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What was the PACE trial?

Action for M.E.’s current research strategy focuses on collaborative biomedical research, including funding PhD studentships and working closely with patients, clinicians and researchers as part of the UK CFS/M.E. Research Collaborative.

In the past, we have supported all forms of research into M.E. As part of this strategy, the charity was asked to be involved in a large-scale randomised controlled trial, called the PACE trial. Scroll down for more about our previous role in the PACE trial, and our position now.

Two of the treatment approaches test in the PACE trial – cognitive behavioural therapy (CBT), and graded exercise therapy (GET) – are based on the theory that the debility of the disease is the result of deconditioning which is the result of a fear of activity, focusing on symptoms, and unhelpful ways of thinking.

Findings published in 2011 indicated that patients treated with CBT and GET (alongside specialist medical care) experienced moderate improvement in self-rated fatigue and physical function, more than those who used adaptive pacing therapy or specialist medical care alone.

Follow-up results published in 2013 indicated a 59 to 61% improvement, and 22% recovery, for patients who used CBT and/or GET compared to adaptive pacing therapy and/or specialist medical care. It should be noted that "recovery" did not mean that the patient returned to the levels of health and fitness they had before they were diagnosed with M.E.


CBT in the PACE trial

CBT was defined in the therapist’s manual for the PACE trial as “complex incremental pacing” which involves “elements of simple pacing to stabilise activity, graded increases in activity […] and also directly addresses participant’s beliefs and fears about their symptoms and functioning.”

This type of CBT is based on a theoretical model defined in 2015, which “supposes that unhelpful interpretations of symptoms, fearful beliefs about engaging in activity, and excessive focus on symptoms are central in driving disability and symptom severity. These cognitive responses are associated with unhelpful behavioural patterns, including avoidance of activity or all-or-nothing behaviour – a pattern of excessive resting alternating with pushing too hard or being overactive when well.” An example of a “fear-avoidance belief” is given as follows: “I am afraid that I will make my symptoms worse if I exercise.”

However, studies have demonstrated that even mild exercise can provoke symptoms in some patients – so fears about the consequences of exercise are well-founded.


GET in the PACE trial

The aim of the GET approach tested in the PACE trial, as defined in the trial manual, was to: “help the participant to gradually engage and participate in physical activity and aerobic exercise [….].” The approach is based on the assumption that “CFS/ME is perpetuated by deconditioning (lack of fitness), reduced physical strength and altered perception of effort consequent upon reduced physical activity.”

However, the International Alliance for M.E.’s 2018 consensus document on M.E. [LINK] says: “People with ME cannot reproduce their performance on a maximal exercise test 24 hours later, despite showing maximal effort, unlike healthy controls, those who are deconditioned (National Academy of Medicine, 2015), those who have cardiopulmonary diseases (Keller et al, 2014), or those with multiple sclerosis (Hodges et al, 2017). This suggests that the theory underlying CBT and GET studies that the debility of M.E. is a result of deconditioning is flawed.

M.E. is a complex, multi-system disease involving neurological, immunological, autonomic, and energy metabolism impairments. The debility in M.E. is much greater than is seen with deconditioning, and studies have demonstrated that even mild exercise can provoke symptoms – so fears about the consequences of exercise are well-founded.


Questions and concerns

Serious concerns about the PACE trial are well documented, with repeated questions raised about its methodology, and the reliability of its results. An open letter to The Lancet, signed by more than 100 scientists, clinicians, parliamentarians and patient organisations, including Action for M.E., has been sent three times, asking the journal to reanalyse the trial’s findings.

Concerns about the trial include:

  • broad criteria for entry into the trial meant that patients who did not experience post-exertional malaise were included, so it cannot be assumed that the results of the trial apply to patients who have this symptom (see below)
  • the PACE trial did not use objective measures to assess the effectiveness of CBT and GET, but instead relied on subjective measures, ie. reporting by patients, which can be unreliable
  • the models of GET and CBT used in the PACE trial assume that M.E. is perpetuated by deconditioning (lack of fitness); however, significant studies disagree that deconditioning is the cause of M.E. and/or CFS, and is in fact a consequence of the condition
  • the GET and CBT approaches tested were delivered under trial conditions, which are unlikely to be replicated in the real world
  • changes to the recovery criteria part-way through the trial meant that “it was possible to score below the level required for trial entry, yet still be counted as ‘recovered’” (Wilshire et al, 2016)
  • the original analysis of the study data “did not consistently follow the procedures set out in the published protocol, and it is unclear whether the conclusions are fully justified by the evidence” (Wilshire et al, 2018)
  • rates of recovery were consistently low and not significantly different across treatment groups, and that “the modest treatment effects obtained on self-report measures in the PACE trial do not exceed what could be reasonably accounted for by participant reporting biases” (Wilshire et al, 2018).

In 2019, the PACE trial authors responded to the re-analysis of trial data referenced above, concluding that, “after carefully reviewing Wilshire et al’s criticisms of the PACE trial findings, we can find no good reason to change its conclusions.”

In a subsequent rejoinder, Carolyn Wilshire and co-author Tom Kindlon highlight that “the PACE authors view the trial protocol as a preliminary plan, subject to honing and improvement as time progresses, whereas we view it as a contract that should not be broken except in extremely unusual circumstances. While the arguments presented by [PACE trial author] Sharpe and colleagues inspire some interesting reflections on the scientific process, they fail to restore confidence in the PACE trial’s conclusions.”

Research into M.E. and/or CFS uses a range of criteria to define the illness being studied. There are in fact more than 20 sets of M.E. and/or CFS case definitions and diagnostic criteria which vary on specificity and sensitivity.

Some do not require hallmark symptoms of M.E. – such as post-exertional malaise – to be present, including the 2005 Reeves, 1994 Fukuda and 1991 Oxford CFS definitions; the latter has, according to a 2014 evidence review by the Agency for Healthcare Research and Quality in the US, a “high risk of including patients who may have an alternate fatiguing illness, or whose illness resolves spontaneously with time” (Smith et al, 2014).

Based on its comparison of definitions, a 2015 National Academy of Medicine report concludes that “the diagnostic criteria for ME have required the presence of specific or different symptoms from those required by the diagnostic criteria for CFS; thus, a diagnosis of CFS is not equivalent to a diagnosis of ME.”


Action for M.E. and the PACE trial

Two of the charity’s previous Chief Executives (prior to 2011) served as independent members of the Trial Steering Committee, and sat on the Trial Management Group. Action for M.E. did not receive any payment for this, and made no contribution to the funding of the trial.

In August 2018, our Chief Executive (since September 2012) said: “By having a role on the Steering Committee and Management Group, there was a de facto endorsement of the use of £5m of research funding to focus on behavioural treatments. Neither I nor the current Board of Trustees would agree to do this now, as reflected by our current research strategy, the focus of which is collaborative biomedical research.

“I am sorry that the charity did not advocate for this considerable level of funding to be invested in biomedical research instead. It was never our intention to contribute to any stigma or misunderstanding about the illness and I sincerely apologise to those who feel that, in not speaking out sooner and more strongly, we have caused harm.

“We will learn from our past mistakes. We will continue to provide practical support to our Supporting Members and others with M.E., to challenge the stigma and neglect they experience, and work with professionals and policy-makers to transform the lives of children, young people and adults with M.E. in the future.”

Action for M.E. does not support any treatment approach:

  • based on the deconditioning hypothesis
  • in which patients’ legitimate concerns about the consequences of exercise are dismissed or ignored.

We fully support treatment approaches which:

  • aim to reduce and stabilise symptoms before any appropriate increase in activity levels is attempted
  • put the person with M.E./CFS in charge of the aims and goals of the overall management plan.


Other published evidence

A 2014 evidence review by the Agency for Healthcare Research and Quality (AHRQ) in the US found that GET “improved measures of fatigue, function, and clinical global impression of change compared with controls;" while a 2017 Cochrane review of exercise therapy for M.E./CFS identified that “moderate-quality evidence showed exercise therapy was more effective at reducing fatigue compared to ‘passive’ treatment or no treatment. Exercise therapy had a positive effect on people’s daily physical functioning, sleep and self-ratings of overall health.”

However, both reviews included studies using the 1991 Oxford criteria, which may include patients with other fatiguing conditions, giving misleading results.

In 2016, the AHRQ reanalysed the evidence after excluding Oxford-criteria studies and found insufficient evidence of effectiveness for GET, noting that studies using definitions requiring hallmark criteria such as post-exertional malaise were “blatantly missing.” It concluded that the Oxford criteria comes with a “high risk of including patients who may have an alternate fatiguing illness, or whose illness resolves spontaneously with time.”

In 2019, Cochrane published an update of its review of GET for M.E./CFS, having set out its intention the previous year to respond to questions concerning its methodology. However, the review remains based on what is now a very outdated protocol, using a research question and methodology from 2002; and only including eight randomised controlled trials that relied on the Oxford criteria and/or the 1994 Centers for Disease Control and Prevention criteria for M.E./CFS, including the PACE trial.

Action for M.E. does not support Cochrane's conclusion that GET “probably has a positive effect on fatigue in adults with CFS compared to usual care or passive therapies. The evidence regarding adverse effects is uncertain. Due to limited evidence it is difficult to draw conclusions about the comparative effectiveness of CBT, adaptive pacing or other interventions.”

Cochrane’s Editor-in-Chief, Dr Karla Soares-Weiser has acknowledged that “a new approach to the publication of evidence in this area is needed; and, today we are committing to the production of a full update of this Cochrane Review, beginning with a comprehensive review of the protocol, which will be developed in consultation with an independent advisory group that we intend to convene. This group will involve partners from patient-advocacy groups from different parts of the world who will help us to embed a patient-focused, contemporary perspective on the review question, methods and findings. By forging better relationships with patients, as well as the groups that represent them and the clinicians who seek to treat them, we can improve the way in which future Cochrane Reviews in this area address important questions and meet patients’ and clinicians’ needs.”

We are encouraged by Dr Soares-Weiser’s commitment to meaningful collaboration with patients, and a comprehensive update of the Cochrane Review of GET for M.E./CFS, which will begin early 2020.