White 2011

Methods	RCT, multi‐centre, 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 antidepressants Illness duration: median 32 (IQR 16 to 68) months (GET 35 (18 to 67) and SMC 25 (15 to 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, specialist medical care (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 chronic fatigue syndrome, 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, adaptive pacing therapy (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 more than 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, cognitive‐behavioural therapy (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, graded exercise therapy (GET): done on the basis of deconditioning and exercise intolerance theories of chronic fatigue syndrome. 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 heart rate ranges were set when necessary to avoid overexertion, which eventually aimed at 30 minutes of light exercise 5 times a 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 (Fatigue Scale, FS; Likert scoring 0, 1, 2, 3; range 0 to 33; lowest score is least fatigue) Physical function (Short Form‐36 (SF‐36) physical function subscale version 2; range 0 to 100; highest score is best function) Safety outcomes (non‐serious adverse events, serious adverse events, serious adverse reactions to trial 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‐Minute walking test (distance in meters walked) Sleep (Jenkins Sleep Scale score for disturbed sleep) Anxiety and depression (Hospital Anxiety and Depression Scale, HADS) Number of chronic fatigue syndrome 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	Quote: "These secondary outcomes were a subset of those specified in the protocol, selected in the statistical analysis plan as most relevant to this report." Our primary interest is the primary outcome reported in accordance with the protocol, so we do not believe that selective reporting is a problem
Other bias	Low risk	We do not suspect other types of bias

ACT, anaerobic activity therapy.

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.

CFS, chronic fatigue syndrome.

COG, cognitive therapy.

ET, exercise therapy.

FS, Fatigue Scale.

FSS, Fatigue Severity Scale.

GET, graded exercise therapy.

HADS, Hospital Anxiety and Depression Scale.

HR, heart rate.

IQR, interquartile range.

ME, myalgic encephalitis.

MOS, Medical Outcome Survey.

NS, Not stated.

PSQI, Pittsburgh Sleep Quality Index.

PSS, Perceived Stress Scale.

RCT, randomised controlled trial.

RELAX, relaxation treatment.

RPE, rating of perceived exertion.

SD, standard deviation.

SF‐36, Short Form 36.

SMC, specialist medical care.

VO₂, oxygen consumption.