Graded exercise therapy compared to activity management for paediatric chronic fatigue syndrome/myalgic encephalomyelitis: pragmatic randomized controlled trial.

The MAGENTA pragmatic parallel groups randomized controlled trial compared graded exercise therapy (GET) with activity management (AM) in treating paediatric myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS). Children aged 8-17 years with mild/moderate ME/CFS and presenting to NHS specialist paediatric services were allocated at random to either individualised flexible treatment focussing on physical activity (GET, 123 participants) or on managing cognitive, school and social activity (AM, 118 participants) delivered by NHS therapists. The primary outcome was the self-reported short-form 36 physical function subscale (SF-36-PFS) after 6 months, with higher scores indicating better functioning. After 6 months, data were available for 201 (83%) participants who received a mean of 3.9 (GET) or 4.6 (AM) treatment sessions. Comparing participants with measured outcomes in their allocated groups, the mean SF-36-PFS score changed from 54.8 (standard deviation 23.7) to 55.7 (23.3) for GET and from 55.5 (23.1) to 57.7 (26.0) for AM giving an adjusted difference in means of -2.02 (95% confidence interval -7.75, 2.70). One hundred thirty-five participants completed the mean SF-36-PFS at 12 months, and whilst further improvement was observed, the difference between the study groups remained consistent with chance. The two study groups showed similar changes on most of the secondary outcome measures: Chalder Fatigue, Hospital Anxiety and Depression Scale: Depression, proportion of full-time school attended, a visual analogue pain scale, participant-rated change and accelerometer measured physical activity, whether at the 6-month or 12-month assessment. There was an isolated finding of some evidence of an improvement in anxiety in those allocated to GET, as measured by the Hospital Anxiety and Depression Scale at 6 months, with the 12-month assessment, and the Spence Children's Anxiety scale being aligned with that finding. There was weak evidence of a greater risk of deterioration with GET (27%) than with AM (17%; p = 0.069). At conventional UK cost per QALY thresholds, the probability that GET is more cost-effective than AM ranged from 18 to 21%. Whilst completion of the SF-36-PFS, Chalder Fatigue Scale and EQ-5D-Y was good at the 6-month assessment point, it was less satisfactory for other measures, and for all measures at the 12-month assessment.  Conclusion: There was no evidence that GET was more effective or cost-effective than AM in this setting, with very limited improvement in either study group evident by the 6-month or 12-month assessment points.  Trial registration: The study protocol was registered at www.isrctn.com (3rd September 2015; ISRCTN 23962803) before the start of enrolment to the initial feasibility phase.

Evidence-Based Care for People with Chronic Fatigue Syndrome and Myalgic Encephalomyelitis.

Chronic fatigue syndrome (CFS), sometimes referred to as myalgic encephalomyelitis (ME) and often as CFS/ME, is an illness characterized by disabling fatigue and other symptoms, typically worsened by activity. The main evidence-based treatments are rehabilitative in nature and include specific types of cognitive behavior therapy (CBT) and graded exercise therapy (GET). In this article, we briefly review the evidence for their safety and effectiveness and propose that much of the controversy about them arises from misunderstandings about their nature and delivery. In particular, we emphasize that successful rehabilitation from CFS/ME does not indicate that the illness is not real. We recommend that rehabilitative treatment always be preceded by a thorough clinical assessment and delivered by appropriately trained therapists working in close collaboration with the patient. We conclude that properly applied rehabilitative treatments offer the best hope of safely improving fatigue and function for patients with CFS/ME. However, we also recognize the need for more research into the treatment of this neglected condition, especially for those most severely disabled by it.

A systematic literature review of randomized controlled trials evaluating prognosis following treatment for adults with chronic fatigue syndrome.

This systematic review investigated randomized controlled trials evaluating cognitive behavioral therapy (CBT) and graded exercise therapy (GET) for adults with chronic fatigue syndrome (CFS). The objective was to determine prognosis following treatment. Studies were eligible if they were peer-reviewed and investigated treatment at least 12 weeks in duration. Studies were excluded if they used co-morbid diagnoses as entry criteria or if they did not measure fatigue, disability, or functioning. Literature published between 1988 and 2021 was searched using MEDLINE, EMBASE, PsycINFO, and Web of Science. Study quality was assessed using the Effective Public Health Practice Project assessment tool. Outcomes were synthesized when three or more studies reported outcomes obtained from the same validated measurement tool. The review included 15 publications comprising 1990 participants. Following CBT, and at short-term to medium-term follow-up, 44% considered themselves better and 11% considered themselves worse. Following GET, and at post-treatment to short-term follow-up, 43% considered themselves better and 14% considered themselves worse. These outcomes were 8-26% more favorable compared to control conditions. Two-thirds of studies were of moderate quality and the remainder were of weak quality. Limitations of this review relate to the clinical heterogeneity of studies and that most outcomes were self-reported. Results suggest some support for the positive effects of CBT and GET at short-term to medium-term follow-up although this requires further investigation given the inconsistent findings of previous reviews. Findings may not be generalizable to severe CFS. This review was registered with PROSPERO (CRD42018086002).

Study protocol of the TIRED study: a randomised controlled trial comparing either graded exercise therapy for severe fatigue or cognitive behaviour therapy with usual care in patients with incurable cancer.

BACKGROUND: Fatigue is a common and debilitating symptom for patients with incurable cancer receiving systemic treatment with palliative intent. There is evidence that non-pharmacological interventions such as graded exercise therapy (GET) or cognitive behaviour therapy (CBT) reduce cancer-related fatigue in disease-free cancer patients and in patients receiving treatment with curative intent. These interventions may also result in a reduction of fatigue in patients receiving treatment with palliative intent, by improving physical fitness (GET) or changing fatigue-related cognitions and behaviour (CBT). The primary aim of our study is to assess the efficacy of GET or CBT compared to usual care (UC) in reducing fatigue in patients with incurable cancer. METHODS: The TIRED study is a multicentre three-armed randomised controlled trial (RCT) for incurable cancer patients receiving systemic treatment with palliative intent. Participants will be randomised to GET, CBT, or UC. In addition to UC, the GET group will participate in a 12-week supervised exercise programme. The CBT group will receive a 12-week CBT intervention in addition to UC. Primary and secondary outcome measures will be assessed at baseline, post-intervention (14 weeks), and at follow-up assessments (18 and 26 weeks post-randomisation). The primary outcome measure is fatigue severity (Checklist Individual Strength subscale fatigue severity). Secondary outcome measures are fatigue (EORTC-QLQ-C30 subscale fatigue), functional impairments (Sickness Impact Profile total score, EORTC-QLQ-C30 subscale emotional functioning, subscale physical functioning) and quality of life (EORTC-QLQ-C30 subscale QoL). Outcomes at 14 weeks (primary endpoint) of either treatment arm will be compared to those of UC participants. In addition, outcomes at 18 and 26 weeks (follow-up assessments) of either treatment arm will be compared to those of UC participants. DISCUSSION: To our knowledge, the TIRED study is the first RCT investigating the efficacy of GET and CBT on reducing fatigue during treatment with palliative intent in incurable cancer patients. The results of this study will provide information about the possibility and efficacy of GET and CBT for severely fatigued incurable cancer patients. TRIAL REGISTRATION: NTR3812 ; date of registration: 23/01/2013.

Early active rehabilitation after arthroscopic rotator cuff repair: a prospective randomized pilot study.

OBJECTIVE: To compare two different rehabilitation strategies, primary passive motion versus early isometric loading of the rotator cuff. DESIGN: Prospective randomized controlled observer-blinded pilot study. SETTING: Institute of Physical Medicine and Rehabilitation. SUBJECTS: Thirty patients after rotator cuff surgery. INTERVENTION: All participants were randomly assigned to one of the two outpatient treatment groups: primary passive motion versus early isometric loading of the rotator cuff. Both groups were treated for 12 weeks and performed additionally a home exercise program. MAIN MEASURES: The primary outcome measure for functional assessment was the Constant Murley score. The secondary outcome measures were the Disabilities of the Arm, Shoulder and Hand score (DASH), active range of motion, pain level and strength. Patients were assessed before, 6, 12 and 24 weeks after surgery. RESULTS: Repeatedly measured metric variables were compared by the Quade rank analysis of covariance and revealed substantially better Constant Murley scores in the early activated group at all 3 assessments (6 weeks: 41 [31;45] versus 30 [23;37]; 12 weeks: 68 [56;77] versus 59 [53;62]; 24 weeks: 79 [76;81] versus 66 [62;74]; data as median [25%;75%]). Postoperative changes of Constant score were in favour of the active group with the biggest difference at week 12 (28 [38;12] versus 9 [27;-4]). Maximal pain levels showed clear more reduction 6 and 24 weeks after surgery in the early activated group. CONCLUSIONS: This pilot study with early isometric loading of the rotator cuff shows better function and less maximal pain. Further research is warranted to confirm our results.

Treatment Outcome and Metacognitive Change in CBT and GET for Chronic Fatigue Syndrome.

BACKGROUND: Studies have reported that Cognitive Behavioural Therapy (CBT) and Graded Exercise Therapy (GET) are effective treatments for Chronic Fatigue Syndrome (CFS). METHOD: One hundred and seventy-one patients undertook a course of either CBT (n = 116) or GET (n = 55) and were assessed on a variety of self-report measures at pre- and posttreatment and follow-up. AIMS: In this paper we present analyses on treatment outcomes for CBT and GET in routine clinical practice and evaluate whether changes on subscales of the Metacognitions Questionnaire-30 (MCQ-30) predict fatigue severity independently of changes in other covariates, and across the two treatment modalities. RESULTS: Both CBT and GET were equally effective at decreasing fatigue, anxiety, and depression, and at increasing physical functioning. Changes on the subscales of the MCQ-30 were also found to have a significant effect on fatigue severity independently of changes in other covariates and across treatment modalities. CONCLUSION: The findings from the current study suggest that CFS treatment protocols for CBT and GET, based on those from the PACE trial, achieve similar to poorer outcomes in routine clinical practice as in a RCT.

Graded exercise with motion style acupuncture therapy for a patient with failed back surgery syndrome and major depressive disorder: a case report and literature review.

Effective treatment of failed back surgery syndrome (FBSS) remains challenging despite urgent medical attention requirements. Depression is a contributing factor to the development and poor prognosis of FBSS, and vice versa. We report the case of a patient with FBSS and major depressive disorder (MDD) treated with graded exercise combined with motion-style acupuncture therapy (MSAT). A 53-year-old male veteran who had undergone lumbar discectomy and laminectomy with instrumented fusion was admitted to the hospital with re-current back pain and radiative pain in the left leg. The effects of failed surgery triggered MDD as a comorbidity. After a six-week routine treatment without remarkable improvement, a three-week program of graded exercise with MSAT was applied. The numeric rating scale (NRS) and short form-36 (SF-36) were used to assess low back pain with radiating leg pain, and daily functioning levels, respectively. The voluntary walking distance of the patients was measured. To analyze the therapeutic effects and other applications of the intervention, we surveyed clinical trials using MSAT or graded exercise therapy (GET). Three weeks of graded exercise with MSAT reduced physical and mental functional disabilities (SF-36, physical component: 15.0 to 37.2, mental component: 21.9 to 30.1) as well as the intensity of low back pain and/or radiative leg pain (NRS: 50 to 30). Furthermore, as the therapeutic intensity gradually increased, there was a significant corresponding increase in daily walking distance (mean daily walking distance, the first week vs. baseline, second, and third week, 3.05 ± 0.56: 2.07 ± 0.79, 4.27 ± 0.96, and 4.72 ± 1.04 km, p = 0.04, p = 0.02, and p = 0.003, respectively). Three randomized controlled trials of GET were included, all showing statistically significant antidepressant effects in the diseased population. Graded exercise with MSAT may be an effective rehabilitative therapy for patients with FBSS and MDD who have impaired daily routines.

eLearning improves allied health professionals' knowledge and confidence to manage medically unexplained chronic fatigue states: A randomized controlled trial.

OBJECTIVES: To evaluate the impact of eLearning by allied health professionals on improving the knowledge and confidence to manage people with medically unexplained chronic fatigue states (FS). METHODS: Using a parallel randomized controlled trial design, participants were randomized 1:1 to a 4-week eLearning or wait-list control group. Knowledge and self-reported confidence in clinical skills to implement a therapeutic intervention for patients with FS were assessed at baseline, post-intervention and follow-up. Secondary outcomes (adherence and satisfaction with online education, knowledge retention) were also assessed. Data was analyzed using intention-to-treat. RESULTS: There were 239 participants were randomized (eLearning n = 119, control n = 120), of whom 101 (85%) eLearning and 107 (89%) control participants completed baseline assessments and were included in the analysis. Knowledge (out of 100) improved significantly more in the eLearning group compared to the control group [mean difference (95% CI) 8.6 (5.9 to 11.4), p < 0.001]. Knowledge was reduced in the eLearning group at follow-up but was still significantly higher than baseline [6.0 (3.7 to 8.3), p < 0.001]. Median change (out of 5) in confidence in clinical skills to implement the FS intervention was also significantly greater in the eLearning group compared to the control group [knowledge: eLearning (1.2), control (0); clinical skills: eLearning (1), control (0.1); both p < 0.001)]. Average time spent on the eLearning program was 8.8 h. Most participants (80%) rated the lesson difficulty as at the "right level", and 91% would recommend it to others. CONCLUSIONS: eLearning increased knowledge and confidence to manage FS amongst allied health professionals and was well-accepted. REGISTRATION: ACTRN12616000296437 https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=370222&isReview=true.

The draft updated NICE guidance for ME/CFS highlights the unreliability of subjective outcome measures in non-blinded trials.

The National Institute for Health and Care Excellence (NICE) recently published its draft updated guideline on the diagnosis and management of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). NICE concluded that ME/CFS is a complex multisystem chronic medical condition for which graded exercise therapy should not be used and cognitive behavioural therapy is only a supportive therapy and not a treatment or cure. The draft guidance also highlighted the unreliability of subjective outcome measures in non-blinded trials. High quality randomised controlled ME/CFS trials are now needed to find pharmacological treatments that lead to substantial objective improvement and restore the ability to work.

Adverse outcomes in trials of graded exercise therapy for adult patients with chronic fatigue syndrome.

OBJECTIVES: Graded exercise therapy (GET) is an effective treatment for chronic fatigue syndrome (CFS), but concerns have been raised about its safety. Two randomised controlled trials have not supported these concerns. We further assessed safety outcomes in all ten published trials of GET for CFS. METHODS: We undertook meta-analyses of three outcomes: Self-ratings of Clinical Global Impression (CGI) change scores of 6 or 7 ("much worse" or "very much worse"), numbers of participants withdrawing from treatments, and numbers of participants dropping out of trial follow up. We provide risk ratios (95% confidence intervals (CI)), comparing GET with control interventions. RESULTS: The 10 trials involved 1279 participants. CGI scores of 6 or 7 were reported by 14/333 (4%) participants after GET and 26/334 (8%) participants after control interventions (RR (CI): 0.62 (0.32, 1.17)). Withdrawals from treatment occurred in 64/535 (12%) participants after GET and 53/534 (10%) participants after control interventions (RR (CI):1.21 (0.86, 1.69)). Drop-outs from trial follow up occurred in 74/679 (11%) participants after GET and 41/600 (7%) participants after control interventions (RR (CI): 1.51 (1.03, 2.22)). The certainty of this evidence was rated low by GRADE, due to imprecision. CONCLUSIONS: There was no evidence of excess harm with graded exercise therapy by either self-rated deterioration or by withdrawing from GET, in comparison to control interventions. More GET participants dropped out of trial follow up in comparison to control interventions. Future research should ascertain the most effective and safest form of graded exercise therapy.

Guided graded exercise self-help for chronic fatigue syndrome: Long term follow up and cost-effectiveness following the GETSET trial.

OBJECTIVE: The GETSET trial found that guided graded exercise self-help (GES) improved fatigue and physical functioning more than specialist medical care (SMC) alone in adults with chronic fatigue syndrome (CFS) 12 weeks after randomisation. In this paper, we assess the longer-term clinical and health economic outcomes. METHODS: GETSET was a randomised controlled trial of 211 UK secondary care patients with CFS. Primary outcomes were the Chalder fatigue questionnaire and the physical functioning subscale of the short-form-36 survey. Postal questionnaires assessed the primary outcomes and cost-effectiveness of the intervention 12 months after randomisation. Service costs and quality-adjusted life years (QALYs) were combined in a cost-effectiveness analysis. RESULTS: Between January 2014 and March 2016, 164 (78%) participants returned questionnaires 15 months after randomisation. Results showed no main effect of intervention arm on fatigue (chi2(1) = 4.8, p = 0.03) or physical functioning (chi2(1) = 1.3, p = 0.25), adjusting for multiplicity. No other intervention arm or time*arm effect was significant. The short-term fatigue reduction was maintained at long-term follow-up for participants assigned to GES, with improved fatigue from short- to long-term follow up after SMC, such that the groups no longer differed. Healthcare costs were £85 higher for GES and produced more QALYs. The incremental cost-effectiveness ratio was £4802 per QALY. CONCLUSIONS: The short-term improvements after GES were maintained at long-term follow-up, with further improvement in the SMC group such that the groups no longer differed at long-term follow-up. The cost per QALY for GES compared to SMC alone was below the usual threshold indicating cost-effectiveness, but with uncertainty around the result.

Monitoring treatment harm in myalgic encephalomyelitis/chronic fatigue syndrome: A freedom-of-information study of National Health Service specialist centres in England.

The use of graded exercise therapy and cognitive behavioural therapy for myalgic encephalomyelitis/chronic fatigue syndrome has attracted considerable controversy. This controversy relates not only to the disputed evidence for treatment efficacy but also to widespread reports from patients that graded exercise therapy, in particular, has caused them harm. We surveyed the National Health Service-affiliated myalgic encephalomyelitis/chronic fatigue syndrome specialist clinics in England to assess how harms following treatment are detected and to examine how patients are warned about the potential for harms. We sent 57 clinics standardised information requests under the United Kingdom's Freedom of Information Act. Data were received from 38 clinics. Clinics were highly inconsistent in their approaches to the issue of treatment-related harm. They placed little or no focus on the potential for treatment-related harm in their written information for patients and for staff. Furthermore, no clinic reported any cases of treatment-related harm, despite acknowledging that many patients dropped out of treatment. In light of these findings, we recommend that clinics develop standardised protocols for anticipating, recording, and remedying harms, and that these protocols allow for therapies to be discontinued immediately whenever harm is identified.

Guided graded Exercise Self-help for chronic fatigue syndrome: patient experiences and perceptions.

Purpose: This study explored patient experiences of Guided graded Exercise Self-help (GES) delivered as part of a randomised controlled trial for people with chronic fatigue syndrome/myalgic encephalomyelitis. The trial found that GES was better than specialist medical care at reducing fatigue and improving physical functioning.Methods: Semi-structured interviews were conducted with patients reporting improvement (n = 9) and deterioration (n = 10), and analysis involved thematic "constant comparison."Results: The improved group described more facilitators to doing GES, and were more likely to describe high levels of self-motivation, whereas the deteriorated group described more barriers to GES (including worse exacerbation of symptoms after GES, greater interference from comorbid conditions, and obstacles to GES in their lives), and had been ill for longer. Having the capacity to do GES was important; of note, those with relatively lower levels of functioning sometimes had more time and space in their lives to support their GES engagement. We identified an important "indeterminate phase" early on, in which participants did not initially improve.Conclusions: GES may be improved by targeting those most likely to improve, and teaching about the indeterminate phase.Implications for rehabilitationUsing the Guided Exercise Self-help booklet alone is unlikely to be sufficient to support patients through Guided Exercise Self-help successfully.Additional guidance from skilled physiotherapists/health professionals who demonstrate an understanding of what it is like to cope with chronic fatigue syndrome/myalgic encephalomyelitis is also important.Those using Guided Exercise Self-help may need additional support through a commonly experienced "indeterminate phase" - an initial phase in the programme where few benefits, along with various challenges associated with increasing activity, are experienced.Individuals who have been ill with chronic fatigue syndrome/myalgic encephalomyelitis for a relatively longer period of time and/or have additional comorbid conditions may benefit from more bespoke therapies with greater health professionals input, delivered by appropriate therapists.

Assessment of the scientific rigour of randomized controlled trials on the effectiveness of cognitive behavioural therapy and graded exercise therapy for patients with myalgic encephalomyelitis/chronic fatigue syndrome: A systematic review.

Cognitive behavioural therapy and graded exercise therapy have been promoted as effective treatments for patients with myalgic encephalomyelitis/chronic fatigue syndrome. However, criticism on the scientific rigour of these studies has been raised. This review assessed the methodological quality of studies on the effectiveness of cognitive behavioural therapy and graded exercise therapy. The methodological quality of the 18 included studies was found to be relatively low, as bias was prominently found, affecting the main outcome measures of the studies (fatigue, physical functioning and functional impairment/status). Future research should focus on including more objective outcome measures in a well-defined patient population.

Severe ME in Children.

A current problem regarding Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is the large proportion of doctors that are either not trained or refuse to recognize ME/CFS as a genuine clinical entity, and as a result do not diagnose it. An additional problem is that most of the clinical and research studies currently available on ME are focused on patients who are ambulant and able to attend clinics and there is very limited data on patients who are very severe (housebound or bedbound), despite the fact that they constitute an estimated 25% of all ME/CFS cases. This author has personal experience of managing and advising on numerous cases of severe paediatric ME, and offers a series of case reports of individual cases as a means of illustrating various points regarding clinical presentation, together with general principles of appropriate management.

Myalgic encephalomyelitis/chronic fatigue syndrome patients' reports of symptom changes following cognitive behavioural therapy, graded exercise therapy and pacing treatments: Analysis of a primary survey compared with secondary surveys.

Cognitive behavioural therapy and graded exercise therapy are promoted as evidence-based treatments for myalgic encephalomyelitis/chronic fatigue syndrome. This article explores patients' symptom responses following these treatments versus pacing therapy, an approach favoured by many sufferers. We analyse data from a large cross-sectional patient survey (n = 1428) and compare our findings with those from comparable patient surveys (n = 16,665), using a mix of descriptive statistics and regression analysis modelling. Findings from analysis of primary and secondary surveys suggest that cognitive behavioural therapy is of benefit to a small percentage of patients (8%-35%), graded exercise therapy brings about large negative responses in patients (54%-74%), while pacing is the most favoured treatment with the lowest negative response rate and the highest reported benefit (44%-82%).

Response: Sharpe, Goldsmith and Chalder fail to restore confidence in the PACE trial findings.

In a recent paper, we argued that the conclusions of the PACE trial of chronic fatigue syndrome are problematic because the pre-registered protocol was not adhered to. We showed that when the originally specific outcomes and analyses are used, the evidence for the effectiveness of CBT and graded exercise therapy is weak. In a companion paper to this article, Sharpe, Goldsmith and Chalder dismiss the concerns we raised and maintain that the original conclusions are robust. In this rejoinder, we clarify one misconception in their commentary, and address seven additional arguments they raise in defence of their conclusions. We conclude that none of these arguments is sufficient to justify digressing from the pre-registered trial protocol. Specifically, the PACE authors view the trial protocol as a preliminary plan, subject to honing and improvement as time progresses, whereas we view it as a contract that should not be broken except in extremely unusual circumstances. While the arguments presented by Sharpe and colleagues inspire some interesting reflections on the scientific process, they fail to restore confidence in the PACE trial's conclusions.

The PACE trial of treatments for chronic fatigue syndrome: a response to WILSHIRE et al.

Chronic Fatigue Syndrome (CFS) is chronic disabling illness characterized by severe disabling fatigue, typically made worse by exertion. Myalgic Encephalomyelitis (ME) is thought by some to be the same disorder (then referred to as CFS/ME) and by others to be different. There is an urgent need to find effective treatments for CFS. The UK Medical Research Council PACE trial published in 2011 compared available treatments and concluded that when added to specialist medical care, cognitive behaviour therapy and graded exercise therapy were more effective in improving both fatigue and physical function in participants with CFS, than both adaptive pacing therapy and specialised medical care alone. In this paper, we respond to the methodological criticisms of the trial and a reanalysis of the trial data reported by Wilshire at al. We conclude that neither the criticisms nor the reanalysis offer any convincing reason to change the conclusions of the PACE trial.

Results of the feasibility phase of the managed activity graded exercise in teenagers and pre-adolescents (MAGENTA) randomised controlled trial of treatments for chronic fatigue syndrome/myalgic encephalomyelitis.

BACKGROUND: Chronic fatigue syndrome (CFS) also known as myalgic encephalomyelitis (ME) is relatively common in young people and causes significant disability. Graded exercise therapy (GET) and activity management are recommended by the National Institute for Health and Care Excellence (NICE) despite a limited evidence-base for either treatment in paediatric CFS/ME. This paper reports on feasibility and acceptability measures from the feasibility phase of the ongoing MAGENTA randomised controlled trial (RCT) investigating GET versus activity management for young people with CFS/ME. METHODS: Setting: Three specialist secondary care National Health Service (NHS) Paediatric CFS/ME services (Bath, Cambridge and Newcastle).Participants: Young people aged 8-17 years with a diagnosis of mild to moderate CFS/ME. Young people were excluded if they were severely affected, referred to cognitive behavioural therapy (CBT) at initial assessment or unable to attend clinical sessions.Interventions: GET and activity management delivered by physiotherapists, occupational therapists, nurses and psychologists. Families and clinicians decided the number (typically 8-12) and frequency of appointments (typically every 2-6 weeks).Outcome Measures: Recruitment and follow-up statistics. We used integrated qualitative methodology to explore the feasibility and acceptability of the trial processes and the interventions. RESULTS: 80/161 (49.7%) of eligible young people were recruited at two sites between September 2015 and August 2016, indicating recruitment to the trial was feasible. Most recruitment (78/80; 97.5%) took place at one centre. Recruitment consultations, online consent and interventions were acceptable, with less than 10% in each arm discontinuing trial treatment. Response rate to the primary outcome (the SF36-PFS at 6 months) was 91.4%. Recruitment, treatment and data collection were not feasible at one centre. The site was withdrawn from the study.In response to data collected, we optimised trial processes including using Skype for recruitment discussions; adapting recruiter training to improve recruitment discussions; amending the accelerometer information leaflets; shortening the resource use questionnaires; and offering interventions via Skype. These amendments have been incorporated into the full trial protocol. CONCLUSIONS: Conducting an RCT investigating GET versus activity management is feasible and acceptable for young people with CFS/ME. TRIAL REGISTRATION: ISRCTN23962803 10.1186/ISRCTN23962803, date of registration: 03 September 2015.

Novel interdisciplinary intervention, GAIN, vs. enhanced usual care to reduce high levels of post-concussion symptoms in adolescents and young adults 2-6 months post-injury: A randomised trial.

BACKGROUND: Evidence for effective interventions to prevent long-term sequelae after concussion is sparse. This study aimed to test the efficacy of Get going After concussIoN (GAIN), an interdisciplinary, individually-tailored intervention of 8 weeks duration based on gradual return to activities and principles from cognitive behavioural therapy. METHODS: We conducted an open-label, parallel-group randomised trial in a hospital setting in Central Denmark Region. Participants were 15-30-year-old patients with high levels of post-concussion symptoms (PCS) 2-6 months post-concussion (i.e., a score ≥20 on the Rivermead Post-concussion Symptoms Questionnaire (RPQ)). They were randomly assigned (1:1) to either enhanced usual care (EUC) or GAIN+EUC. Masking of participants and therapists was not possible. The primary outcome was change in RPQ-score from baseline to 3-month FU. All analyses were done on an intention-to-treat basis using linear mixed-effects models. This trial is registered with ClinicalTrials.gov, number NCT02337101. FINDINGS: Between March 1, 2015, and September 1, 2017, we included 112 patients. Patients allocated to GAIN+EUC (n=57) reported a significantly larger reduction of PCS than patients allocated to EUC (n=55) with a mean adjusted difference in improvement of 7·6 points (95% confidence interval (CI) 2·0-13·1, p=0·008), Cohen's d=0·5 (95% CI 0·1-0·9). Number needed to treat for prevention of one additional patient with RPQ ≥20 at 3-month FU was 3·6 (95% CI 2·2-11·3). No adverse events were observed. INTERPRETATION: Compared with EUC, GAIN+EUC was associated with a larger reduction of post-concussion symptoms at 3-month FU. FUNDING: Central Denmark Region and the foundation "Public Health in Central Denmark Region - a collaboration between municipalities and the region".