Rethinking the treatment of chronic fatigue syndrome—a reanalysis and evaluation of findings from a recent major trial of graded exercise and CBT

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Abstract

Background

The PACE trial was a well-powered randomised trial designed to examine the efficacy of graded exercise therapy (GET) and cognitive behavioural therapy (CBT) for chronic fatigue syndrome. Reports concluded that both treatments were moderately effective, each leading to recovery in over a fifth of patients. However, the reported analyses 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.

Methods

Here, we present results based on the original protocol-specified procedures. Data from a recent Freedom of Information request enabled us to closely approximate these procedures. We also evaluate the conclusions from the trial as a whole.

Results

On the original protocol-specified primary outcome measure – overall improvement rates – there was a significant effect of treatment group. However, the groups receiving CBT or GET did not significantly outperform the Control group after correcting for the number of comparisons specified in the trial protocol. Also, rates of recovery were consistently low and not significantly different across treatment groups. Finally, on secondary measures, significant effects were almost entirely confined to self-report measures. These effects did not endure beyond two years.

Conclusions

These findings raise serious concerns about the robustness of the claims made about the efficacy of CBT and GET. 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.

Keywords

Chronic fatigue syndromeMyalgic encephalomyelitisGraded exercise therapyCognitive behavioral therapy

Background

For some time now, the officially recommended treatments for chronic fatigue syndrome (CFS) in many countries have been graded exercise therapy (GET) and cognitive behavioural therapy (CBT). In an effort to provide high quality evidence of the efficacy of these treatments, White and colleagues undertook a large randomised trial, informally referred to as the PACE trial [1]. Reports from the PACE trial concluded that GET and CBT were moderately effective treatments for CFS, both leading to recovery in over a fifth of patients [2, 3, 4, 5, 6, 7]. The trial’s size and its promotion as a success have made it enormously influential in the attempt to treat CFS [8].

However, there are some significant concerns with the published reports of the trial. First, the outcomes and analyses presented in these reports did not always follow the procedures set out in the original published protocol [1]. Since the purpose of a trial protocol is to prevent ad hoc modifications that may unduly favour the study hypotheses, it is important to carefully scrutinise the justification for these changes and how they may have influenced outcomes. Also, it is unclear whether some of the trial’s conclusions about treatment efficacy were fully justified by the evidence. Here, we present several new analyses of the trial data, using methods that align with those specified in the original trial protocol, and drawing on data recently made available as part of a Freedom of information application ([9]). This dataset, henceforth referred to as the FOIA dataset, is available to the public (see Declarations section for instructions on how to download the dataset). We also explore several other aspects of the findings not considered in the published reports, and evaluate the conclusions from the trial as a whole.

Summary of the PACE trial

PACE was a large randomised trial whose primary aim was to assess the effectiveness of GET and CBT as treatments for CFS (early publications refer to it as a “randomised controlled trial”, but “randomised trial” is more appropriate, given that several nuisance variables were not fully controlled across trial arms, e.g., contact hours). Participants were 641 adults with mild-to-moderate CFS defined by the Oxford criteria [10]: the principal symptom must be fatigue, which must have had a definite onset, resulted in significant disability, and have persisted for at least six months. Participants also had to score 65 or less on the Short-Form Health Survey Physical Function subscale [11]. Also, they had to report experiencing at least six of the 11 fatigue items on the Chalder Fatigue Questionnaire (CFQ [12]), as “more than” or “much more than” than prior to illness.

Participants were randomised into four groups. All were offered at least three medical consultations. The first group, which we will call Control, received no further treatment (the trial publications use the term Specialised Medical Care). The other groups received up to 15 therapy sessions over 36 weeks. One group received CBT, one GET, and the fourth group received a novel treatment, Adaptive Pacing Therapy. Both the CBT and the GET interventions were built upon a behavioural/deconditioning model of CFS. This model proposes that there is no major ongoing disease process underlying CFS – only deconditioning due to recent inactivity, and its various consequences. When patients attempt to increase their activity, they experience normal fatigue, stiffness and other symptoms, which they misinterpret as signs of continuing disease. The patients then become more focused on their symptoms, and fearful of further activity, creating a self-perpetuating cycle [2]. The GET programme was designed to help CFS patients overcome this purported fear of exercise and intense symptom-focusing through graded exposure to exercise, and thereby also reverse any deconditioning that had occurred. Participants were asked to choose an aerobic activity they enjoyed, and to gradually increase the duration and intensity of that activity under the supervision of a therapist. The CBT programme had similar aims, but addressed the fear of activity, maladaptive illness beliefs and symptom focusing using a combination of CBT and practical activities ([2], p. 825). Participants were encouraged to view their symptoms as arising from anxiety, intense symptom focusing and/or deconditioning. The sessions addressed fears about exercise and other “unhelpful cognitions” that may perpetuate symptoms, and encouraged participants to try gradually increasing their activity ([2], p. 825).

Adaptive Pacing Therapy, in which patients were advised not to exceed a certain level of activity, was created specifically for the trial. Results for this trial arm did not differ significantly from those for the Control arm for any of the outcomes considered in this article. Consequently, we will not discuss them further here.

Primary outcomes

The primary outcome for the trial, as specified in the trial protocol published in 2007, was the percentage of patients who fulfilled the specified criteria for overall improvement 52 weeks after randomisation [1]. Two measures contributed to the definition of improvement: self-rated fatigue, measured using the Chalder Fatigue Questionnaire [12], and self-rated disability, measured using the SF-36 Physical Function subscale [11]. The minimum levels of improvement required on each of these two measures are given in Table 1 (Definition A). However, in May 2010, several months after data collection was complete, this primary outcome measure was replaced with two continuous measures: fatigue and physical function ratings on the two scales described above (see [13, 14] for details). According to the researchers, the changes were made “before any examination of outcome data was started…” ([13], p. 25).
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