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.
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