The benefits reported for psychotherapy and exercise therapy in a recent major trial of chronic fatigue syndrome are modest and not statistically reliable when reanalyzed using the trial’s original published protocol, according to a study published in the open access journal BMC Psychology.
The PACE trial was a randomized trial designed to examine the effectiveness of graded exercise therapy (GET) and cognitive behavioral therapy (CBT) for chronic fatigue syndrome (CFS). The results of the trial, published across a number of journals, 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 trial’s original protocol. Using trial data obtained under a Freedom of Information request, the authors of the latest study recalculated the results of the PACE trial based on procedures specified in the original protocol (published in BMC Neurology in 2007).
Lead author Carolyn Wilshire, said: “Our reanalysis was designed to explore how the PACE trial outcomes would have looked if the investigators had adhered to the primary outcome they described in their original published protocol. We also looked into the published data on long-term outcomes to examine whether they had been influenced by the treatments patients had received after the trial had ended.
“We found that 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. Rates of recovery were consistently low and not significantly different across treatment groups.”
In the PACE trial, 641 participants were randomized into four groups: a control group, a CBT group, a GET group, and a fourth group that received a novel treatment, Adaptive Pacing Therapy (APT).
The primary outcome for the trial, as specified in the protocol published in 2007, was the percentage of patients showing overall improvement 52 weeks after randomization. Two measures contributed to the definition of improvement: self-rated fatigue and self-rated disability. However, in May 2010, this primary outcome measure was replaced with two continuous measures: fatigue and physical function ratings.
In 2011, the first major publication from the trial reported results based on this new primary outcome. It was found that, following treatment, scores on both these continuous measures improved in all groups, but significantly more so in the CBT and GET groups; 59% of CBT participants and 61% of GET participants were classed as having improved overall. However, 45% of control participants did so too.
Based on the protocol-specified definition of improvement, the reanalysis found that 20% of CBT patients and 21% of GET patients improved, along with 10% of control patients. These percentages accord with those calculated by the PACE investigators and posted to the Primary Investigator’s institutional website shortly after researchers were directed to release the data under FOI legislation.
A secondary outcome in the protocol was the proportion of patients who met the specified definition of recovery at the end of the trial. The definition of recovery considered each participant’s scores on two key self-rated measures (fatigue, physical function), one further measure of overall self-rated improvement and finally, whether the participant still met various CFS case definitions.
However, results for this outcome did not appear in published research articles. Instead, a 2013 paper reported recovery rates based on a more generous definition of recovery. According to these new criteria, 22% of patients in each of the CBT and GET groups qualified as recovered, but only 7% in the control group.
In the reanalysis, using the protocol-specified definition of recovery and recalculating using two different approaches, rates of recovery never exceeded 8% in any treatment group, and there were no statistically significant effects of treatment on recovery rates.
The original investigators did a two-year follow-up study, and at this time, there were no statistically reliable differences amongst treatment groups in levels of self-reported fatigue and physical function. It was suggested that many participants had engaged in additional CBT or GET after the trial had ended, which may have obscured any apparent differences amongst treatment groups. However, the new study isolated scores for those patients who did not receive any post-trial CBT or GET, and found that even for this subgroup, there was no evidence of any long-term treatment-related benefits.
Wilshire and colleagues conclude that “Until there is positive evidence to suggest otherwise, the conclusion we must draw is that PACE’s treatment effects are not sustained over the long term, not even on self-report measures. CBT and GET have no long-term benefits at all. Patients do just as well with good basic medical care.”
Wilshire also said that “An additional, major problem with the PACE trial is that the primary measures were based on participants’ self-assessments. These can be highly misleading when people know exactly which treatment they’re getting. Some groups were even assured their treatment was ‘highly effective’, even though this was the very question the trial set out to answer. As a result, people are likely to have rated their improvements as greater than they actually were. To be sure the effects were genuine, we would need to see accompanying objective improvements, such as an increase in people’s activity or employment hours. These were not observed. Therefore, findings of the trial cannot safely be used to support behavioural interventions for chronic fatigue syndrome”
Limitations of the reanalysis include the use of the dataset obtained under FOI legislation, which was not as complete as the original dataset. The analyses did not incorporate a number of important stratification variables that were unavailable in the FOI dataset.
The authors caution that their re-examination of long-term data was informal, as full replication of the 2015 analysis was not possible with the available data. The analyses did not include important potentially confounding variables that might differ amongst trial arms, and a comprehensive analysis might possibly produce a different result.
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Notes to editor
1. Rethinking the treatment of chronic fatigue syndrome - a reanalysis and evaluation of findings from a recent major trial of graded exercise and CBT. Wiltshire et al (2018), BMC Psychology. DOI: 10.1186/s40359-018-0218-3
The article is available at the journal website.
2. BMC Psychology is an open access, peer-reviewed journal that considers manuscripts on all aspects of psychology, human behavior and the mind, including developmental, clinical, cognitive, experimental, health and social psychology, as well as personality and individual differences. The journal welcomes quantitative and qualitative research methods, including animal studies.
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