PACE trial

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Contents



Summary

The PACE trial was designed to asses the efficiency of CBT and GET for what the authors of the PACE trial protocol refer to as "CFS/ME". An umbrella term used in the UK to subsume ME, CFS, idiopathic chronic fatigue and the mental health disorder 'Fatigue Syndrome'. A term that is not supported by the World Health Organization. The trial was also intended to assess something called "adaptive pacing", which the PACE trial protocol claims to be the same as pacing, where the patient "listens to their body". However, "adaptive pacing" requires that a participant plans and practises activity and relaxation according to a timetable.


Although the PACE trial was designed to be a randomised controlled trial (RCT), the published research paper dropped the "controlled" part of the description. [1]

"In our parallel-group randomised trial, patients meeting Oxford criteria for chronic fatigue syndrome were recruited from six secondary-care clinics in the UK and randomly allocated by computer-generated sequence to receive specialist medical care (SMC) alone or with adaptive pacing therapy (APT), CBT, or GET."
White et al, 'Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial' (The Lancet, 18 February 2011) [2]


The Oxford criteria for CFS used was used as the patient selection criteria, but not all patients included had a diagnosis of CFS.


Trial design

MRC Scientific Abstract

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

  • Principal Investigator: Professor P D White, Queen Mary, University of London, London
  • Research Organisation: Queen Mary, University of London
  • Reference: G0200434
  • Grant Category: Grant
  • Board Portfolio: Late Phase Trials
  • Health Category: Other
  • Research Activity: Evaluation of Treatments and Therapeutic Interventions
  • Start date: 14 Jun 2004
  • End Date: 13 Sep 2010
  • (£2,779,295)


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.


PACE trial protocol

The PACE trial protocol was published on the 8 March 2007 in BMC Neurology.

Protocol for the PACE trial[3]


Entry Criteria

Originally the Oxford criteria was to be used for the PACE trial. After a public outcry over this, the MRC announced that a “secondary analysis” would be performed using the “London criteria”. [4] and what is claimed to be the CDC Fukuda criteria, but are actually the Revees criteria, 2003. [5]


The “London” criteria have never been published and are not available as a reference for identification. They were mentioned in the National Task Force Report in 1994 as being one of nine different proposed definitions and descriptions. They have never been used in research (before criteria can be used in research, they need to be submitted for peer review and published in an accessible form). The “London” criteria have not even been consistently defined – there are different versions of them and a definitive version has not been identified. The authors of the “London” criteria remain to be established as there are divergent claims about who the authors might be. The “London” criteria have never been accepted into common usage, nor have they ever been validated or operationalised.


As the Oxford entry criteria expressly excludes neurological disorders, “secondary analysis” using any additional criteria will not identify those with the neurological disease ME/CFS.[6] Trial Investigators will also have the option to “select out” patients whom they believe will not respond in the desired way to the programme or who are too unwell to remain in the trials.[7]


Letter to General Practitioners (GP's) asking for participants for the PACE trial

"If you have a patient with definite or probable CFS/ME, whose main complaint is fatigue (or a synonym), whom you think might be interested and suitable for the study, please consider referring them to XXXXX XXXXX CFS/ME clinic at XXXXX XXXXX [one of the PACE trial centres]. They would be medically assessed in the normal way in the clinic and, if appropriate, offered treatment there either on a normal clinical basis or as part of the PACE trial, once screened for eligibility. If they are not eligible for the PACE trial, and no appropriate treatment is available, advice on self-management and alternative treatments, such as the expert patients programme, will be given."
PACE trial authors, 'Application to the West Midlands MREC' (ME Action UK, Page 5 of 8, 2006) [8]


Further research on behalf of the PACE trial management group

'Psychiatric misdiagnoses in patients with chronic fatigue syndrome'

  • Doctors assessing patients in a chronic fatigue syndrome clinic miss psychiatric diagnoses more often than misdiagnosing them. Missed diagnoses are common. CFS clinic doctors should be trained to diagnose psychiatric disorders. [9]

Publication

Publication imminent

On the 3rd September 2010, the ME Association highlighted a story on the PACE trial that had been reported in Link magazine (issue 39, September 2010) the very same day. The article stated that, data collected for the one-year follow up of the PACE trial was currently being analysed in preparation for publication of the findings and that Professor Peter White of St Bartholomew's Hospital, London, was to report on it's progress and baseline data, to delegates at the British Association of CFS/ME (BACME) October conference, on the 13 & 14 October 2010, Milton Keynes. The ME Association added, that the release of this PACE trial information may well have an effect on a decision by NICE as to when they commence a review of the 2007 Guideline on "CFS/ME". [10]


On the 23 December 2010, IACFS/ME published its latest version of their quarterly called Bulletin (Fall 2010). In this edition Professor Peter White, in a reply to criticism of his study, 'Predictions and associations of fatigue syndromes and mood disorders that occur after infectious mononucleosis' (2001), stated that the PACE Trial would show GET to be an effective treatment for CFS in the absence of comorbid mood disorders. [11]


"...the first published trial of GET excluded patients with comorbid mood disorders. The PACE trial, which is the largest ever trial of graded exercise therapy, compared to other rehabilitative interventions, for people with CFS will report next year. This will provide the most definitive test so far of both the efficacy and safety of this treatment."
Peter White, 'Letter to the Editor: Reply to Sampson' (IACFS/ME: Bulletin, Volume 18, Issue 3, 12 September 2010) [12]


Publication of the PACE Trial

On the 18 February 2011, the PACE Trial was published in The Lancet [13] The day before, a press conference had been organised by The Lancet at the Science Media Centre.[14] The news was reported in several news sources. [15][16][17]


  • The West Midlands Multicentre Research Ethics Committee (MREC 02/7/89) approved the study.


PACE trial (7 UK centres) of chronic fatigue syndrome (CFS) treatments (MRC; £5.0M)[18]


Results

The PACE trial results for fatigued people has demonstrated that CBT and GET are not effective. This conclusion is taken from the data within the published paper. Firstly, it is important to be aware that the effectiveness of specialist medical care (SMC) has not been established and therefore, although this study has no placebo arm, the SMC group is the control or no treatment arm. CBT in the trial was initiated according to the hypothesis that disability was the result of the fear based avoidance of exercise. Yet, there was a non significant worsening for the 6 minute walking test for the CBT arm (21 meters further) compared to the control group or SMC (22 meters). This result clearly shows that the CBT hypothesis, that disability is caused by a fear based avoidance of exercise, is incorrect. The data on improvement in the trial also showed that there there was a single figure percentage improvement in fatigue and sf-36 scores in the CBT and GET groups compared to control, indicating very strongly that psychological factors play an absolutely minimal role in the generation of symptoms for fatigue, not ME/CFS.


Results of the PACE trial can be found here


Criticism of the published PACE Trial

PACE trial official complaint from Professor Hooper

PACE trial official complaint to the Lancet from Professor Hooper

PACE trial official complaint to the Lancet - The Document

Rejected Letters to the Lancet

Angela Kennedy correspondence with the Lancet regarding the PACE trial

'Letter to Richard Horton of The Lancet on his comments on PACE' from Jo Best


Professor Hooper's complaint, and publication of further comments & responses in The Lancet

In March 2011, Professor Hooper submitted a complaint to the Lancet regarding the publication of the PACE trial.


On the 17 May 2011, eight letters of criticism regarding the PACE trial were published in the Lancet. [19][20][21][22][23][24][25][26] Together with a response from the authors [27] and an editorial from The Lancets' editor, Richard Horton, who complained about having received the letters. [28]

"Many of the letters critique the definitions of secondary outcomes, question protocol changes, and express concern over generalisability. But one cannot help but wonder whether the sheer anger and coordination of the response to this trial has been born not only from the frustration many feel about a disabling condition, but also from an active campaign to discredit the research. White and colleagues have been accused of having “formed their opinion about the intended outcome” before the trial began. This view is unjustified and unfair. The researchers should be praised for their willingness to test competing ideas and interventions in a randomised trial. The evidence might even suggest that it is the critics of the PACE trial who have formed their opinions first, ignoring the findings of this rigorously conducted work."
Richard Horton, 'Patients' power and PACE' (The Lancet, 17 May 2011) [29]


Authors response and The Lancet editorial

On the 17 May 2011, The Lancet published a response from the authors of the PACE trial and an editorial from Richard Horton. [30][31]

"In conclusion, however we compared the results and however we defined CFS and myalgic encephalomyelitis, we found that cognitive behaviour therapy and graded exercise therapy provided a significant and clinically useful advantage of moderate size over adaptive pacing therapy and specialist medical care, but were no less safe. We suggest that the issue is not whether these treatments work and are safe, but how to make them available to those who might benefit from them."
White, Goldsmith, Johnson, Walwyn, Baber, Chalder & Sharpe, 'The PACE trial in chronic fatigue syndrome — Authors' reply' (The Lancet, 17 May 2011) [32]

Also on the 17 May 2011, The Lancet forwarded to Professor Hooper a response from the PACE trail authors. Significantly, in the letter, the authors admitted that they had not studied those who met the umbrella term used by NICE ("CFS/ME") or ME. In an initial response to this letter from Peter White, Professor Hooper pointed out that this was not what the PACE trial authors had previously stated.

"In their letter, Peter White et al state: “The PACE trial paper refers to chronic fatigue syndrome (CFS) which is operationally defined; it does not purport to be studying CFS/ME”.


The sentence continues by stating that the PACE Trial studied: “CFS defined simply as a principal complaint of fatigue that is disabling, having lasted six months, with no alternative medical explanation (Oxford criteria)”.


This is exactly what the ME/CFS community has been saying from the outset, namely that the PACE Trial was not studying those with ME."

“...there thus ought to have been no dispute that the PACE Trial Investigators were not studying those with ME, but the Investigators have persistently confirmed that they were studying those with ME,"


On the 28 May 2011, Professor Hooper sent a detailed response to Peter White's letter to Richard Horton, editor of the Lancet.


Correction to the Comment by Bleijenberg and Knoop in the Lancet

On the 6 June 2011, an email was sent to Zoe Mullan, Senior Editor at The Lancet, highlighting the incorrect statements made by Bleijenberg and Knoop in the article accompanying the published PACE trial. Specifically the claim of a 30% recovery rate with CBT and GET for the participants of the PACE trial. On the 8 June 2011, Zoe Mullan replied, stating that as recovery was not reported in the trial that they would be correcting the comment.


Requests for unpublished data on the PACE trial


Links

Publication

PACE trial publication

PACE trial publication & use of the media

Articles after the publication of the PACE Trial

Responses to the publication of the PACE Trial - Negative

Responses to the publication of the PACE trial - Positive

Science Media Centre & the publication of the PACE trial

FOI request

NICE Guidelines

Sharpe/Horton PACE trial interview on ABC Radio Australia

Further articles on the PACE trial publication


Pre Publication

PACE trail documents/articles

Research ethics committee application

PACE Trial criticism, pre-publcation

BACME & PACE trial


Complaints

Complaints to the MRC/Government regarding the PACE trial

Professor Hooper's complaint to the Lancet regarding the PACE trial + Responses

Professor Hooper's complaint regarding the comment by Bleijenberg and Knoop in the Lancet

Angela Kennedy's complaint to the Lancet Ombudsman regarding the PACE trial

Further complaints to the Lancet regarding the PACE trial

Comments to the Lancet regarding the PACE trial - Published correspondence

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