The PACE trial; A RCT of CBT, graded exercise, adaptive pacing and usual medical care for the chronic fatigue syndrome

Lead Research Organisation: Queen Mary, University of London
Department Name: Wolfson Institute

Abstract

Chronic fatigue syndrome (CFS, also known as ME) affects 1 in 50 people. The main symptom is severe disabling fatigue made worse by activity. Its cause is unknown and we do not know how best to treat it
Treatments that may help include: specialist medical care alone (SMC) and SMC supplemented with one of the following special therapies: adaptive pacing therapy (APT); cognitive behaviour therapy (CBT); graded exercise therapy (GET).
SMC comprises medical follow up visits, self-help advice and drug treatment of symptoms
APT involves learning to balance activity and rest.
CBT helps patients to understand and cope better with the illness.
GET involves gradually increasing physical activity.
The trial will compare these treatments in 600 patients with CFS/ME, who will be followed up for a year. The aim is to see which treatments are best in reducing fatigue and enabling patients to do more. We will also look to see whether they have harmful effects and find out how they work.
The results of the trial will allow patients, doctors and health service planners to choose the best, safest and most cost –effective treatment for CFS/ME.

Technical Summary

The chronic fatigue syndrome (CFS, sometimes called ME) is a debilitating medically unexplained condition which has a prevalence of between 0.5% and 2% in the population of the UK. It has major effects on the health and welfare of both patients and their families. Two treatments that have shown promise for CFS are cognitive behaviour therapy (CBT) and graded exercise therapy (GET). However the evidence for these therapies is based on small trials, and surveys have suggested that they may make some patients worse. We do not know either how they work or who responds best to each treatment. Patient organisations routinely recommend a different approach of adaptive pacing therapy (APT) that is popular, but lacks empirical support. APT is based on the theory that sufferers have a fixed amount of available energy. The recent report to the CMO on the management of CFS was unable to recommend one of these treatments above the others. There is therefore a need for a trial which compares therapies, seeks evidence of adverse effects, and also examines predictors and mechanisms of response. The proposed trial will compare the efficacy, adverse effects, and cost-effectiveness of adding CBT, GET, or APT to usual medical care and compare them to the control treatment of usual medical care alone.
We will recruit 600 subjects who meet operationalised criteria for CFS, from six hospital clinics, into a single blind randomised controlled trial of the four treatments. Fourteen sessions of each of the three specific therapies will be given over five months and those recieving UMC alone will be put on a waiting list for their choice of therapy. Outcome will be assessed up to one year after entry. The two primary outcomes of self-rated fatigue and impairment of physical function, will allow us to assess differential effects of treatment on fatigue and function. Secondary outcomes will include other subjective measures of symptoms, mood, and function and objective measures of physical activity and fitness, as well as cost.
The results will inform health services about the efficacy and cost-effectiveness of these treatments for CFS. A better understanding the mechanism of successful treatment will provide a basis for the rational development of more efficient therapies. Knowledge of predictors will allow health professionals to match treatments to individual patients. Finally, it will provide information to patients and patients organisations about the benefits and adverse effects of available treatments for CFS.

Publications

10 25 50
 
Description Cochrane review of exercise therapy for CFS
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact Systematic review and meta analysis showing that graded exercise therapy is an effective and safe intervention to improve the health of patients suffering from CFS.
URL http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD003200.pub3/pdf/standard
 
Description Graded exercise therapy manual featured in HANDI guidance
Geographic Reach National 
Policy Influence Type Citation in clinical reviews
URL http://www.racgp.org.au/your-practice/guidelines/handi/interventions/other/graded-exercise-therapy-f...
 
Description IAPT scheme extended to long term conditions and medically unexplained symptoms
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
Impact 2 principal investigators are members of the Department of Health steering group to extend the Increasing Access to Psychological Therapies to UK primary care patients with medically unexplained symptoms.
 
Description IAPT team training
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact PDW provided advice and leadership to an IAPT DoH pathfinder site to provide graded exercise therapy to patients with longterm health conditions and medically unexplained symptoms.
 
Description Information Technology Act of 2014
Geographic Reach National 
Policy Influence Type Participation in a national consultation
Impact The IT Act of 2014 includes an exemption to the existing Freedom of Information Act 2000, to exempt current research from the FOI act requests, so long as release of data can be shown to be detrimental to the research. This will protect UK research in the future, and the PACE trial, which has taken 168 FOI requests since 2011, with some damage to the trial as a consequence, provided a precedent that helped to move this exemption forward.
URL http://www.justice.gov.uk/downloads/information-access-rights/foi/foi-exemption-s22a.pdf
 
Description NICE affirmed guideline on management of CFS/ME
Geographic Reach National 
Policy Influence Type Citation in other policy documents
Impact NICE publically affirmed that the results of the PACE trial strengthened the evidence base for cognitive behaviour therapy and graded exercise therapy in its current (2007) guideline. Original guideline - http://publications.nice.org.uk/chronic-fatigue-syndromemyalgic-encephalomyelitis-or-encephalopathy-cg53.
URL http://publications.nice.org.uk/chronic-fatigue-syndromemyalgic-encephalomyelitis-or-encephalopathy-...
 
Description MRC Clinical Trials Grant Extension
Amount £725,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 05/2009 
End 06/2011
 
Description MRC PhD fellowship
Amount £1 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2011 
End 12/2014
 
Title Individual Patient data Cochrane review 
Description The Cochrane collaboration have agreed to an individual patient data meta-analysis and meta-regression of the efficacy of graded exercise therapy for CFS, which will include the PACE data. The data from the PACE trial has been passed on to the authors, and we have joined with the authors to approve the protocol, currently under review at the Cochrane collaboration, and are co-authors of the proposed IPD meta-analysis. 
Type Of Material Database/Collection of Data/Biological Samples 
Year Produced 2012 
Provided To Others? Yes  
Impact We are aware of the preliminary results, which give clear data on efficacy of graded exercise therapy, which will be very useful to clinicians around the world. 
 
Description Cochrane IPD review and meta-analysis of exercise therapy in CFS 
Organisation King's College London
Department Health Psychology
Country United Kingdom 
Sector Academic/University 
PI Contribution We have provided individual patient data for this Cochrane group meta-analysis, as well as our active involvement in design and writing.
Collaborator Contribution Our colleagues from Norway are leading on the design, analysis and writing. Other colleagues are providing similar input as ourselves.
Impact Protocol published. Larun L, Odgaard-Jensen J, Brurberg KG, Chalder T, Dybwad M, Moss-Morris RE, Sharpe M, Wallman K, Wearden A, White PD, Glasziou PP. Exercise therapy for chronic fatigue syndrome (individual patient data) (Protocol). Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD011040. DOI: 10.1002/14651858.CD011040.
Start Year 2011
 
Description Cochrane IPD review and meta-analysis of exercise therapy in CFS 
Organisation University of Bergen
Department Knowledge Center
Country Norway 
Sector Academic/University 
PI Contribution We have provided individual patient data for this Cochrane group meta-analysis, as well as our active involvement in design and writing.
Collaborator Contribution Our colleagues from Norway are leading on the design, analysis and writing. Other colleagues are providing similar input as ourselves.
Impact Protocol published. Larun L, Odgaard-Jensen J, Brurberg KG, Chalder T, Dybwad M, Moss-Morris RE, Sharpe M, Wallman K, Wearden A, White PD, Glasziou PP. Exercise therapy for chronic fatigue syndrome (individual patient data) (Protocol). Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD011040. DOI: 10.1002/14651858.CD011040.
Start Year 2011
 
Description Cochrane IPD review and meta-analysis of exercise therapy in CFS 
Organisation University of Manchester
Department Manchester Academic Health Science Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution We have provided individual patient data for this Cochrane group meta-analysis, as well as our active involvement in design and writing.
Collaborator Contribution Our colleagues from Norway are leading on the design, analysis and writing. Other colleagues are providing similar input as ourselves.
Impact Protocol published. Larun L, Odgaard-Jensen J, Brurberg KG, Chalder T, Dybwad M, Moss-Morris RE, Sharpe M, Wallman K, Wearden A, White PD, Glasziou PP. Exercise therapy for chronic fatigue syndrome (individual patient data) (Protocol). Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD011040. DOI: 10.1002/14651858.CD011040.
Start Year 2011
 
Description Cochrane IPD review and meta-analysis of exercise therapy in CFS 
Organisation University of Oxford
Department Department of Psychiatry
Country United Kingdom 
Sector Academic/University 
PI Contribution We have provided individual patient data for this Cochrane group meta-analysis, as well as our active involvement in design and writing.
Collaborator Contribution Our colleagues from Norway are leading on the design, analysis and writing. Other colleagues are providing similar input as ourselves.
Impact Protocol published. Larun L, Odgaard-Jensen J, Brurberg KG, Chalder T, Dybwad M, Moss-Morris RE, Sharpe M, Wallman K, Wearden A, White PD, Glasziou PP. Exercise therapy for chronic fatigue syndrome (individual patient data) (Protocol). Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD011040. DOI: 10.1002/14651858.CD011040.
Start Year 2011
 
Description Cochrane IPD review and meta-analysis of exercise therapy in CFS 
Organisation University of Western Australia
Department School of Primary Aboriginal and Rural Health Care
Country Australia 
Sector Academic/University 
PI Contribution We have provided individual patient data for this Cochrane group meta-analysis, as well as our active involvement in design and writing.
Collaborator Contribution Our colleagues from Norway are leading on the design, analysis and writing. Other colleagues are providing similar input as ourselves.
Impact Protocol published. Larun L, Odgaard-Jensen J, Brurberg KG, Chalder T, Dybwad M, Moss-Morris RE, Sharpe M, Wallman K, Wearden A, White PD, Glasziou PP. Exercise therapy for chronic fatigue syndrome (individual patient data) (Protocol). Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD011040. DOI: 10.1002/14651858.CD011040.
Start Year 2011
 
Title PACE trial treatment manuals 
Description The website www.pacetrial.org/trialinfo/ contains links to all seven PACE trial treatment manuals, all bar one being free for download and use by clinicians around the world. The manuals were published in March 2011. 
Type Therapeutic Intervention - Psychological/Behavioural
Current Stage Of Development Wide-scale adoption
Year Development Stage Completed 2006
Development Status Closed
Impact Clinicians from around the world have told us that they have used them and found them helpful. We are aware of some being translated into German already. 
URL http://www.pacetrial.org/trialinfo/
 
Title Self help guide for graded exercise therapy for CFS 
Description The research physiotherapists in the PACE trial developed, piloted and published a self-help guide to help patients with chronic fatigue syndrome do graded exercise therapy. 
Type Therapeutic Intervention - Psychological/Behavioural
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2009
Development Status Under active development/distribution
Impact This has been used as a complementary aid by patients attending chronic fatigue syndrome clinics in the UK, and has been disseminated to clinicians in other countries. 
 
Description British Association of Cognitive and Behavioural Psychotherapists (BABCP) Annual Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Presentation to clinical psychologists

Implementation in clinical practice
Year(s) Of Engagement Activity 2011
 
Description Clinicians' conferences 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Health professionals
Results and Impact Several talks at regional meetings of BACME, eg in Bristol, Newcastle, London, and keynote speaker in March 2012 for their national biennial conference.

Good feedback from clinicians and reports of implementing changes to clinical practice
Year(s) Of Engagement Activity 2011
 
Description European Health Psychology Conference 2011 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Health professionals
Results and Impact Plenary presentation

Clinical implementation
Year(s) Of Engagement Activity 2011
 
Description Newsletters to PACE trial participants 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Summary of the trial results, written in lay language was sent by post to all 640 participants in the trial in the week after the main results were published.

Informal feedback very positive.
Year(s) Of Engagement Activity 2011
 
Description Press Conference 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Press conference to release results of long term follow up from PACE trial, organised by Science Media Centre
Year(s) Of Engagement Activity 2016
URL http://www.sciencemediacentre.org/cfsme-pace-trial-follow-up-study/
 
Description Press conference 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Press conference, hosted by Science Media Centre, to announce results of mediation study from the PACE trial, which was well covered in international media.
Year(s) Of Engagement Activity 2016
URL http://www.sciencemediacentre.org/cfsme-the-next-step-in-the-controversy-2/
 
Description Publicity in ME charites' newletters and magazines 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Many articles in such magazines

Some controversy over findings, but two charities particularly receptive.
Year(s) Of Engagement Activity 2011
 
Description Royal College of Psychiatrists 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Health professionals
Results and Impact One presentation to ~170 liaison psychiatrists at annual conference in Glasgow. Another to the RCPSych annual conference in Brighton, attended by ~200 in audience.

Well received by both audiences
Year(s) Of Engagement Activity 2011,2014
 
Description Scienc media centre press conference - Health economics 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Press conference in August 2012 to publicise the cost-effectiveness results.

PIcked up by UK national media and some international media.
Year(s) Of Engagement Activity 2012
 
Description Science Media Centre press conference 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact This was the press conference to launch the main results published in The Lancet, and the story of the trial results was published in major newspapers, radio, and TV, including all the UK national main papers and New York Times and other international media. Feb 2011.

Large spread to international public.
Year(s) Of Engagement Activity 2011
 
Description World conferences to clinicians 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Health professionals
Results and Impact My colleagues and I have presented this work to: Health Psychology MSc course, (Ireland), European Association of Consultation and Liaison Psychiatry (Budapest, Hungary), World Congress of Psychosomatic Medicine, (Seoul, Korea), American Academy of Psychosomatic Medicine (USA)


Positive feedback from all.
Year(s) Of Engagement Activity 2011,2012