PACE trial

The PACE Trial (short for "Pacing, graded Activity, and Cognitive behaviour therapy; a randomised Evaluation" was a large-scale trial of treatments for people with Chronic Fatigue Syndrome (CFS), also known as Myalgic Encephalomyelitis (ME).

The study compared standardised specialist medical care (SMC) alone to SMC plus Adaptive Pacing Therapy (APT), Cognitive Behavioral Therapy (CBT), or Graded Exercise Therapy (GET). The experimenters hypothesised that the CBT and GET groups would do best, and reported that this is what the trial's results showed  but the claim has proved controversial

The PACE trial dominates clinical policy in the United Kingdom and other countries, in both government funded health care and private medical insurance.

Background
The PACE trial was funded by the UK Medical Research Council, Department of Health for England, Scottish Chief Scientist Office, and - apparently uniquely for a clinical trial - the Department for Work and Pensions. It cost £5 million and is the most expensive piece of research into ME/CFS ever conducted.

Recruitment of patients began in March 2005 and data collection was completed in January 2010. The study protocol was published in BMC Neurology in 2007. The main study outcomes were published in The Lancet in 2011 and the experimenters continue to publish papers on the trial.

The principal investigators were Professors Peter White, Trudie Chalder, and Michael Sharpe. Although not an author, Professor Simon Wessely provided feedback on their report. He stated in November 2015 that "there are also more trials in the pipeline".

Study design
641 patients were randomised into four groups in the study. All received specialist medical care (SMC), which consisted of medication for symptoms such as insomnia and pain, and general advice to avoid extremes of rest and inactivity. One group received SMC alone. Patients in another group additionally received adaptive pacing therapy (APT), and were advised to stay within the limits of activity imposed by the disease to give their bodies the best chance of recovery. The other two groups were both told that they were not ill but deconditioned, and that if they gradually increased their activity, there was nothing to prevent their recovery. The cognitive behavioural therapy (CBT) group focused on addressing their presumed fear of activity while the graded exercise (GET) group focused on increasing their activity in a structured manner, with regular aerobic exercise as the eventual goal.

Patients in the APT, CBT and GET groups were offered up to 14 sessions with a therapist over a six-month period, to support them in following their therapy programmes, with a top-up session at 36 weeks. They also received a lengthy manual  explaining their therapy. All participants were offered at least three sessions of SMC.

Patients were assessed at baseline, 12 weeks, 24 weeks and 52 weeks. The main outcome measures were self-rated fatigue and physical function. Secondary measures included the study's objective variables such as a six-minute walking test, a fitness test and economic measures including the number of days of work lost due to fatigue, and the receipt of sickness benefits.

Patients were also followed up (using subjective ratings only) at least two years after randomisation.

Findings
The trial's results showed that patients in the CBT and GET groups improved more in self-rated fatigue and physical function than the APT or SMC groups. However, apart from a marginal effect on the six-minute walking test, all of the study's objective measures and the long-term follow-up data (self-ratings of fatigue and physical function) showed no difference between groups. Because all groups received SMC, this indicates that APT, CBT and GET added nothing to these outcomes and that there was no evidence that these treatments were effective. However, the study authors have continued to interpret the results as indicating that CBT and GET are effective treatments for ME/CFS.

The authors made no claims about patients recovering in their 2011 Lancet paper, though an accompanying Lancet editorial did so, as did one of the study authors at a press conference. However, the authors did claim, in a 2013 paper specifically about recovery, that 22% of patients in the CBT and GET groups had recovered following these therapies. But critics have pointed out that the authors replaced the recovery criteria that they had specified in the study protocol with others that were far easier to meet. The study authors have refused to publish the results according to the original analyses or to provide anonymised individual patient-data so that others can conduct the analyses.

There is great controversy about the authors' refusal to release the data underlying this or any other analysis in the study to independent researchers. They have provided individual patient data to a Cochrane review team but the team includes all of PACE's principal investigators.

Impact
The PACE trial and other studies that use the Oxford criteria for diagnosis of ME/CFS have had major international impact on popular perceptions of the disease and also on public policies toward treating and researching it.

Media


On February 27, 2011, when the first PACE trial paper was published, researchers Michael Sharpe and Trudie Chalder held a press conference to discuss their findings. Chalder stated, “twice as many people on graded exercise therapy and cognitive behaviour therapy got back to normal.” That assertion has been criticized for grossly overstating the study's actual findings.

The claims made about the study were covered uncritically in the UK and international press. For example, The Daily Mail stated, "Fatigued patients who go out and exercise have best hope of recovery", while The New York Times declared "Psychotherapy Eases Chronic Fatigue Syndrome". According to the British Medical Journal's report on the trial, some participants were "cured."

Many other PACE papers followed, although with relatively little media attention until October 2015, when long-term follow-up results were published in The Lancet Psychiatry. The Daily Telegraph ran a front-page story with the headline, "Exercise and positivity can overcome ME." The piece stated, "Chronic Fatigue Syndrome is not actually a chronic illness and sufferers can overcome symptoms by increasing exercise and thinking positively, Oxford University has found". The article quoted Professor Sharpe describing ME as a “self-fulfilling prophesy” that happens when patients live within their limits. The article was altered following public pressure but no formal retraction was made.

In the UK the Science Media Centre is a government-funded body that describes its purpose as being to improve science journalism. Its reporting on ME/CFS has been criticized for bias towards a psychological etiology for the disease.

Research and treatment
The PACE trial dominates clinical policy in the United Kingdom and other countries, both in government funded health care and private medical insurance.

Because the Oxford criteria definition of CFS is very broad (requiring six months of fatigue but not necessarily any other symptoms), PACE and other studies that use it are seen as muddying the research evidence-base by including patients with other conditions. It is for this reason that a 2015 report by the U.S. National Institutes of Health called for the Oxford definition to be retired, stating "continuing to use the Oxford definition may impair progress and cause harm".

PACE and other Oxford-definition studies have an impact on how ME/CFS patients are treated clinically through their impact on "evidence-based" clinical guidelines. For instance, in the U.K., the primary NHS treatment recommendations (the NICE guidelines ) are for cognitive behavioral therapy (CBT) and graded exercise therapy (GET), based largely on the results of Oxford-definition studies. In the U.S., these studies have led a number of medical education providers, including the CDC, to recommend CBT and GET and/or to link poor prognosis to a patient's belief that the disease is organic.

This impact of PACE and other Oxford-definition studies on clinical guidelines is still seen even though the 2015 Institute of Medicine report on ME/CFS stated that the disease is not psychological and is characterized by a systemic intolerance to even trivial activity. For example, UpToDate's clinical guidelines recommend the IOM criteria for diagnosis but PACE-style CBT and GET for treatment, even though such treatment would be inappropriate for patients diagnosed by the IOM criteria.

Selection of patients
The PACE trial used the Oxford criteria for diagnosis. Many patients and specialist clinicians consider them overly broad, and the National Institutes of Health 2015 P2P report on ME/CFS recommended that the Oxford definition be retired for this reason.

Changes in criteria for effectiveness and recovery


The authors abandoned their protocol-specified main outcome and recovery analyses partway through the trial and replaced them with others.

Most notably, they introduced post-hoc "normal ranges" for fatigue and physical function. These ranges have been heavily criticised for having thresholds so low that patients could worsen from trial entry and yet be within these normal ranges. The "normal range" for physical function (measured on the SF-36 100-point scale) was 60 and above, even though patients had to score 65 or lower to enter the trial. A score of 60 is close to the mean physical function score (57) of patients with Class II coronary heart failure.

The PACE authors used the "normal ranges", in conjunction with other thresholds, to define clinical effectiveness in the Lancet paper and recovery rates in a later paper in Psychological Medicine.

Results according to the protocol-specified analyses have never been published and all Freedom of Information requests for them or for the underlying data have been refused.

Use of subjective main outcome measures
The study has been criticised for having subjective primary analyses in an unblinded trial. Subjective measures are known to be susceptible to bias, as can arise from expectations and social pressure. The CBT and GET groups, but not the others, were told that there was nothing to stop them from recovering if they gradually increased their activity, and critics have argued that these differential expectations could have inflated their self-assessments.

Conflicts of interest and lack of informed consent
The forty-two scientists and clinicians who wrote an open letter to the Lancet complaining about the PACE trial criticized the study authors' failure to disclose a potential conflict of interest to trial participants. They wrote:

"'The investigators violated their promise in the PACE protocol to adhere to the Declaration of Helsinki, which mandates that prospective participants be 'adequately informed' about researchers’ “possible conflicts of interest.” The main investigators have had financial and consulting relationships with disability insurance companies, advising them that rehabilitative therapies like those tested in PACE could help ME/CFS claimants get off benefits and back to work. They disclosed these insurance industry links in The Lancet but did not inform trial participants, contrary to their protocol commitment. This serious ethical breach raises concerns about whether the consent obtained from the 641 trial participants is legitimate.'"

Newsletter to participants
The investigators published a newsletter for participants while the trial was still underway. Critics have said that this could have influenced patients' self-reported outcomes. There were a number of positive testimonials from patients in the trial, but they did not name their therapies. The PACE authors have argued that this meant that there would be no bias in favour of CBT and GET but Professor James Coyne has dismissed the idea that bias would be expected to affect the groups equally.

The newsletter did, however, announce that the new NICE guidelines, "based on the best available evidence... recommended therapies [that] include Cognitive Behavioural Therapy, Graded Exercise Therapy and Activity Management." There was no explanation of what "Activity Management" was: no group had that title in the PACE trial. Dr. Bruce Levin, a professor of biostatistics at Columbia University and an expert in clinical trial design, said, “To let participants know that interventions have been selected by a government committee ‘based on the best available evidence’ strikes me as the height of clinical trial amateurism”.

The newsletter also contained a less than positive assessment of research on the possibility of an infectious component of ME/CFS, including research by Jose Montoya on herpesviruses and by John Chia on enteroviruses. The newsletter said of Dr Chia's work, for example, "The laboratory work looked convincing, but many patients had significant gastro-intestinal symptoms and even signs, casting some doubt on the diagnoses of CFS being the correct or sole diagnosis in these patients." It is possible that this negative view of evidence of an ongoing infection would have made the rationale for APT appear less plausible and that for CBT and GET more plausible, thus biasing the participants.

An account of another study, in contrast, gave a positive assessment of CBT, saying "cognitive behaviour therapy was associated with an increase in grey matter of the brain and this increase was associated with improved cognitive function".

Risks and side effects
A survey conducted by the ME Association in 2012 showed that 74% of patients had their symptoms worsen after a course of GET. In contrast, the PACE trial found no apparently meaningful difference in rates of adverse events between the four trial groups, suggesting that APT, CBT and GET added no risk to SMC alone (since all four groups received SMC). However, critics have questioned whether patients actually increased their activity sufficiently in the CBT and GET groups to trigger many serious adverse events: the lack of improvement in the step-fitness test in all groups indicates that this is distinctly possible.

Response to criticism
The trial investigators have replied to criticism of the trial on a number of occasions, in response to letters to The Lancet concerning their main analyses, Psychological Medicine concerning their recovery analyses, and Lancet Psychiatry concerning their secondary mediation analyses and long-term follow-up paper. A letter to the BMJ by Tom Kindlon drew a reply from the authors that in turn received 31 responses of its own.

The investigators have also responded to a 14,000-word critique by public health expert and journalist Dr David Tuller. Dr Tuller wrote a rebuttal to their response. He has said, “The PACE authors have long demonstrated great facility in evading questions they don’t want to answer”.

Professor James Coyne reported that he agreed to debate the authors on health website National Elf about the trial but that they declined. Professor Simon Wessely was given the vacated National Elf spot and wrote a lengthy article praising the trial, noting that he once described it as "a thing of beauty" and saying, "It would be nice to think that perhaps we can now all move on. We can accept that PACE was a good trial and we can have some confidence in its findings".

Controversy
The PACE Trial has been heavily criticised by patient groups and some researchers and science journalists for a number of methodological problems since its publication. <ref name="viroblog2015110