The FatiGo trial concluded that multidisciplinary rehabilitation treatment is more effective for chronic fatigue syndrome/myalgic encephalomyelitis in the long term than cognitive behaviour therapy and that multidisciplinary rehabilitation treatment is more cost-effective for fatigue and cognitive behaviour therapy for quality of life. However, FatiGo suffered from a number of serious methodological flaws. Moreover, it ignored the results of the activity metre, its only objective outcome. This jeopardizes the validity of FatiGo. Its analysis shows that there was no statistically significant difference between multidisciplinary rehabilitation treatment and cognitive behaviour therapy and neither are (cost-)effective. FatiGo’s claims of efficacy of multidisciplinary rehabilitation treatment and cognitive behaviour therapy for chronic fatigue syndrome/myalgic encephalomyelitis are misleading and not justified by their results.

Background information The FatiGo (Fatigue-Go) trial was a multicentre, randomized controlled trial involving 122 patients with CFS/ME. It compared the efficacy of CBT and MRT which consisted of ‘CBT and, depending on the individual analysis, elements of body awareness therapy, gradual reactivation, pacing, mindfulness, gradual normalization of sleep/wake rhythm and social reintegration’. FatiGo used two subjective primary outcomes (fatigue and health-related quality of life) and a number of subjective secondary outcomes including one objective outcome (the activity monitor also known as the actometer). Outcomes were assessed prior to treatment and at 26 and 52 weeks after treatment initiation, that is, at the end of treatment and 26 weeks later. FatiGo concluded that ‘MRT is more effective in reducing long-term fatigue severity than CBT in patients with CFS’ and ‘patients showed an improvement in quality of life over time, but between-group differences were not significant’ (Vos-Vromans et al., 2016a).

The protocol Patients were selected between December 2008 and January 2011. Therapy lasted 6 months. The protocol was submitted on 17 March 2011 (accepted on the 16 April 2012 and published on the 30 May 2012 (Vos-Vromans et al., 2012) even though ‘a fundamental principle in the design of randomized trials involves setting out in advance the endpoints that will be assessed in the trial, as failure to prespecify endpoints can introduce bias into a trial and creates opportunities for manipulation’ (Evans, 2007). Therefore a protocol should be published before the start of a trial and not when it (in FatiGo’s case) has (almost) finished.

Problems with the design of the study FatiGo was an unblinded trial with two treatment groups without a ‘placebo’ control group that used two subjective primary outcomes. Even though, according to a systematic review of the interventions for the treatment and management of CFS by Whiting et al. (2001), one of the problems with subjective outcomes is that patients ‘may feel better able to cope with daily activities because they have reduced their expectations of what they should achieve, rather than because they have made any recovery as a result of the intervention’. Therefore more objective measures of the effect of any intervention should be used. Also, unblinded trials should use objective primary outcomes alone or in combination with subjective ones to avoid the erroneous interference of efficacy in its absence (Edwards, 2017; Lilienfeld et al., 2014). FatiGo could have done this very easily by using their objective secondary outcome (the activity monitor) as a primary one. Why it did not do it is unclear. The risk for false-positive results was made even bigger because there was a large difference in treatment hours between the MRT (44.5) and the CBT (16) groups (Vos-Vromans et al., 2016a). This creates serious biases towards finding a positive effect for the intervention regardless of whether it is effective or not (Coyne, 2016).

Selection criteria Only 33.5 per cent (122/364) of those screened for the FatiGo trial actually entered it. FatiGo used the Fukuda criteria which require at least 6 months of chronic fatigue in combination with a minimum of four out of eight symptoms (Vos-Vromans et al., 2016a). The problem with these criteria, even though they are the most commonly used criteria for CFS/ME, is that the main characteristic of the disease, an abnormally delayed (muscle) recovery after trivial exertion (Ramsay, 1988), which in this day and age is often called post-exertional malaise, is an optional requirement and not compulsory (Fukuda et al., 1994). The consequence of this is that a group of patients selected by using the Fukuda criteria also includes patients with depression labelled as CFS/ME patients, whereas both the Canadian Consensus Criteria from 2003 and the International Consensus Criteria from 2011 differentiate patients with ME from those who are depressed and identify patients who are more physically and cognitively disabled (Carruthers et al., 2011). Also, at trial entry, patients had to fill in the hospital anxiety and depression scale yet no mention is made by FatiGo of how many of the participants suffered from depression and/or anxiety. In a study by Moss-Morris et al. (2005) that also used the Fukuda criteria, as many as 30–42 per cent of the sample were suffering from depression and anxiety respectively according to the authors themselves. This is of particular importance, as a meta-analysis by Tolin (2010) found that CBT is the most effective treatment for depression. Therefore, including patients with depression might lead to the erroneous inference of efficacy of CBT for CFS/ME in its absence.

The biopsychosocial model FatiGo was based on the biopsychosocial model that after a viral infection, which has been cleared by the body, there is no underlying illness anymore. Instead, patients have developed the belief that they suffer from a physical illness. This leads to the avoidance of exercise and activity and results in deconditioning which is the cause of their problems/symptoms. CBT for CFS/ME, which is different from ‘ordinary’ CBT, was designed to modify these dysfunctional beliefs and behaviours and usually includes a graded increase in activity (Vos-Vromans et al., 2016a). The biopsychosocial model is an assumption- and opinion-based model for which objective evidence has never been presented and which is at odds with the physiological abnormalities in CFS/ME (Vink, 2017a).

Discussion The FatiGo trial concluded that MRT is more effective for CFS/ME in the long term than CBT (Vos-Vromans et al., 2016a). It also concluded that MRT is more cost-effective for fatigue and CBT for the quality of life (Vos-Vromans et al., 2017). However, analysis of the study shows that it suffered from a number of serious methodological flaws. The unblinded trial used two subjective primary outcomes (fatigue and quality of life). This combination is known to lead to the erroneous inference of efficacy in its absence. The likelihood of this was made even bigger because of the large difference in contact hours between the two groups (44.5 vs 16) even though these should be the same. The only way to correct for these problems in unblinded trials is by using well-designed control groups and objective primary outcomes (Edwards, 2017; Lilienfeld et al., 2014). Another fundamental design flaw of the trial was that it compared CBT against MRT which was CBT plus a number of things. However these were not properly specified, as they were tailored to the individual needs. Yet, in a properly designed trial, patients in a treatment group should all receive the same treatment. Furthermore, the trial did not have a ‘placebo’ control group (for example relaxation therapy, specialist medical care or pacing) to correct for the placebo effect and other confounding factors. Furthermore, the fatigue scores showed that neither MRT nor CBT were effective and the mean EQ-5D-3L quality of life scores after CBT and MRT were the same as for people with five or more (CBT) or four chronic health conditions (MRT) (Olesen et al., 2016). Moreover, quality of life was still worse than in stroke, ischaemic heart disease, colon cancer (Hvidberg et al., 2015), the total population or in people without a chronic condition (Olesen et al., 2016). Also FatiGo ignored the results of the activity monitor, its only objective outcome measure. Analysis of these results showed that CBT and MRT at best only led to a minimal objective improvement of 5–6 per cent. The trial suffered from many methodological problems as discussed before. For example, post-exertional malaise, the cardinal feature of the disease was not compulsory for diagnosis. Patients with co-morbid depression or anxiety were not excluded from the study even though that has been recommended by an international group of experts including the main proponents of the biopsychosocial model in 2003. It was recommended by consensus because ‘the presence of a medical or psychiatric condition that may explain the chronic fatigue state excludes the classification as CFS in research studies because overlapping pathophysiology may confound findings specific to CFS’ (Reeves et al., 2003). Moreover, other trials that used a ‘placebo’ control group and objective outcomes did not show any objective or clinical significant improvement (Vink, 2016; White et al., 2011). Therefore, it is likely that this minimal improvement was caused by the natural fluctuation of the disease, the inclusion of patients who do not have the disease, the absence of a properly designed control group, the high percentage of patients who were excluded from the trial (66.5%), and the high percentage of participants (34.4%) for whom there were no activity monitor results, as those who do not improve or suffer adverse reactions are the ones most likely to drop out of treatment (Lilienfeld et al., 2014) and/or other confounding factors and not by the treatments under investigation. But, even if this was not the case, then no one would classify an operation, an antibiotic or any other treatment as effective if it would lead to just 5–6 per cent improvement. Even more so as a major criterion for defining CFS/ME is a reduction in physical capacity of at least 50 per cent compared to pre-illness levels (Fukuda et al., 1994; Holmes, 1988).

Conclusion The FatiGo trial suffered from a number of severe methodological flaws. On top of this, it ignored the results of the activity metre, its only objective outcome. Its analysis shows that MRT and CBT are neither effective nor cost-effective. Re-analysis of FatiGo also shows that one should be extremely careful accepting claims of efficacy of psychological interventions in the absence of objective proof to support such claims. Even more so when trials use objective outcomes but ignore the results, as was the case in FatiGo, or even worse, when they do not report them at all.

Acknowledgements The authors would like to thank M.V.’s parents for typing out his speech memos.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article. Funding

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