White 2011.

Study characteristics
Methods	RCT, multicentre, 4 parallel arms
Participants	Diagnostic criteria: Oxford (56% satisfied London ME criteria) Number of participants: n = 641 Gender: 495 (77%) female Age, mean (SD): 38 (12) years Earlier treatment: NS Co‐morbidity: 219 (34%) with any depressive disorder, 260 (41%) used ADs Illness duration: median 32 (IQR 16‐68) months (GET 35 (18‐67); SMC 25 (15‐57) months) Work and employment status: mean baseline score at the work and social adjustment scale, 27.4 Setting: secondary/tertiary care Country: UK
Interventions	Group 1, SMC: provided by doctors with specialist experience in CFS. All participants were given a leaflet explaining the illness and the nature of this treatment. Treatment consisted of an explanation of CFS, generic advice such as to avoid extremes of activity and rest, specific advice on self‐help according to the particular approach chosen by the participant (if receiving SMC alone) and symptomatic pharmacotherapy (especially for insomnia, pain and mood, n = 160) Group 2, APT: based on the envelope theory aimed at optimum adaptation to the illness by helping the participant to plan and pace activity to reduce or avoid fatigue, achieve prioritised activities and provide the best conditions for natural recovery. Therapeutic strategies consisted of identifying links between activity and fatigue by using a daily diary, with corresponding encouragement to plan activity to avoid exacerbations, developing awareness of early warnings of exacerbation, limiting demands and stress, regularly planning rest and relaxation and alternating different types of activities, with advice not to undertake activities that demanded > 70% of participants’ perceived energy envelopes. Increased activities were encouraged if participants felt able, and as long as they did not exacerbate symptoms (n = 160) Group 3, CBT: done on the basis of the fear avoidance theory of CFS. The aim of treatment was to change the behavioural and cognitive factors assumed to be responsible for perpetuation of participants’ symptoms and disability. Therapeutic strategies guided participants to address unhelpful cognitions, including fears about symptoms or activities, by testing them through behavioural experiments. These experiments consisted of establishing a baseline of activity and rest and a regular sleep pattern, then making collaboratively planned gradual increases in both physical and mental activity. Participants were helped to address social and emotional obstacles to improvement through problem solving (n = 161) Group 4, GET: done on the basis of deconditioning and exercise intolerance theories of CFS. The aim of treatment was to help participants gradually return to appropriate physical activities and reverse deconditioning, thereby reducing fatigue and disability. Therapeutic strategies consisted of establishment of a baseline of achievable exercise or physical activity, followed by a negotiated, incremental increase in the duration of time spent being physically active. Target HR ranges were set when necessary to avoid overexertion, which eventually aimed at 30 min of light exercise 5 times/week. When this rate was achieved, the intensity and aerobic nature of the exercise (usually walking) were gradually increased in response to participant feedback and with mutual planning (n = 160)
Outcomes	Primary outcomes Fatigue (FS; Likert scoring 0, 1, 2, 3; range 0‐33; lowest score is least fatigue) Physical functioning (SF‐36 physical functioning subscale version 2; range 0‐100; highest score is best functioning) Safety outcomes (non‐serious adverse events, serious adverse events, serious adverse reactions to study treatments, serious deterioration and active withdrawals from treatment) Adverse events (i.e. any clinical change, disease or disorder reported, whether or not related to treatment) Secondary outcomes Changes in overall health (Global Impression Scale, score between 1 and 7, where 1 = very much better, 4 = no change) Overall disability: work and social adjustment scale 6‐MWT (distance in meters walked) Sleep (Jenkins Sleep Scale score for disturbed sleep) Anxiety and depression (HADS) Number of CFS symptoms (individual symptoms of postexertional malaise and poor concentration or memory) Use of health service resources Outcomes assessed at 12 weeks, 24 weeks (end of treatment) and 52 weeks (follow‐up)
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Participants were allocated to treatment groups through the Mental Health and Neuroscience Clinical Trials Unit (London, UK) after baseline assessment and obtainment of consent. A database programmer undertook treatment allocation, independently of the trial team. The first three participants at each of the six clinics were allocated with straightforward randomisation. Thereafter allocation was stratified by centre, alternative criteria for chronic fatigue syndrome and myalgic encephalomyelitis and depressive disorder (major or minor depressive episode or dysthymia), with computer‐generated probabilistic minimisation"
Allocation concealment (selection bias)	Low risk	Quote: "Once notified of treatment allocation by the Clinical Trials Unit, the research assessor informed the participant and clinicians"
Blinding (performance bias and detection bias) of participants and personnel?	High risk	Quote: "As with any therapy trial, participants, therapists, and doctors could not be masked to treatment allocation and it was also impractical to mask research assessors. The primary outcomes were rated by participants themselves"
Blinding (performance bias and detection bias) of outcome assessors?	High risk	Quote: "The statistician undertaking the analysis of primary outcomes was masked to treatment allocation"
Incomplete outcome data (attrition bias) All outcomes	Low risk	None found
Selective reporting (reporting bias)	Low risk	The protocol and the statistical analysis plan were not formally published prior to recruitment of participants, and some readers therefore claim the study should be viewed as being a post hoc study. The study authors oppose this, and have published a minute from a Trial Steering Committee (TSC) meeting stating that any changes made to the analysis since the original protocol was agreed by TSC and signed off before the analysis commenced.
Other bias	Low risk	We do not suspect other types of bias

ACT: anaerobic activity therapy; AD: antidepressant; APT: adaptive pacing therapy; BAI: Beck Anxiety Inventory; BDI‐II: Beck Depression Inventory; BPI: Brief Pain Inventory; CBT: cognitive‐behavioural therapy; CDC: Centers for Disease Control and Prevention; CF: chronic fatigue; CFS: chronic fatigue syndrome; COG: cognitive therapy; DSM‐III: Diagnostic and Statistical Manual of Mental Disorders from the American Psychiatric Association, 3rd edition (Revised); ET: exercise therapy; FS: Fatigue Scale; FSS: Fatigue Severity Scale; GET: graded exercise therapy; GP: general practitioner; HADS: Hospital Anxiety and Depression Scale; HR: heart rate; IQR: interquartile range; ITT: intention‐to‐treat; ME: myalgic encephalitis; MOS: Medical Outcome Survey; NS: not stated; PSQI: Pittsburgh Sleep Quality Index; PSS: Perceived Stress Scale; QoL: quality of life; QOLS: Quality of Life Scale; RCT: randomised controlled trial; RPE: rating of perceived exertion; SD: standard deviation; SF‐36: Short Form 36; SMC: specialist medical care; VO₂: oxygen consumption; 6MWT: six‐minute walking test