The Lancet, Early Online Publication, 17 May 2011
doi:10.1016/S0140-6736(11)60651-X
The PACE trial in chronic fatigue syndrome Authors' reply
PD White a, KA Goldsmith b, AL Johnson c d, R Walwyn b, HL Baber a, T Chalder e, M Sharpe f, on behalf of the coauthors
The PACE trial for patients with chronic fatigue syndrome (CFS) found that supplementation of specialist medical care with either cognitive behaviour therapy or graded exercise therapy was more effective in reducing fatigue and physical disability than was supplementation of specialist medical care with adaptive pacing therapy or specialist medical care alone. We chose patient-rated measures of fatigue and physical function as primary outcomes because this is how the disorder is defined.
The commonest concern of correspondents was our conclusion that these differences indicated moderate clinical usefulness. We based this conclusion on standard recommendations. First, we predefined a clinically useful difference between treatment group means for both primary outcomes, using the conventional criterion of 05 SD of baseline values;1 seven of eight comparisons between either cognitive behaviour therapy or graded exercise therapy and either adaptive pacing therapy or specialist medical care exceeded this difference. Second, we determined the proportion of participants who had improved by a predefined clinically useful amount by both primary outcomes at 1-year follow-up: 59% and 61% after cognitive behaviour therapy and graded exercise therapy versus 42% and 45% after adaptive pacing therapy and specialist medical care, respectively. Third, we calculated the proportions within the general population normal ranges for both primary outcomes at 1 year: 30% and 28% after cognitive behaviour therapy and graded exercise therapy versus 16% and 15% after adaptive pacing therapy and specialist medical care, respectively. Fourth, we interpreted the overall pattern of treatment comparisons across all outcomes,2 including the proportions of participants who rated themselves as very much or much better in their overall health: 41% after both cognitive behaviour therapy and graded exercise therapy versus 31% after adaptive pacing therapy and 25% after specialist medical care.
We determined the normal range by use of the conventional mean plus or minus 1 SD from what we regarded as the most relevant general population data. For physical function, this was a demographically representative sample (in our paper we stated that this was a UK working-age population, whereas more accurately this should have been an English adult population).3 For fatigue, this was a population sample of patients registered with a general practitioner in the southeast of England, who had consulted for a health problem at some time in the year after completion of the fatigue measure (ie, they were not consulting at the time). It is important to clarify that our paper did not report on recovery; we will address this in a future publication.
Changes to the original published protocol were made to improve either recruitment or interpretability, such as changing the proposed composite primary outcomes to single continuous scores. The analysis was guided by a Statistical Analysis Strategy (which we intend to publish), which was completed before analysis of outcome data, and which was much more detailed than the plan in the protocol; this is now conventional in the conduct of clinical trials. The eight secondary outcomes presented in our paper were selected for clinical relevance. All these decisions and plans were approved by the Trial Steering Committee, were fully reported in our paper, and were made before examining outcome data to avoid outcome reporting bias.
The safety of patients was a very important aspect of our trial and was measured in five distinct ways, using definitions and reporting standards of the European Union Clinical Trials Directive for medicinal products.4 Before the trial, patient organisations were most concerned about graded exercise therapy, which the trial found to be as safe as the other treatments, even though it increased physical activity (walking) more than the other treatments. The way treatments are delivered in a trial does not necessarily generalise to clinical practice, which is why we emphasised the importance of treatment delivery by appropriately qualified clinicians, who are properly trained and supervised.
PACE trial participants represented typical secondary-care CFS patients: young to middle-aged, significantly disabled, and ill for a mean of 27 years. The commonest reason for ineligibility of those screened in clinics was not having CFS, and the commonest stated reason for declining research assessment or randomisation was a clear preference for a specific PACE trial treatment. The findings do not generalise to the most disabled patients, as we only included those able to attend hospital regularly.
There are several descriptions of pacing, which is why we standardised it as adaptive pacing therapy. The manuals for this and the other treatments are available on the trial website. 84% of participants in adaptive pacing therapy regarded adaptive pacing therapy as logical before treatment, and 85% were satisfied with it after treatment, which suggests that they were not confused by it.
In conclusion, however we compared the results and however we defined CFS and myalgic encephalomyelitis, we found that cognitive behaviour therapy and graded exercise therapy provided a significant and clinically useful advantage of moderate size over adaptive pacing therapy and specialist medical care, but were no less safe. We suggest that the issue is not whether these treatments work and are safe, but how to make them available to those who might benefit from them.
We declare that we have no conflicts of interest other than those described in the original paper.
References
1 Guyatt GH, Osaba D, Wu AW, et al. Methods to explain the clinical significance of health status measures. Mayo Clinic Proc 2002; 77: 371-383. PubMed
2 Bowling A, Bond M, Jenkinson C, Lamping DL. Short form 36 (SF-36) health survey questionnaire: which normative data should be used? Comparisons between the norms provided by the Omnibus Survey in Britain, the Health Survey for England and the Oxford Healthy Life Survey. J Public Health Med 1999; 21: 255-270. PubMed
3 Dworkin RH, Turk DC, McDermott MP, et al. Interpreting the clinical importance of group differences in chronic pain clinical trials: IMMPACT recommendations. Pain 2009; 146: 238-244. CrossRef | PubMed
4 White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn Ron behalf of the PACE trial group. Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurol 2007; 7: 6. CrossRef | PubMed
a Barts and the London School of Medicine, Queen Mary University London, London EC1A 7BE, UK
b Mental Health and Neuroscience Clinical Trials Unit, Institute of Psychiatry, King's College London, London, UK
c Medical Research Council Biostatistics Unit, Institute of Public Health, University of Cambridge, Cambridge, UK
d Medical Research Council Clinical Trials Unit, London, UK
e Academic Department of Psychological Medicine, King's College London, London, UK
f Psychological Medicine Research, School of Molecular and Clinical Medicine, University of Edinburgh, Edinburgh, UK
