Chronic fatigue treatment trial
People want to learn as much as possible from the PACE trial for chronic fatigue syndrome
Cite this as: BMJ 2013;347:f5731
Rapid responses are electronic letters to the editor. They enable our users to debate issues raised in articles published on bmj.com. Although a selection of rapid responses will be included as edited readers' letters in the weekly print issue of the BMJ, their first appearance online means that they are published articles. If you need the url (web address) of an individual response, perhaps for citation purposes, simply click on the response headline and copy the url from the browser window.
Displaying 1-5 out of 5 published
I would like to use this forum to inform BMJ readers that I had a discussion with Tony Sedgewick, head of the South Australian Institute for Fitness Research and Training, in 1982.
I explained that I had completed almost a year of training at his institute in 1978, by making modifications to the standard exercise program to suit my requirements, and that I had since learned that international researchers were finding that chronic fatigue patients "could not or would not train" for sufficient time to gain meaningful scientific data.
He understood clearly, that if I could do it, then so could some other patients so, when his two researchers were too busy to do the study, he asked me to design and co-ordinate the research myself.
The first 12 week program was successful, and the second verified the method, and then I left the project.
However, the exercise principles which I established were a reliable that any researcher could use in the future. It essentially recommended that the person trained at their own rate, within their own limits, and improved very gradually in a specific way, and adjust their daily activities etc. as well.
I prepared a research paper with the details and sent one copy to the Australian Medical Journal, and then another to the New Guinea Medical Journal, but they were not accepted for publication.
Nevertheless, the success of the project was widely reported in local, interstate, and probably international newspapers between 1982 and 1983.
I designed that program so that the people who participated would not be required to do the type of exercise which caused problems.
I then became involved in other activities and projects.
However, in recent years I have seen many modern research projects which use almost exactly the same principles which I developed.
I made that possible by solving the problem by producing the type of exercise regime that some patients could and did follow for the required period of time.
The text and charts for that research paper can be seen by using the Google search engine to navigate to The Posture Theory website, and then by using the drop down menu at the top to locate the specific webpage related to the Chronic Fatigue Syndrome, and then by reading the first few lines to find the link to the paper.
Competing interests: I developed the design principles based on my own experience, for safely conducting research into chronic fatigue and exercise at the South Australian Institute for Fitness Research and Training in 1982
No affiliation, Unit 6, No.6 Hartman Ave., Modbury, South Australia
Click to like:
People reading the response by White and colleagues could be forgiven for thinking there were inaccuracies in my letter. I said none of the primary outcome measures have been published as in the protocol.1 This is true. The new primary outcome measures do use data from the same questionnaires; however, altering how an outcome is reported by using a different threshold or method of analysis can be considered a significant change.2
It is true that the investigators did alert readers to some changes to outcome measures; however other outcomes e.g. on safety, were also changed without this being highlighted or explained.1,3
Only 0.26% (10/3774) of the adverse events have been reported with both the intervention and details of the event.3 Moreover, patient compliance was considered to be adequate if a participant simply attended (which could be by phone) 10 out of the 15 sessions. For the six-minute walk test, the chief objective measure, there were minimal improvements recorded for graded exercise therapy, and no improvement recorded for cognitive behavioural therapy, so I question we have good data on the safety of dutifully adhering to these graded activity-oriented interventions, given the abnormal response to exertion in the condition.3
Three of the four elements of the recovery definition in the protocol were
changed.1,4 Two of the new thresholds for recovery could be satisfied by participants scoring worse than at baseline.1,4
Minutes from the trial's steering committee, released via an earlier FOI, show that the criteria for a 'positive outcome' (one of the original primary outcome measures) had been made more demanding, involving a SF36 physical functioning score of 75, in order to ensure improvements were "more than trivial" from a baseline score of 65. The post-hoc recovery criteria required a score of just 60, down from 85.4
1. White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R; PACE trial group.
Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurol 2007;7:6.
2. Evans S. When and how can endpoints be changed after initiation of a randomized clinical trial? PLoS Clin Trials 2007;2, e18.
3. Kindlon T. Reporting of harms associated with graded exercise therapy and cognitive behavioural therapy in myalgic encephalomyelitis/chronic fatigue syndrome. Bulletin of the IACFS/ME 2011;19:59-111.
4. White PD, Goldsmith K, Johnson AL, Chalder T, Sharpe M; PACE Trial Management Group. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychol Med 2013; published online 31 Jan.
Competing interests: I work in a voluntary capacity for the Irish ME/CFS Association
Irish ME/CFS Association, PO Box 3075, Dublin 2, Ireland
Click to like:
Further to the discussion in relation to the PACE trial’s altered outcome measures, all the proposed primary analyses (e.g. the ‘primary efficacy measures’) were either abandoned or changed after the trial protocol was published. [1,2,3]
Many other important outcome analyses were either changed (e.g. 'recovery') or abandoned (e.g. 'clinically important difference') or created afresh (e.g. ‘improvement rates’, ‘clinically useful difference’, and ‘normal range’) after the protocol was published.
Publicly available information indicates that at least some of the most important analyses were post-hoc (e.g. ‘normal range’, ‘recovery’.)  Questions have been raised in relation to the statistical methodology and thresholds used for these published analyses [5,6].
It has been argued that the protocol defined analyses may be more helpful for patients and clinicians than the post-hoc analyses. For example, the post-hoc ‘recovery’ threshold of ≥60 for SF-36 physical function scores indicates severe physical impairment.  So it is no surprise that freedom of information (FOI) requests have been made in an attempt to obtain protocol-related data from this publicly funded medical trial.
In response to a FOI request Queen Mary University London (QMUL), has refused to publish the protocol defined analyses for improvement or recovery on the grounds that the analyses have not been carried out . This goes against the broad scientific consensus that all medical trial data should be made available [8,9]. QMUL, the Medical Research Council, and the UK government (which partially funded the trial) all have policies which concur with Research Councils UK’s data policy: “Publicly funded research data are a public good, produced in the public interest, which should be made openly available with as few restrictions as possible in a timely and responsible manner that does not harm intellectual property.” [10,11,12].
1. White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R; PACE trial group. Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurol. 2007 Mar 8;7:6.
2. White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL, Bavinton J, Angus BJ, Murphy G, Murphy M, O'Dowd H, Wilks D, McCrone P, Chalder T, Sharpe M; PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011 Mar 5;377(9768):823-36.
3. White PD, Goldsmith K, Johnson AL, Chalder T, Sharpe M. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychol Med. 2013 Oct;43(10):2227-35.
4. White PD , Goldsmith KA , Johnson AL, Walwyn R, Baber HL, Chalder T, Sharpe M, on behalf of all the co-authors. Letter to the Editor of the Lancet. “Response to the complaint to The Lancet of March 2011”. (Internet) (Accessed on 1st Oct 2013) http://www.forward-me.org.uk/Reports/White%20to%20Lancet%20re%20Hooper%20complaint%20(2).pdf
5. Oceanblue. PACE trial: Rejected letter to the Lancet. (Internet) (Last accessed 1st Oct 2013) http://www.mecfsforums.com/mwiki/index.php?title=PACE_trial:_Rejected_le...
6. Courtney R. Letter to the Editor: ‘Recovery from chronic fatigue syndrome after treatments given in the PACE trial’: an appropriate threshold for a recovery? Psychol Med. 2013 Aug;43(8):1788-9.
7. Courtney. Freedom of Information Request “PACE Trial: Recovery Rates and Positive Outcome Rates” (Internet) (accessed 1st Oct 2013) https://www.whatdotheyknow.com/request/pace_trial_recovery_rates_and_po
8. Chalmers I, Glasziou P, Godlee F. All trials must be registered and the results published. BMJ. 2013 Jan 9;346:f105.
9. AllTrials campaign website (List of supporting organisations) (Internet) (Last accessed 1st Oct 2013) http://www.alltrials.net/supporters/#sthash.QIDHDWcx.dpbs
10. Queen Mary, University of London. Research Data Management Policy. (Internet) (Last accessed 1st Oct 2013) http://www.arcs.qmul.ac.uk/policy_zone/research/QMUL_research_data_manag...
11. RCUK Common Principles on Data Policy. (Internet) (Last accessed on 1st Oct 2013) http://www.rcuk.ac.uk/research/Pages/DataPolicy.aspx
12. Hansard. Written Answers. Wednesday 12 December 2012. Research: Data Sharing. Column WA241. (Internet) (Last accessed 1st Sep 2013.) http://www.publications.parliament.uk/pa/ld201213/ldhansrd/text/121212w0...
Competing interests: None declared
Click to like:
Tom Kindlon states that access to the committee minutes of the PACE trial is needed to “..to find out why outcome measures were changed”.1 We disagree.
First, the primary outcome measures were the same ones as described in the protocol – fatigue and physical disability.2 Second, details and explanations of independently approved changes to the scoring system and analysis of the outcomes are already in the public domain; both in the published papers and on the PACE trial website (http://www.pacetrial.org/faq/).3,4
Third, his suggestion that there were problems in the reporting of harms is also incorrect.1 Unusually for a non-drug trial, we adopted the same stringent procedures as recommended by the European Union Clinical Trials Directive for Pharmacological Interventions. We measured safety by serious adverse reactions and events, non-serious adverse events, withdrawals from treatment because of worsening, self-rated global worsening, and a composite measure of serious deterioration.2,3 All adverse events were reviewed by an independent panel.
Finally, readers should know that the Information Tribunal’s unanimous judgement on the appeal was that: “The tribunal has no doubt that properly viewed in its context, this request should have been seen as vexatious - it was not a true request for information - rather its function was largely polemical.”5
PD White 1, T Chalder 2, M Sharpe 3, T Johnson 4, K Goldsmith 5
1 Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London,
2 Academic Department of Psychological Medicine, King's College London,
3 Department of Psychiatry, University of Oxford, Oxford, UK
4 MRC Clinical Trials Unit at UCL, London
5 Biostatistics Department, Institute of Psychiatry, King’s College London,
1. Kindlon T. People want to learn as much as possible from the PACE trial for chronic fatigue syndrome. BMJ 2013;347:f5731.
2. White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R; PACE trial group. Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurol 2007;7:6.
3. White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL, Bavinton J, Angus BJ, Murphy G, Murphy M, O’Dowd H, Wilks D, McCrone P, Chalder T, Sharpe M. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet 2011;377:823-36.
4.W hite PD, Johnson AL, Goldsmith K, Chalder T, Sharpe MC. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychol Med 2013;1-9, published online 31 Jan. doi:10.1017/S0033291713000020.
5. General Regulation Chamber (Information Rights) First Tier Tribunal. Mitchell versus Information Commissioner. EA 2013/0019. http://www.informationtribunal.gov.uk/DBFiles/Decision/i1069/20130822%20....
Competing interests: PDW has done voluntary and paid consultancy work for the United Kingdom government and a reinsurance company. TC has received royalties from Sheldon Press and Constable and Robinson. MS has done voluntary and paid consultancy work for the United Kingdom government, has done consultancy work for an insurance company, and has received royalties from Oxford University Press. KAG and ALJ declare that they have no conflicts of interests.
Barts and the London Medical School, St Bartholomew's Hospital, London EC1A 7BE
Click to like:
Why would anyone expect to learn anything of scientific importance from the £5m PACE (Pacing, Graded Activity, and Cognitive Behaviour Therapy—a Randomised Evaluation) trial for patients suffering from chronic fatigue syndrome (CFS) or myalgic encephalitis (ME)? 1
The brilliant work of John McLaren-Howard, Sarah Myhill and Norman Booth has revealed that the illness is due to mitochondrial dysfunction. This discovery revolutionizes the world’s understanding of the condition. Mitochondrial function is typically impaired in two ways: substrate or co-factor deficiency, and inhibition by chemicals, exogenous or endogenous. For the former, additional nutrients are recommended where there is a deficiency, and for the latter, improvement of anti-oxidant status and selective chelation therapy or far-infrared saunas were used.2-4
Myhill and colleagues note that the outcome measures described by the PACE authors as “moderate” are in fact minuscule in comparison to the improvements that they measure in biomedical tests. In contrast, they write that there is no proven mechanism by which either CBT or GET (graded exercise therapy), favoured by the PACE trial, can ameliorate, let alone rectify, mitochondrial dysfunction. In fact excessive exercise can result in further tissue damage.2
1 Kindlon T. Chronic fatigue treatment trial People want to learn as much as possible from the PACE trial for chronic fatigue syndrome.BMJ 2013;347:f5731.
2 Myhill S, Booth NE, McLaren-Howard J. Targeting mitochondrial dysfunction in the treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) - a clinical audit. Int J Clin Exp Med. 2013;6:1-15.
3 Booth NE, Myhill S, McLaren-Howard J. Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Int J Clin Exp Med. 2012;5(3):208-20.
4 Myhill S, Booth NE, McLaren-Howard J. Chronic fatigue syndrome and mitochondrial dysfunction. Int J Clin Exp Med. 2009;2:1-16.
Competing interests: None declared
Retired, Kingston-upon-Thames, KT2 7JU, UK
Click to like: