 15/LO/2131 
CSP reference: 188134 
 
 
 
Protocol authorised by: 
 
Name & Role 
Date 
 
 
 
 
Dr.Sarah Elkin- 
Consultant Respiratory 
Physician 
 
Dr.Patrick Mallia 
Consultant Respiratory 
Physician 
 
 
        04.04.2016 
 
 
        04.04.2016 
 
 
 
  
 
 
 
 
 
 
 
 
 
Study Management Group 
 
Chief Investigator: Mr. Vijay Padmanaban 
 
Co-investigators: Dr.Sarah Elkin, Dr.Patrick Mallia 
 
Study Management: NIHR imperial BRC 
 
 
 
 
 
 
 
 

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Clinical Queries 
 
Clinical queries should be directed to Chief Investigator who will direct the query to the 
appropriate person 
 
 
Sponsor 
 
Imperial College Healthcare NHS Trust is the main research Sponsor for this study.  For 
further information regarding the sponsorship conditions, please contact the Head of 
Regulatory Compliance at: 
 
 
 
Joint Research Compliance Office 
Imperial College London & Imperial College Healthcare NHS Trust 
5th Floor, Lab Block 
Charing Cross Hospital 
Fulham Palace Road 
London 
W6 8RF 
Tel: 0203 311 0212 
Fax: 0203 311 0203 
 
 
Funder 
 
NIHR Imperial BRC/ Imperial Charity- Research Fellowship 
 
 
This protocol describes the study and provides information about procedures for entering participants.  
Every care was taken in its drafting, but corrections or amendments may be necessary. These will be 
circulated to investigators in the study.  Problems relating to this study should be referred, in the first 
instance, to the Chief Investigator.  
 
This study will adhere to the principles outlined in the NHS Research Governance Framework for Health 
and Social Care (2nd edition). It will be conducted in compliance with the protocol, the Data Protection 
Act and other regulatory requirements as appropriate.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
1. 
INTRODUCTION 
5 
1.1 BACKGROUND 
5 
2.  STUDY OBJECTIVES 
6 
3.  STUDY DESIGN 
7 
3.1 STUDY OUTCOME MEASURES 
8 
4. 
PARTICIPANT ENTRY 
8 
4.1 PRE-REGISTRATION EVALUATIONS 
8 
4.2 INCLUSION CRITERIA 
8 
4.3 EXCLUSION CRITERIA 
8 
4.4 WITHDRAWAL CRITERIA 
8 
5. 
ADVERSE EVENTS 
9 
5.1 DEFINITIONS 
9 
5.3 REPORTING PROCEDURES 
9 
6. 
ASSESSMENT AND FOLLOW-UP 
10 
7. 
STATISTICS AND DATA ANALYSIS 
10 
8. 
REGULATORY ISSUES 
10 
8.1 ETHICS APPROVAL 
10 
8.2 CONSENT 
10 
8.3 CONFIDENTIALITY 
11 
8.4 INDEMNITY 
11 
8.5 SPONSOR 
11 
8.6 FUNDING 
11 
8.7 AUDITS AND INSPECTIONS 
11 
9. 
STUDY MANAGEMENT 
11 
10. 
PUBLICATION POLICY 
11 
11. 
REFERENCES 
12 
EXAMPLE APPENDICES 
12 
APPENDIX 1. 
SUMMARY OF INVESTIGATIONS, TREATMENT AND ASSESSMENTS 
12 
 
 
 
 
 
 

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GLOSSARY OF ABBREVIATIONS 
COPD 
Chronic Obstructive Pulmonary Disease 
PR 
Pulmonary Rehabilitation 
LTOT 
Long Term Oxygen Therapy 
SpO2 
Oxygen Saturations 
BTS 
British Thoracic Society 
CRQ 
Chronic Respiratory Questionnaire 
CAT 
COPD Assessment Tool 
HAD 
Hospital Anxiety and Depression score 
6MWT 
6 Minute Walk Test 
6MWD 
6 Minute Walk distance 
 
KEYWORDS 
COPD, Ambulatory Oxygen, Pulmonary Rehabilitation 
 
 
 
 
STUDY SUMMARY 
 
TITLE The Role of Ambulatory Oxygen in Improving the Effectiveness of Pulmonary 
Rehabilitation for COPD patients 
 
DESIGN Single Blinded Randomised Controlled Trial 
AIMS Assess the effects of ambulatory oxygen on outcomes from Pulmonary 
Rehabilitation 
OUTCOME MEASURES 6 Minute Walk Distance, Muscle strength, Dyspnoea, Quality of life 
questionnaires, anxiety and Depression score 
POPULATION COPD patients only 
ELIGIBILITY COPD patients between the age of 35-85, eligible for PR and who desaturate 
on exercise 
DURATION 1 year 
 
 
 
 
 
 
 
 

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1. 
INTRODUCTION  
 
1.1 
BACKGROUND 
Pulmonary rehabilitation (PR) is recognized as a core component of the management of 
patients with COPD (1) and has been clearly demonstrated to improve exercise capacity, 
reduce dyspnoea and improve quality of life. Although the benefits of PR in COPD are well 
established there remain a number of unanswered questions regarding how to maximise 
performance during PR, including the use of ambulatory oxygen. Studies investigating the 
effects of oxygen use during PR have had conflicting results with one study finding no benefit 
(2), while another study did report improved walking distance in patients administered oxygen 
(3). This latter study is used to justify the use of oxygen in PR programmes but the assessment 
was carried out while breathing the gas to which patients were randomised so it remains 
unknown if this was an acute effect of the oxygen or a true training effect. Limitations of these 
studies include inclusion of patients on LTOT, use of a standard oxygen flow rate rather than 
targeting to correct hypoxemia, limited outcome measures and short term follow-up. It is not 
known if short term improvements in exercise capacity translate into increased activity after 
patients complete PR. More sophisticated methods of measuring activity using pedometers 
are now available that can be used to assess whether oxygen during PR improves activity. 
Current practice appears to be moving towards administration of oxygen to COPD patients 
with exercise-induced desaturation during PR despite the lack of evidence that this has any 
benefits. In addition patients may be given ambulatory oxygen to use long term after 
completing PR, however it is not known whether patients continue to use oxygen as studies 
have shown that use of ambulatory oxygen in their home environments is generally poor (4). 
This has considerable cost implications due both to the direct costs of providing oxygen and 
the staff time required assessing patients. This lack of evidence is recognised in the British 
Thoracic Society (BTS) guidelines on PR(1). The guidelines state that ‘Supplemental oxygen 
during pulmonary rehabilitation should be offered to those who fulfil the assessment criteria 
for long term or ambulatory oxygen unless there are compelling clinical reasons to use 
alternative criteria.’ However the evidence level for this recommendation is Grade D which is 
the weakest level of evidence. Therefore it remains unknown whether oxygen improves 
outcomes in PR in COPD patients with exercise-induced desaturation. 
 
 
 
 
 
 

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1.2 
RATIONALE FOR CURRENT STUDY 
As described in the previous section the evidence base for the use of oxygen in PR is very 
limited. In the BTS guideline on PR it is stated that the one study that showed benefit for 
oxygen ‘carried a significant risk of bias that influenced its findings. Therefore its results require 
replication before they can be widely applied’, and that ‘Supplemental oxygen may be of 
benefit in selected individuals, but there is currently little information to inform this choice.’ 
Therefore further studies are needed to assess the effects of oxygen on outcomes from PR to 
justify its cost this. More sophisticated methods of measuring activity using pedometers are 
now available that were not available in previous studies of oxygen during PR. Therefore the 
rationale for the current study is to investigate the use of oxygen in COPD patient undergoing 
PR using a more robust study design and improved methods of assessing exercise capacity. 
 
 
2.  STUDY OBJECTIVES 
The aims of this study are to 
1. Assess the effects of oxygen on outcomes from PR. 
2. Assess how many patients wish to continue to use ambulatory oxygen. 
3. Assess the usage of ambulatory oxygen following completion of PR. 
 
The hypothesis is that use of oxygen in selected patients improves exercise capacity during 
PR. The measurable aims will be exercise capacity and on-going usage of oxygen in this 
patient group. 
 
Primary Objective 
Assess the effects of ambulatory oxygen on outcomes from Pulmonary Rehabilitation 
 
Secondary Objectives 
1. Assess the proportion of patients that wish to continue to use ambulatory oxygen. 
2. Assess the usage of ambulatory oxygen following completion of Pulmonary Rehabilitation 
3. Assess whether initiation of ambulatory oxygen before or after PR has any influence on 
adherence to usage at 8 and 12 weeks. 
 
 
 
 
 

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3.  STUDY DESIGN 
The study will be a randomised, single-blinded study comparing oxygen with air in COPD 
patients undergoing PR. The study subjects will be patients with a confirmed diagnosis of 
COPD who have been accepted for PR and who are not hypoxemic at rest, but have exercise-
induced desaturation (defined as a fall in SaO2 of ≥4% to at least <90%, or any fall to a SaO2 
<90%) and demonstrate positive improvement with use of ambulatory oxygen as per the 
British Thoracic Society 2015 Home Oxygen Guidelines. It is standard practice for patients to 
have this assessment prior to commencing PR and as part of the assessment the flow rate 
required to increase the SaO2 to >90% during exercise will be determined. Patients will be 
recruited from PR programs at Imperial College Healthcare NHS Trust Hospital Sites. 20 
patients are required in each group to detect a 30% effect size on the 6 minute walk test 
(6MWT) with 80% power at the 5% significance level and 29 patients in each group to detect 
a 25% effect with 80% power (5). Therefore a minimum of 20 patients per group will be 
included.  
Baseline assessments prior to commencing PR will include symptom and quality of life 
assessments including Borg scale for assessment of breathlessness, Chronic Respiratory 
Questionnaire (CRQ), COPD Assessment Tool (CAT) and the Hospital Anxiety and 
Depression score (HAD); a 6MWT to measure exercise capacity and Handheld dynamometer 
to measure muscle strength. In addition we will measure activity at home during and after PR 
using pedometers as this has never been investigated previously. A yamax Digi-walker SW-
200 pedometer will be used to count the number of steps taken per day. Patients will be 
instructed to wear the device on left side of the body all the time, except when sleeping or 
showering. Pedometer placement was standardised by placing it on the belt or waistband, in 
the midline of the thigh, consistent with the manufacturers recommendation and with other 
studies conducted previously (6, 7). Patients will be record daily step counts on daily diary 
cards until their final follow up. The subjects will be randomised to receive either oxygen at the 
flow rate determined at the initial assessment to a maximum flow rate of 6 litres per minute, or 
room air. The subjects will then undergo a standard program of PR over 6 – 8 weeks and then 
undergo reassessment. The measures of exercise capacity at the follow up assessment will 
be carried out off oxygen and will be carried out by an observer blinded as to whether they 
received oxygen or not during PR. All patients will be provided with ambulatory oxygen for 
domiciliary after completing PR. All patients will have repeat assessments at 8 and 12 weeks 
after completion of PR. At these visits data will also be collected on activity, number of 
exacerbations and hospitalisations and on-going usage of ambulatory oxygen. 
 
 

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3.1 
STUDY OUTCOME MEASURES 
Primary Outcome measure  
Exercise capacity measured with the 6 Minute Walk Test (6MWT) 
 
Secondary outcome measure 
1) Quality of Life Questionnaire 
2) Measure of Anxiety and Depression 
3) Muscle strength 
4) Borg dyspnoea score 
 
4. 
PARTICIPANT ENTRY  
 
4.1 
PRE-REGISTRATION EVALUATIONS  
6 Minute Walk Test as part of ambulatory oxygen assessment 
 
4.2 
INCLUSION CRITERIA 
1) A confirmed diagnosis of Chronic Obstructive Pulmonary Disease (COPD) 
2) Fulfil the clinical criteria for Pulmonary Rehabilitation (PR) 
3) Demonstrate exercise-induced desaturation (defined as a fall in SaO2 ≥4% to at least 
<90%, or any fall to a SaO2 <90%) and demonstrate positive improvement with use of 
ambulatory oxygen as per the British Thoracic Society 2015 Oxygen Guidelines 
 
4.3 
EXCLUSION CRITERIA 
1) Use of long term oxygen therapy 
2) Unable to provide informed consent 
3) Significant respiratory disease other than COPD 
4) Any patient needing more than 6 litres per minute oxygen to correct desaturation 
5) Severe desaturation: SaO2 < 80% during 6 Minute Walk Test 
6) Any absolute contraindication to Pulmonary Rehabilitation 
 
4.4 
WITHDRAWAL CRITERIA 
Standard clinical practice criteria for PR will be used, as per BTS PR guidelines. 
 
 
 

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5. 
ADVERSE EVENTS 
 
5.1 
DEFINITIONS   
Adverse Event (AE): any untoward medical occurrence in a patient or clinical study subject.   
 
Serious Adverse Event (SAE): any untoward and unexpected medical occurrence or effect 
that: 
 
Results in death 
 
Is life-threatening – refers to an event in which the subject was at risk of death 
at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe 
 
 
Requires 
hospitalisation, 
or 
prolongation 
of 
existing 
inpatients’ 
hospitalisation 
 
Results in persistent or significant disability or incapacity 
 
Is a congenital anomaly or birth defect 
 
Medical judgement should be exercised in deciding whether an AE is serious in other 
situations.  Important AEs that are not immediately life-threatening or do not result in death or 
hospitalisation but may jeopardise the subject or may require intervention to prevent one of 
the other outcomes listed in the definition above, should also be considered serious. 
 
5.3 
REPORTING PROCEDURES 
All adverse events should be reported.  Depending on the nature of the event the reporting 
procedures below should be followed.  Any questions concerning adverse event reporting 
should be directed to the Chief Investigator in the first instance.   
 
5.3.1 Non serious AEs 
All such events, whether expected or not, should be recorded.   
 
5.3.2 Serious AEs 
An SAE form should be completed and faxed to the Chief Investigator within 24 hours.  
However, relapse and death due to COPD Exacerbation and hospitalisations for elective 
treatment of a pre-existing condition do not need reporting as SAEs. 
 
All SAEs should be reported to the JRCO, Imperial College healthcare NHS trust where in the 
opinion of the Chief Investigator, the event was: 
 
‘related’, ie resulted from the administration of any of the research procedures; 
and 
 
‘unexpected’, ie an event that is not listed in the protocol as an expected 
occurrence 
 
Reports of related and unexpected SAEs should be submitted within 15 days of the Chief 
Investigator becoming aware of the event, using the NRES SAE form for non-IMP studies.  
The Chief Investigator must also notify the Sponsor of all SAEs. 
 
Local investigators should report any SAEs as required by their Local Research Ethics 
Committee, Sponsor and/or Research & Development Office. 
 
Contact details for reporting SAEs 
Fax:02033110203 Attention Joint Research compliance office 
Please send SAE forms to: Vijay Padmanaban 
Tel: 07919533414 (Mon to Fri 09.00 – 17.00) 

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6. 
ASSESSMENT AND FOLLOW-UP  
The subjects will attend for 2 additional visits at 2 months and 3 months after completing PR 
for follow-up assessments that will involve completing questionnaires and measurements of 
exercise capacity (6 Minute Walk Test).  
 
Definition of end of study 
All patients recruited to the study will have completed the study when they attend for the 3 
month follow up assessments. 
 
 
7. 
STATISTICS AND DATA ANALYSIS 
20 patients are required in each group to detect a 30% effect size on the 6MWT with 80% 
power at the 5% significance level and 29 patients in each group to detect a 25% effect with 
80% power. Therefore a minimum of 20 patients per group will be included. The following 
statistical methods will be used for data analysis – T test, ANOVA and test for correlation 
between variables 
Data and all appropriate documentation will be stored for a minimum of 10 years after the 
completion of the study, including the follow-up period.   
 
 
8. 
REGULATORY ISSUES 
8.1 
ETHICS APPROVAL 
The Chief Investigator has obtained approval from the Local Research Ethics Committee.  The 
study must be submitted for Site Specific Assessment (SSA) at each participating NHS Trust. 
The Chief Investigator will require a copy of the Trust R&D approval letter before accepting 
participants into the study. The study will be conducted in accordance with the 
recommendations for physicians involved in research on human subjects adopted by the 18th 
World Medical Assembly, Helsinki 1964 and later revisions. 
 
8.2 
CONSENT  
Consent to enter the study must be sought from each participant only after a full explanation 
has been given, an information leaflet offered and time allowed for consideration.  Signed 
participant consent should be obtained.  The right of the participant to refuse to participate 
without giving reasons must be respected.  After the participant has entered the study the 
clinician remains free to give alternative treatment to that specified in the protocol at any stage 
if he/she feels it is in the participant’s best interest, but the reasons for doing so should be 

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recorded.  In these cases the participants remain within the study for the purposes of follow-
up and data analysis.  All participants are free to withdraw at any time from the protocol 
treatment without giving reasons and without prejudicing further treatment. 
 
8.3 
CONFIDENTIALITY 
The Chief Investigator will preserve the confidentiality of participants taking part in the study 
and is registered under the Data Protection Act. 
 
8.4 
INDEMNITY 
Imperial College Healthcare NHS Trust holds standard NHS Hospital Indemnity and insurance 
cover with NHS Litigation Authority for NHS Trusts in England, which apply to this study  
 
8.5 
SPONSOR 
Imperial College Healthcare NHS Trust will act as the main Sponsor for this study.  Delegated 
responsibilities will be assigned to the NHS trusts taking part in this study.   
 
8.6 
FUNDING 
NIHR Imperial BRC is funding this study.  Total of 50000£ for a year, has been awarded to the 
chief investigator as part of the Research fellowship 
 
8.7 
AUDITS  
The study may be subject to inspection and audit by Imperial College healthcare NHS trust 
under their remit as sponsor and other regulatory bodies to ensure adherence to GCP and the 
NHS Research Governance Framework for Health and Social Care (2nd edition).  
 
 
9. 
STUDY MANAGEMENT 
The day-to-day management of the study will be co-ordinated by the chief investigator   
 
 
10. 
PUBLICATION POLICY 
 
The results of the study will be presented at relevant conferences and published in peer review 
journals. 
 
 

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11. 
REFERENCES 
1) C Bolton et al. BTS Guideline on Pulmonary Rehabilitation in Adults September 2013 
Volume 68 Supplement 2 Thorax 2013 
 
2) Garrod R et al. Supplemental oxygen during pulmonary rehabilitation in patients 
with COPD with exercise hypoxaemia. Thorax. 2000 Jul;55(7):539-43 
 
3) Dyer F et al. Ambulatory oxygen improves the effectiveness of pulmonary 
rehabilitation in selected patients with chronic obstructive pulmonary disease.Chron 
Respir Dis. 2012 May;9(2):83-91 
 
4) Lacasse Y et al. Randomised trial of ambulatory oxygen in oxygen-dependent 
COPD. Eur Respir J. 2005 Jun;25(6):1032-8. 
 
5) Spruit MA et al. Determinants of poor 6-min walking distance in patients with COPD: 
the ECLIPSE cohort Respir Med. 2010 Jun;104(6):849-57 
 
6)Crouter SE et al. Validity of 10 electronic pedometers for measuring steps, distance 
and energy cost. Medicine and science in sports and exercise. 2003;35(8):1455:60 
 
7)Schneider PL et al. Pedometers measures of free living physical activity: 
comparision of 13 models. Medicine and science in sports and exercise 
2004;36(2):331-5 
 
Appendix 1. Summary of investigations, treatment and assessments 
 
Baseline 
PR 
At completion 
of PR 
8 weeks after 
PR 
12 weeks after 
PR 
6MWT 
X 
 
X 
X 
X 
Borg scale 
X 
X 
X 
X 
Chronic Respiratory 
Questionnaire (CRQ), 
X 
X 
X 
X 
COPD Assessment 
Tool (CAT) 
X 
X 
X 
X 
Hospital Anxiety and 
Depression score 
(HAD) 
X 
X 
X 
X 
Pedometer 
X 
X 
X 
X 
Muscle strength 
X 
X 
X 
X 
Informed consent 
X