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Background: Chronic Fatigue Syndrome (CFS) is characterised by persistent fatigue, disability and a range of other symptoms. The PACE trial was randomised to compare four non-pharmacological treatments for patients with CFS in secondary care clinics. The aims of this sub study were to describe the use of complementary and alternative medicine (CAM) in the trial sample and to test whether CAM use correlated with an improved outcome., Method: CAM use was recorded at baseline and 52weeks. Logistic and multiple regression models explored relationships between CAM use and both patient characteristics and trial outcomes., Results: At baseline, 450/640 (70%) of participants used any sort of CAM; 199/640 (31%) participants were seeing a CAM practitioner and 410/640 (64%) were taking a CAM medication. At 52weeks, those using any CAM fell to 379/589 (64%). Independent predictors of CAM use at baseline were female gender, local ME group membership, prior duration of CFS and treatment preference. At 52weeks, the associated variables were being female, local ME group membership, and not being randomised to the preferred trial arm. There were no significant associations between any CAM use and fatigue at either baseline or 52weeks. CAM use at baseline was associated with a mean (CI) difference of 4.10 (1.28, 6.91; p=0.024) increased SF36 physical function score at 52weeks, which did not reach the threshold for a clinically important difference., Conclusion: CAM use is common in patients with CFS. It was not associated with any clinically important trial outcomes., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: Chronic fatigue syndrome affects between 0.006% and 3% of the population depending on the criteria of definition used, with women being at higher risk than men., Methods and Outcomes: We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of selected treatments for chronic fatigue syndrome? We searched: Medline, Embase, The Cochrane Library, and other important databases up to November 2013 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review)., Results: At this update, searching of electronic databases retrieved 169 studies. After deduplication and removal of conference abstracts, 86 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 71 studies and the further review of 15 full publications. Of the 15 full articles evaluated, two systematic reviews, one RCT, and one further follow-up report of an RCT were added at this update. We performed a GRADE evaluation for 23 PICO combinations., Conclusions: In this systematic overview, we categorised the effectiveness of four interventions based on information relating to the effectiveness and safety of antidepressants, cognitive behavioural therapy, corticosteroids, and graded exercise therapy.

Objective: Adverse events (AEs) are health related events, reported by participants in clinical trials. We describe AEs in the PACE trial of treatments for chronic fatigue syndrome (CFS) and baseline characteristics associated with them., Methods: AEs were recorded on three occasions over one year in 641 participants. We compared the numbers and nature of AEs between treatment arms of specialist medical care (SMC) alone, or SMC supplemented by adaptive pacing therapy (APT), cognitive behaviour therapy (CBT) or graded exercise therapy (GET). We examined associations with baseline measures by binary logistic regression analyses, and compared the proportions of participants who deteriorated by clinically important amounts., Results: Serious adverse events and reactions were infrequent. Non-serious adverse events were common; the median (quartiles) number was 4 (2, 8) per participant, with no significant differences between treatments (P=.47). A greater number of NSAEs were associated with recruitment centre, and baseline physical symptom count, body mass index, and depressive disorder. Physical function deteriorated in 39 (25%) participants after APT, 15 (9%) after CBT, 18 (11%) after GET, and 28 (18%) after SMC (P<.001), with no significant differences in worsening fatigue., Conclusions: The numbers of adverse events did not differ significantly between trial treatments, but physical deterioration occurred most often after APT. The reporting of non-serious adverse events may reflect the nature of the illness rather than the effect of treatments. Differences between centres suggest that both standardisation of ascertainment methods and training are important when collecting adverse event data., (Copyright © 2013. Published by Elsevier Inc.)

Background: Pain is a common symptom of chronic fatigue syndrome (CFS). We investigated the effects of the treatments used in the PACE trial [cognitive behavioural therapy (CBT), graded exercise therapy (GET), adaptive pacing therapy (APT) and specialist medical care (SMC)] on pain in CFS., Method: We compared pain outcomes including individual painful symptoms, taken from the CDC criteria for CFS and co-morbid fibromyalgia. We modelled outcomes adjusting for baseline variables with multiple linear regression., Results: Significantly less frequent muscle pain was reported by patients following treatment with CBT compared to SMC (mean difference = 0.38 unit change in frequency, p = 0.02), GET versus SMC (0.42, p = 0.01) and GET versus APT (0.37, p = 0.01). Significantly less joint pain was reported following CBT versus APT (0.35, p = 0.02) and GET versus APT (0.36, p = 0.02). Co-morbid fibromyalgia was less frequent following GET versus SMC (0.03, p = 0.03). The effect sizes of these differences varied between 0.25 and 0.31 for muscle pain and 0.24 and 0.26 for joint pain. Treatment effects on pain were independent of 'change in fatigue'., Conclusions: CBT and GET were more effective in reducing the frequency of both muscle and joint pain than APT and SMC. When compared to SMC, GET also reduced the frequency of co-morbid fibromyalgia; the size of this effect on pain was small.

Background: The publication of protocols by medical journals is increasingly becoming an accepted means for promoting good quality research and maximising transparency. Recently, Finfer and Bellomo have suggested the publication of statistical analysis plans (SAPs).The aim of this paper is to make public and to report in detail the planned analyses that were approved by the Trial Steering Committee in May 2010 for the principal papers of the PACE (Pacing, graded Activity, and Cognitive behaviour therapy: a randomised Evaluation) trial, a treatment trial for chronic fatigue syndrome. It illustrates planned analyses of a complex intervention trial that allows for the impact of clustering by care providers, where multiple care-providers are present for each patient in some but not all arms of the trial., Results: The trial design, objectives and data collection are reported. Considerations relating to blinding, samples, adherence to the protocol, stratification, centre and other clustering effects, missing data, multiplicity and compliance are described. Descriptive, interim and final analyses of the primary and secondary outcomes are then outlined., Conclusions: This SAP maximises transparency, providing a record of all planned analyses, and it may be a resource for those who are developing SAPs, acting as an illustrative example for teaching and methodological research. It is not the sum of the statistical analysis sections of the principal papers, being completed well before individual papers were drafted., Trial Registration: ISRCTN54285094 assigned 22 May 2003; First participant was randomised on 18 March 2005.

Background: A multi-centre, four-arm trial (the PACE trial) found that rehabilitative cognitive behaviour therapy (CBT) and graded exercise therapy (GET) were more effective treatments for chronic fatigue syndrome (CFS) than specialist medical care (SMC) alone, when each was added to SMC, and more effective than adaptive pacing therapy (APT) when added to SMC. In this study we compared how many participants recovered after each treatment., Method: We defined recovery operationally using multiple criteria, and compared the proportions of participants meeting each individual criterion along with two composite criteria, defined as (a) recovery in the context of the trial and (b) clinical recovery from the current episode of the illness, however defined, 52 weeks after randomization. We used logistic regression modelling to compare treatments., Results: The percentages (number/total) meeting trial criteria for recovery were 22% (32/143) after CBT, 22% (32/143) after GET, 8% (12/149) after APT and 7% (11/150) after SMC. Similar proportions met criteria for clinical recovery. The odds ratio (OR) for trial recovery after CBT was 3.36 [95% confidence interval (CI) 1.64–6.88] and for GET 3.38 (95% CI 1.65–6.93), when compared to APT, and after CBT 3.69 (95% CI 1.77–7.69) and GET 3.71 (95% CI 1.78–7.74), when compared to SMC (p values < or =0.001 for all comparisons). There was no significant difference between APT and SMC. Similar proportions recovered in trial subgroups meeting different definitions of the illness., Conclusions: This study confirms that recovery from CFS is possible, and that CBT and GET are the therapies most likely to lead to recovery.

Background: The PACE trial compared the effectiveness of adding adaptive pacing therapy (APT), cognitive behaviour therapy (CBT), or graded exercise therapy (GET), to specialist medical care (SMC) for patients with chronic fatigue syndrome. This paper reports the relative cost-effectiveness of these treatments in terms of quality adjusted life years (QALYs) and improvements in fatigue and physical function., Methods: Resource use was measured and costs calculated. Healthcare and societal costs (healthcare plus lost production and unpaid informal care) were combined with QALYs gained, and changes in fatigue and disability; incremental cost-effectiveness ratios (ICERs) were computed., Results: SMC patients had significantly lower healthcare costs than those receiving APT, CBT and GET. If society is willing to value a QALY at £30,000 there is a 62.7% likelihood that CBT is the most cost-effective therapy, a 26.8% likelihood that GET is most cost effective, 2.6% that APT is most cost-effective and 7.9% that SMC alone is most cost-effective. Compared to SMC alone, the incremental healthcare cost per QALY was £18,374 for CBT, £23,615 for GET and £55,235 for APT. From a societal perspective CBT has a 59.5% likelihood of being the most cost-effective, GET 34.8%, APT 0.2% and SMC alone 5.5%. CBT and GET dominated SMC, while APT had a cost per QALY of £127,047. ICERs using reductions in fatigue and disability as outcomes largely mirrored these findings., Conclusions: Comparing the four treatments using a health care perspective, CBT had the greatest probability of being the most cost-effective followed by GET. APT had a lower probability of being the most cost-effective option than SMC alone. The relative cost-effectiveness was even greater from a societal perspective as additional cost savings due to reduced need for informal care were likely.

Background: Trial findings show cognitive behaviour therapy (CBT) and graded exercise therapy (GET) can be effective treatments for chronic fatigue syndrome, but patients' organisations have reported that these treatments can be harmful and favour pacing and specialist health care. We aimed to assess effectiveness and safety of all four treatments., Methods: In our parallel-group randomised trial, patients meeting Oxford criteria for chronic fatigue syndrome were recruited from six secondary-care clinics in the UK and randomly allocated by computer-generated sequence to receive specialist medical care (SMC) alone or with adaptive pacing therapy (APT), CBT, or GET. Primary outcomes were fatigue (measured by Chalder fatigue questionnaire score) and physical function (measured by short form-36 subscale score) up to 52 weeks after randomisation, and safety was assessed primarily by recording all serious adverse events, including serious adverse reactions to trial treatments. Primary outcomes were rated by participants, who were necessarily unmasked to treatment assignment; the statistician was masked to treatment assignment for the analysis of primary outcomes. We used longitudinal regression models to compare SMC alone with other treatments, APT with CBT, and APT with GET. The final analysis included all participants for whom we had data for primary outcomes. This trial is registered at http://isrctn.org, number ISRCTN54285094., Findings: We recruited 641 eligible patients, of whom 160 were assigned to the APT group, 161 to the CBT group, 160 to the GET group, and 160 to the SMC-alone group. Compared with SMC alone, mean fatigue scores at 52 weeks were 3·4 (95% CI 1·8 to 5·0) points lower for CBT (p = 0·0001) and 3·2 (1·7 to 4·8) points lower for GET (p = 0·0003), but did not differ for APT (0·7 [-0·9 to 2·3] points lower; p = 0·38). Compared with SMC alone, mean physical function scores were 7·1 (2·0 to 12·1) points higher for CBT (p = 0·0068) and 9·4 (4·4 to 14·4) points higher for GET (p = 0·0005), but did not differ for APT (3·4 [-1·6 to 8·4] points lower; p=0·18). Compared with APT, CBT and GET were associated with less fatigue (CBT p = 0·0027; GET p = 0·0059) and better physical function (CBT p=0·0002; GET p<0·0001). Subgroup analysis of 427 participants meeting international criteria for chronic fatigue syndrome and 329 participants meeting London criteria for myalgic encephalomyelitis yielded equivalent results. Serious adverse reactions were recorded in two (1%) of 159 participants in the APT group, three (2%) of 161 in the CBT group, two (1%) of 160 in the GET group, and two (1%) of 160 in the SMC-alone group., Interpretation: CBT and GET can safely be added to SMC to moderately improve outcomes for chronic fatigue syndrome, but APT is not an effective addition., Funding: UK Medical Research Council, Department of Health for England, Scottish Chief Scientist Office, Department for Work and Pensions., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Chronic fatigue syndrome (CFS, also called myalgic encephalomyelitis /encephalopathy or ME) is a debilitating condition with no known cause or cure. Improvement may occur with medical care and additional therapies of pacing, cognitive behavioural therapy and graded exercise therapy. The latter two therapies have been found to be efficacious in small trials, but patient organisations surveys have reported adverse effects. Although pacing has been advocated by patient organisations, it lacks empirical support. Specialist medical care is commonly provided but its efficacy when given alone is not established. This trial compares the efficacy of the additional therapies when added to specialist medical care against specialist medical care alone., Methods: 600 patients, who meet operationalised diagnostic criteria for CFS, will be recruited from secondary care into a randomised trial of four treatments, stratified by current co morbid depressive episode and different CFS/ME criteria. The four treatments are standardised specialist medical care either given alone, or with adaptive pacing therapy or cognitive behaviour therapy or graded exercise therapy. Supplementary therapies will involve fourteen sessions over 23 weeks and a booster session at 36 weeks. Outcome will be assessed at 12, 24, and 52 weeks after randomisation. Two primary outcomes of self-rated fatigue and physical function will assess differential effects of each treatment on these measures. Secondary outcomes include adverse events and reactions, subjective measures of symptoms, mood, sleep and function and objective measures of physical activity, fitness, cost-effectiveness and cost-utility. The primary analysis will be based on intention to treat and will use logistic regression models to compare treatments. Secondary outcomes will be analysed by repeated measures analysis of variance with a linear mixed model. All analyses will allow for stratification factors. Mediators and moderators will be explored using multiple linear and logistic regression techniques with interactive terms, with the sample split into two to allow validation of the initial models. Economic analyses will incorporate sensitivity measures., Discussion: The results of the trial will provide information about the benefits and adverse effects of these treatments, their cost-effectiveness and cost-utility, the process of clinical improvement and the predictors of efficacy.

Aims To review studies evaluating the treatment of chronic fatigue and chronic fatigue syndrome, to describe predictors of response to treatment and to discuss the role of the occupational health physician.Methods A literature search was carried out using Medline and PsychInfo.Results Studies evaluating cognitive behaviour therapy, graded exercise therapy, pharmacological interventions (e.g. antidepressants and corticosteroids), immunological interventions and nutritional supplements were reviewed. The most promising results have been found with cognitive behaviour therapy and graded exercise therapy, and some predictors of outcome have been identified. Most of the other interventions were evaluated in just one or two studies and therefore evidence is insufficient to draw firm conclusions.Conclusions By applying the models of fatigue that form the bases for cognitive behaviour therapy and graded exercise therapy, occupational health physicians may play an important role in helping the patients with chronic fatigue syndrome to reduce their symptoms, improve their functioning and return to work. [ABSTRACT FROM AUTHOR]