Rehabilitative treatments for chronic fatigue syndrome: long-term follow-up from the PACE trial

Summary

Background

The PACE trial found that, when added to specialist medical care (SMC), cognitive behavioural therapy (CBT), or graded exercise therapy (GET) were superior to adaptive pacing therapy (APT) or SMC alone in improving fatigue and physical functioning in people with chronic fatigue syndrome 1 year after randomisation. In this pre-specified follow-up study, we aimed to assess additional treatments received after the trial and investigate long-term outcomes (at least 2 years after randomisation) within and between original treatment groups in those originally included in the PACE trial.

Methods

The PACE trial was a parallel-group randomised controlled trial of patients meeting Oxford criteria for chronic fatigue syndrome who were recruited from six secondary care clinics in the UK between March 18, 2005, and Nov 28, 2008. Participants were randomly allocated to receive SMC alone or plus APT, CBT, or GET. Primary outcomes (were fatigue measured with Chalder fatigue questionnaire score and physical functioning with short form-36 subscale score, assessed 1 year after randomisation. In this long-term follow-up, we sent postal questionnaires to assess treatment received after the trial and outcomes a minimum of 2 years after randomisation. We assessed long-term differences in outcomes within and between originally randomised groups. The PACE trial is registered at http://isrctn.org , number ISRCTN54285094.

Findings

Between May 8, 2008, and April 26, 2011, 481 (75%) participants from the PACE trial returned questionnaires. Median time from randomisation to return of long-term follow-up assessment was 31 months (IQR 30–32; range 24–53). 210 (44%) participants received additional treatment (mostly CBT or GET) after the trial; with participants originally assigned to SMC alone (73 [63%] of 115) or APT (60 [50%] of 119) more likely to seek treatment than those originally assigned to GET (41 [32%] of 127) or CBT (36 [31%] of 118; p<0·0001). Improvements in fatigue and physical functioning reported by participants originally assigned to CBT and GET were maintained (within-group comparison of fatigue and physical functioning, respectively, at long-term follow-up as compared with 1 year: CBT −2·2 [95% CI −3·7 to −0·6], 3·3 [0·02 to 6·7]; GET −1·3 [–2·7 to 0·1], 0·5 [–2·7 to 3·6]). Participants allocated to APT and to SMC alone in the trial improved over the follow-up period compared with 1 year (fatigue and physical functioning, respectively: APT −3·0 [–4·4 to −1·6], 8·5 [4·5 to 12·5]; SMC −3·9 [–5·3 to −2·6], 7·1 [4·0 to 10·3]). There was little evidence of differences in outcomes between the randomised treatment groups at long-term follow-up.

Interpretation

The beneficial effects of CBT and GET seen at 1 year were maintained at long-term follow-up a median of 2·5 years after randomisation. Outcomes with SMC alone or APT improved from the 1 year outcome and were similar to CBT and GET at long-term follow-up, but these data should be interpreted in the context of additional therapies having being given according to physician choice and patient preference after the 1 year trial final assessment. Future research should identify predictors of response to CBT and GET and also develop better treatments for those who respond to neither.

Funding

UK Medical Research Council, Department of Health for England, Scottish Chief Scientist Office, Department for Work and Pensions, National Institute for Health Research (NIHR), NIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust, King's College London.

Introduction

Chronic fatigue syndrome is characterised by chronic disabling fatigue in the absence of an alternative diagnosis (panel). Myalgic encephalomyelitis is thought by some people to be the same disorder and by others to be a different disease. The prevalence of chronic fatigue syndrome is between 0·2% and 2·6% of people worldwide,⁵ and, if untreated, prognosis for recovery is poor.⁶

In March, 2005, we started the PACE trial, a multicentre randomised trial to compare outcomes after the most commonly used non-pharmacological treatments in patients with chronic fatigue syndrome.⁷ When we planned the trial, some evidence had shown that cognitive behavioural therapy (CBT) and graded exercise therapy (GET) could improve patient outcomes. However, these rehabilitative treatments were controversial among patient organisations who regarded adaptive pacing therapy (APT) and specialist medical care (SMC) as better alternatives. The PACE trial aimed to compare the outcomes of patients who were randomly allocated to one of the following four interventions: SMC alone, SMC plus APT, SMC plus CBT, or SMC plus GET. The trial found that at 1 year (52 weeks) follow-up from randomisation, patients allocated to CBT or GET had significantly greater improvements in their fatigue and physical functioning than had those allocated to either APT or to SMC alone.⁷

Research in context

Evidence before this study

For the original PACE trial report, we searched PubMed and the Cochrane Library for articles about non-pharmacological interventions for chronic fatigue syndrome published up to Nov 6, 2010. The previous Research in context panel concluded that the untreated outcome for patients with chronic fatigue syndrome was poor, and that evidence existed that cognitive behavioural therapy (CBT) and graded exercise therapy (GET) improved this. The PACE trial confirmed that CBT and GET with specialist medical care (SMC) were more effective than SMC alone in improving fatigue and physical functioning 1 year after randomisation, but that adaptive pacing (APT) plus SMC was not.

For this study we searched PubMed to Feb 1, 2015 for follow-up studies of more than 1 year in patients who had received a PACE trial treatment. The reports identified were almost all of small studies of CBT. They suggested that the benefits from CBT are maintained. We did not find any long-term follow-up study after GET (although a single follow-up of an educational intervention that included advice on graded activity found the benefits were maintained) or APT.

Added value of this study

This follow-up of participants in the PACE trial provides robust evidence that the improvements in fatigue and function with CBT and GET are maintained in the longer-term (after 2·5 years). It does not provide evidence that CBT and GET are better than SMC and APT in the longer term because patients allocated to these treatments had improved to a similar degree by the time of the follow-up. The interpretation of this finding is complicated by the fact that many of these patients had received CBT or GET after the trial final follow-up assessment. Importantly, no significant worsening in perceived health occurred during the follow-up period after any of the trial treatments.

Implications of all the available evidence

Taken together, the available evidence confirms that the rehabilitative treatments of CBT and GET for chronic fatigue syndrome are associated with long-term improvement in fatigue and functioning for patients with chronic fatigue syndrome. However, the observation that some patients remain unwell at long-term follow-up reminds us that more effective treatments are still needed for these patients.

Other long-term follow-up studies of participants in trials of treatments for chronic fatigue syndrome have been reported.8, 9, 10, 11, 12 We report the findings of a pre-specified long-term (minimum 2 years after randomisation) follow-up of the PACE trial participants. After the final 1 year trial outcome, participants were able to access additional trial therapies according to need. We aimed to describe additional therapy (APT, CBT, GET) that participants received after 1 year; compare the outcomes of participants within each randomised treatment group at long-term follow-up with the final 1 year outcome assessment; and compare the long-term outcomes between the original randomised trial treatment groups, bearing in mind the limitations on interpretation imposed by the provision of additional, non-randomly allocated therapy during the post-trial follow-up period.