PACE trial for chronic fatigue syndrome (still) being put through its paces: a reply

I'm bringing the paper published by Michael Sharpe and colleagues [1] to your attention today in the interest of balance and peer-reviewed 'right to reply'.

The Sharpe paper concerns the PACE trial, the study which reported 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 [chronic fatigue syndrome], than both adaptive pacing therapy and specialised medical care alone."

Anyone with a little bit of knowledge about the PACE trial will know that it's a 'contentious' topic within CFS (and ME, myalgic encephalomyelitis) circles. Indeed, the Sharpe paper comes about as a direct result of a reanalysis paper (see here) which reported findings raising "serious concerns about the robustness of the claims made about the efficacy of CBT [cognitive behavioural therapy] and GET [graded exercise therapy]" in the context of CFS/ME. 'Serious concerns' is putting it mildly considering how others have described the PACE trial and some of its tenets (see here).

Sharpe et al, who were authors listed on the original PACE trial paper [2], have had to defend their work/findings before in the peer-reviewed realm (see here). Same as before, the name Carolyn Wilshire is addressed and her teams reanalysis of the PACE trial data [3]. Said data was, I might add, (partially) released only following intervention from the Information Commissioners Office (ICO) here in Blighty (see here). More recent events have similarly reiterated that 'access to raw study data' is something that CFS/ME researchers perhaps need to bear in mind at study conception (see here).

I'm not going to clinically dissect the Sharpe paper in this post because (a) 'interpretation' forms quite a bit of the reply to the Wilshire reanalysis, and (b) your opinion on the scientific quality of the Sharpe reply is most likely going to be shaped by where you stand in terms of the whole CBT/GET for CFS/ME discussion. Indeed, a peer-reviewer of the Sharpe paper also said as much (see here). What I will comment on is how the Wilshire reanalysis paper and the more recent Sharpe reply to the reanalysis paper might further inform research more generally with CFS/ME in mind.

Oh, and it's probably just a coincidence that the Sharpe paper comes out only days after a news headline reads "Online activists are silencing us, scientists say" talking about a familiar topic.

So:

• Point 1: Design a good trial analysis plan and stick to it. From my 'outsider looking in' perspective, the changes made to "the scoring of the pre-specified outcomes" regarding fatigue and physical functioning in the PACE trial, however innocent they might have been, have created tension. Lots of tension. Such changes, whether agreed by "Trial Data Monitoring and Steering Committees" or not, can be construed in various different ways. It's better not to make such changes in the first place.
• Point 2: If you are going to study something like physical functioning in relation to CFS/ME, don't just rely on things like questionnaires and Likert scales; use actigraphy too. Self-report is always a good thing but I've never understood why, with the wide range of cost-effective technology out there (available I believe, even in the early 2000s), wearable trackers such as pedometers or similar were not also utilised during such studies (see here). If you're spending £5 million on a trial, a few quid for some pedometers is not exactly going to break the bank and will inevitably bring some further quality data to the table.
• Point 3: Recovery. As per other discussions (see here), most people would characterise recovery as a complete remission of symptoms and/or return to typical functioning. If you're not going to use this description, don't use the word recovery. Use something else instead. Indeed, use 'partial remission' or 'improvement' if you need to but don't call anything less than the complete remission of symptoms 'recovery'.
• Point 4: Long-term outcomes. It's probably best to avoid any sweeping statements after the arms of a trial - a "randomised trial" not necessarily a "randomised controlled trial" according to Wilshire et al - have been completed. More so when you're measuring such long-term outcomes via a postal question minus any objective measure(s) (see point 2). It's probably also a good idea to ask patients about their quality of life too and whether that has changed (see here).
• Point 5: Even if your paper states in no uncertain terms that: "The effectiveness of behavioural treatments does not imply that the condition is psychological in nature" the use of something like CBT for CFS/ME implies that you probably think there is a substantial psychological 'component' to the condition. This is compounded when you're for example, a Professor of Psychological Medicine. If you were pitting CBT in particular against a specific pharmacological or biological intervention 'for CFS/ME' (see here for example), I'd be more inclined to see your view in a more 'rounded sense'. Indeed, if you were to study one or two biological parameters as well as behavioural ones looking for any change following intervention, you might convince more people that psychology is not the primary line you take. And whilst on the topic of psychology and CFS/ME, it's probably also best not to use 'psychobabble' terms like 'deconditioning' in your research. Such terms are pretty much scientifically untestable and, given the recent discussions about the legacy of some adherents to something like psychosomatic research (see here), is likely to be consigned to the scientific dustbin as some later point.

I think I've covered the main points as I see them. Please feel free to agree/disagree as you wish.

End of Line.

Addition: 26 March 2019. Not quite 'End of Line' it seems, as a reply to a reply to a reply emerges [4]. Peer reviewed science is far from slow...

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[1] Sharpe M. et al. The PACE trial of treatments for chronic fatigue syndrome: a response to WILSHIRE et al. BMC Psychology. 2019; 7: 15.

[2] White PD. et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011; 377(9768):823-36.

[3] Wilshire CE. et al. Rethinking the treatment of chronic fatigue syndrome—a reanalysis and evaluation of findings from a recent major trial of graded exercise and CBT. BMC Psychology. 2018; 6: 6.

[4] Wilshire CE. & Kindlon T. Response: Sharpe, Goldsmith and Chalder fail to restore confidence in the PACE trial findings. BMC Psychology. 2019; 7: 19.

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PACE trial for chronic fatigue syndrome (still) being put through its paces

'Chronic fatigue trial results 'not robust', new study says' went the BBC headline reporting on the findings published by Carolyn Wilshire and colleagues [1].

Authors report peer-reviewed results following their re-examining various aspects of the PACE trial - "pacing, graded activity, and cognitive behaviour therapy: a randomised evaluation" - with regards to chronic fatigue syndrome (CFS) also known as myalgic encephalomyelitis (ME).

This latest research and accompanying media attention continues a quite long-running saga (see here) known in some quarters as 'PACE-gate' (see here) where questions have been raised about a premier study that was "designed to examine the effectiveness of graded exercise therapy (GET) and cognitive behavioural therapy (CBT)" in relation to CFS/ME. Quite a few of those interventions are set within the still unfortunately believed idea that CFS/ME represents a 'biopsychosocial' illness (see here) and that 'changing mindsets and/or behaviour' will magically transform peoples lives. I say 'still unfortunately believed' because patient experiences do not seemingly match some of the peer-reviewed science in this area (see here).

The various twists-and-turns (see here and see here) around the PACE trial have involved bigger discussions about trial design, outcome threshold 'issues' and even the accessibility of research study data. Indeed, the Information Commissioner here in Blighty has even played a hand in the PACE saga (see here) leading to some rather messy and very public arguments.

The paper by Wilshire et al continues a theme from this research group re-examining the PACE trial protocols and findings. It encompasses various elements in terms of definitions of 'overall improvement' and even 'recovery' (see here) between 'specified in trial protocol' and 'used in published reports'. Wilshire and colleagues report: "Our findings suggest that, had the investigators stuck to their original primary outcome measure, the outcomes would have appeared much less impressive."

Insofar as recovery rates - other work [2] related to the original PACE trial paper had indicated some impressive recovery rates following CBT and/or GET - Wilshire has more things to say here too. So: "when recovery rates were calculated using the definition specified in the published protocol, these were extremely low across the board, and not significantly greater in the CBT or GET groups than in the Control group." It might seem like common-sense to know what recovery should look like when it comes to CFS/ME, but again, the waters have been continually muddied (see here).

"Some notable strengths of the PACE study included the large sample size..., the random allocation of patients to treatment arms, the use of a well-formulated protocol to minimise drop-outs, and the reporting of the full CONSORT trial profile (including detailed information about missing data)." Wilshire et al illustrate how the PACE trial was, initially, a good piece of science from a methodological point of view, but: "the design, analysis and reporting of the results introduced some significant biases."

And now it may be time to move on: "The time has come to look elsewhere for effective treatments." CBT and/or GET are still the topics of study when it comes to ME/CFS (see here and see here) but are seemingly finding it more and more difficult to find acceptance. The recent news that NICE are looking to update their guidance on CFS/ME in light of 'changes' made by other official bodies (see here) and some significant patient (and political) power, reflect an increasingly changing mood. An increasing realisation that talking and exercise therapies might not be the best treatment options for a somatic condition that has the propensity to *significantly* drain both health and other aspects of quality of life (see here).

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[1] Wilshire CE. et al. Rethinking the treatment of chronic fatigue syndrome—a reanalysis and evaluation of findings from a recent major trial of graded exercise and CBT. BMC Psychology. 2018; 6: 6.

[2] White PD. et al. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychol Med. 2013 Oct;43(10):2227-35.

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What nearly 1500 patients with ME/CFS actually think about CBT, GET and pacing therapy

Today I'm discussing the findings reported by Keith Geraghty and colleagues [1] (open-access might be available here).

Looking at some interesting data derived from a rather large patient survey, authors examined what people diagnosed with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) actually thought about / experienced when it came to three intervention options: cognitive behavioural therapy (CBT), graded exercise therapy (GET) and pacing therapy (PT). A little bit of context about these interventions can be seen here including reference to some other peer-reviewed published work from members of this authorship group.

Based on the results of a survey offered by one of the premier UK organisations devoted to ME/CFS - certainly the one I tend to use when it comes to defining the spectrum that is ME/CFS - Geraghty et al add something to a body of research looking at the 'real world' impact (or not) of the various interventions currently advised for 'treating' CFS/ME (at least here in the UK). Their analyses suggested that: "While a small percentage of patients report some benefit from either CBT or GET, the majority experience no benefit." Even worse: "GET brings about a substantive deterioration in symptoms for almost half of patients"; something important to mention in the context of other, similar, intervention results being published earlier this year (see here).

At this point, I'll also refer you to other discussions of the Geraghty paper (see here).

Details are important to the Geraghty results. Including quite a sizeable cohort (N=1428) and asking over 200 questions "regarding treatment, particularly CBT, GET or PT", results were also compared against other patient survey results in the context of the intervention(s) being scrutinised. The combined results painted a similar sort of picture when it comes to experiences of the interventions insofar as "CBT brought about improvement in symptoms for approximately 35 per cent of respondents (65% unchanged/worse)" and "25 per cent of GET reported improvement in symptoms (17% unchanged/54% worse)." All this needs to be read in the context of the primary medical tenet: first, do not harm.

Geraghty et al acknowledge that there are limitations to their study results; not least that recall bias might be a potentially important issue and also that delivery of said interventions  might not have been carried out in "a uniform manner" (something also mentioned in the paper by Collin & Crawley [2]). With all due respect to the respondents, I might also add that independent confirmation of their diagnosis - knowing how important this - might also have provided some further methodological strength to the results too.

But in the context that patient surveys "offer a valuable insight into the ‘patient experience’" and how controversial some (all?) of these intervention options have been/continue to be in relation to CFS/ME (see here), these latest results represent an important research voice. They suggest yet again, that blanket recommendations for treating CFS/ME may have lots of potential effects (some positive but also quite a few negative) for many, many people diagnosed with such debilitating conditions. And once again, in the words of Jonathan Edwards [3] "If they [those diagnosed with ME/CFS] are still ill, presumably these approaches have failed and the priority is to find something more effective." Indeed (but don't hold your breath at least here in Blighty).

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[1] Geraghty K. et al. 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. J Health Psychol. 2017 Aug 1:1359105317726152.

[2] Collin SM. & Crawley E. Specialist treatment of chronic fatigue syndrome/ME: a cohort study among adult patients in England. BMC Health Serv Res. 2017 Jul 14;17(1):488.

[3] Edwards J. PACE team response shows a disregard for the principles of science. J Health Psychol. 2017 Aug;22(9):1155-1158.

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Is current guidance for the management of CFS/ME in England fit for purpose?

"This multi-centre study in the NHS has shown that CFS/ME [chronic fatigue syndrome/myalgic encephalomyelitis] is a long term condition that persists for the majority of adult patients even after receiving specialist treatment."

So said the study results published by Simon Collin & Esther Crawley [1] (open-access) providing important information on some 400 patients diagnosed with CFS/ME who were in receipt of "NHS specialist CFS/ME services in England." Said specialist services, we are told, follow "guidance provided by the National Institute for Health & Care Excellence (NICE), including specific guidelines for diagnosis, specialist care, and ongoing management, with an overall patient-centred approach to treatment."

In case you've not followed the link to the NICE guidance covering CFS/ME, specialist care here in England generally describes various elements including the use of cognitive behavioural therapy (CBT) and/or graded exercise therapy (GET) based on the PACE trial results [2] and findings from other studies. Yes, the same PACE trial that 'continues to give' when it comes to arguments/debates (delete as appropriate) in CFS/ME circles (see here); see also the end of this post for more links to more recent happenings.

The Collin/Crawley research looked at several groups - newly referred and former patients - who attended one of eleven CFS/ME specialist services and who completed various questionnaires concerning the presentation  of fatigue, physical function and other aspects like mood and pain. Importantly: "They were also asked “Do you think that you are still suffering from CFS/ME?”" at follow-up either some 1 year after their initial clinical assessment or in some cases, 2-5 years later.

Results: "50–65% experienced little or no change in their condition 1–5 years after accessing a specialist service and 10–20% reported a deterioration, up to 30% of patients reported very much or much better health (and the majority of those who experienced little or no change had improved slightly)."

There are a few ways you could look at such results. You could say that specialist CFS/ME services are doing a fairly good job for approximately a third of patients who use them based on the figures reported. The authors do note some variability between the services that were included for analysis and given also that CFS/ME probably includes various 'sub-groups' under its banner, I'm not surprised therefore that there were potential best-responders and non-responders to the intervention(s) put in place.

The other way you could look at these data is with slightly less enthusiasm. Upwards of about two-thirds of patients surveyed saw no real difference to their symptoms long-term even after accessing such specialist services. More worryingly, a significant minority ("10-20%") reported deterioration; assuming this deterioration was in part or whole linked to their receipt of said specialist services, this is potentially in direct contravention of the tenet: first do no harm. These percentages - cumulatively up to 70%+ of patients - suggesting that specialist treatment might not necessarily be fit for purpose, need also to be analysed in the context of the costs associated with such specialist provisions in these days of rationing in many other parts of the NHS (see here for an example).

There is another detail included in the Collin/Crawley paper that requires comment: "Comparison with previous literature." The authors specifically focus in on the results for CBT and GET described in the PACE trial. They note: "The proportions of PACE trial participants (in the CBT and GET arms) who rated their overall health as very much or much better at 12 and 31 months were 41% and 42–48%, respectively, compared with 28% and 30% in our study (at 12 months and 2–5 years)." The authors suggest that differences in the number/intensity of sessions provided in the PACE trial and in 'real-life' might be one variable to account for the disparity reported on but I think we have to be a little bit careful here before saying specialist services either 'aren't doing it right' or 'aren't providing enough of a service'. There is for example, a debate currently rumbling on whether the recovery statistics subsequently produced from the PACE trial were entirely representative of the data produced (see here and see here for discussion on the authors reply). Minus any sweeping generalisations but in that context, I think one has to consider that there may be simpler answers to the disparity between studies: in a real-life context, CBT and GET are not as good an intervention for CFS/ME as some people might think. Indeed, it's potentially relevant that the US CDC has omitted CBT and GET from their current guidance for CFS/ME (see here) on top of similar changes to other guidance on this topic (see here). I know there may be some push-back to the idea that CBT and GET may not be the most suitable methods for 'treating' CFS/ME but nonetheless...

The Collin/Crawley paper provides a good snapshot of what patients themselves are saying about the current methods of treating/managing CFS/ME here in England. The picture the data paints is one of quite a bit more to do when it comes to how we care for some of the most ill people in society (see here for the quality of life comparisons). The focus on CBT for example, and the idea that those with the condition perhaps just need 'a change of attitude' towards their illness, is seemingly not working as well as some might wish. Although GET has shown some signs of efficacy for some with CFS/ME (see here), the sweeping generalisation that such an intervention is suitable for all with CFS/ME is also not borne out by the data and indeed, could potentially be quite damaging to some.  And patients are now saying that in the peer-reviewed science arena as well as on other forums too. Indeed, I again draw your attention to a quote from the opinion piece by Jonathan Edwards [3]: "If they [people with CFS/ME] are still ill, presumably these approaches have failed and the priority is to find something more effective." Who would disagree with such a sentiment?

To close, and related to today's post, has the dust settled yet regarding that special issue about the PACE trial published in the Journal of Health Psychology? I would say not...

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[1] Collin SM. & Crawley E. Specialist treatment of chronic fatigue syndrome/ME: a cohort study among adult patients in England. BMC Health Services Research. 2017; 17: 488.

[2] White PD. et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011 Mar 5;377(9768):823-36.

[3] Edwards J. PACE team response shows a disregard for the principles of science. 2017. J Health Psychology. March 28.

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On your marks, GETSET...

I don't doubt that the article published by Lucy Clark and colleagues [1] (open-access) on the topic of testing "the efficacy and safety of graded exercise delivered as guided self-help" in the context of chronic fatigue syndrome (CFS) is going to divide opinion. I say that on the basis that graded exercise therapy (GET) as part of a suite of interventions linked into the PACE trial for example, has taken up masses of column inches in the lay and science media over the years and seems set to do so for some time to come.

I'm going to try and talk about the Clark paper as context-free as I can, bearing in mind that science does not exist in some sort of vacuum detached from real-life. I say that on the basis that this is supposed to be a science-related blog and whilst being very much aware of the discussion/politics around the potential rights-and-wrongs of various components of the PACE trial, I don't want them to necessarily spill over to this piece of new science.

So, GETSET - graded exercise therapy guided self-help trial - was the name of trial [2] and the design was such that "an open-label, pragmatic randomised controlled trial done at two UK National Health Service (NHS) secondary-care clinics for chronic fatigue syndrome in central London and Kent" was employed. Over 200 participants diagnosed with CFS - "who met the UK National Institute for Health and Care Excellence criteria for chronic fatigue syndrome" - were included for study; half of which were allocated to receive 'specialist medical care' (SMC) with the other half receiving SMC with "additional guided graded exercise self-help (GES)." The trial lasted for 8-12 weeks and the primary outcomes were "fatigue (measured by the Chalder Fatigue Questionnaire) and physical function (assessed by the Short Form-36 physical function subscale)" delivered at baseline and 12 weeks and relying on self-report. We are also told that "Participants were also followed up at 12 months after randomisation, and these results will be published in a separate paper."

Results: as per some further commentary on the study [3] by someone not totally unknown to some of the authors on the Clark paper, the use of SMC + GES did seem to show some effects on self-reported fatigue scores insofar as correlating with "significantly lower mean fatigue score... and higher self-reported physical function score... than did patients managed with specialist medical care alone." They also reported that: "participants in the GES groups had better outcomes than did participants in the control group for work and social adjustment scores, depression, and anxiety, but not for general physical symptoms." Importantly however, it is noted that (a) "physiotherapists reported that 43 participants (42%) adhered to GES completely or very well, 31 (30%) moderately well, and 30 (29%) slightly or not at all" and (b) only about 20% of those receiving GES "noted improvements (“much” or “very much better”) in overall health" and even less (15%) in relation to the symptoms of CFS. This was not a study demonstrating total and universally successful outcomes.

Outside of just those outcomes, the important issue of side-effects or adverse events potentially associated with intervention were also analysed: "non-serious adverse events were reported by 27 (28%) of 97 participants who received guided graded exercise self-help and by 23 (23%) of 102 patients who received specialist medical care only, with no significant differences between the two groups." A couple of participants also dropped out of the study who were using GES but generally intervention seemed to be "well-tolerated" according to the authors.

Limitations? Well, the authors do discuss a few; not least that 'self-report' was the main avenue for data collection. Likewise: "We did not measure any objective outcomes, such as actigraphy, which might have tested the validity of our self-rated measures of physical activity." That last point is quite a large study weakness throughout a lot of research looking at physical activity in many areas, particularly given the availability of some rather accurate and reliable equipment these days (see here). Indeed, the fact that the GES intervention was supervised by physiotherapists yet seemingly had no objective measures of anything physiotherapist-related is a little unusual. I might also add that whilst fatigue is a primary symptom of CFS, there are various other symptom manifestations (e.g. post-exertional malaise, PEM) that also require a lot more investigation in terms of effects from intervention; something particularly pertinent to any intervention that has an 'exertional' component to it. It's also important to note something else discussed by authors: "this trial was not designed to test causative factors in chronic fatigue syndrome, and the relative efficacy of a behavioural intervention does not imply that chronic fatigue syndrome is caused by psychological factors." Perhaps something of an olive branch is meant by that statement, particularly in light of the issues noted with something like the biopsychosocial (BPS) model being [deleteriously] applied to CFS down the years (see here).

There is a need for further research in this area before anyone gets ahead of themselves with the Clark results as some media headlines seem to have. Other studies [4] combined with opinion from some patient organisations (see here) have highlighted potential issues following the use of GET, and in particular it's use as a 'blanket form of treatment' for CFS. Indeed, 'blanket forms of treatment' have in my mind, been a source of real pain and discomfort to many people suffering (yes, suffering) with CFS; something hopefully being addressed by other research talking about subgroups and phenotypes (see here) and expected changes to clinical guidance here in Blighty for example due quite soon.

As to the question of mechanism(s) pertinent to GET being applied to 'some' CFS, we're still left wanting. I could speculate about issues such as 'de-conditioning' that is bound to be part-and-parcel of CFS and how GET could be targeting this variable. But really, nobody knows everything there is to know about how something like GET might impact on physiology because no-one seems to have measured it in any great detail. Again, quite a few of the trials from the group(s) behind GETSET and PACE have tended to be quite 'light' on physiological measurements before and after intervention; something that perhaps needs to be addressed.

So, there you have it. Some potentially important results but also an area that requires any awful lot more study before any sweeping generalisations are made and made without patient involvement. I await also the follow-up results from this research team to see what happened in the longer term...

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[1] Clark LV. et al. Guided graded exercise self-help plus specialist medical care versus specialist medical care alone for chronic fatigue syndrome (GETSET): a pragmatic randomised controlled trial. Lancet. 2017. June 22.

[2] Clark LV. et al. Graded Exercise Therapy Guided Self-Help Trial for Patients with Chronic Fatigue Syndrome (GETSET): Protocol for a Randomized Controlled Trial and Interview Study. JMIR Res Protoc. 2016 Jun 8;5(2):e70.

[3] Clauw DJ. Guided graded exercise self-help as a treatment of fatigue in chronic fatigue syndrome. Lancet. 2017. June 22.

[4] Núñez M. et al. Health-related quality of life in patients with chronic fatigue syndrome: group cognitive behavioural therapy and graded exercise versus usual treatment. A randomised controlled trial with 1 year of follow-up. Clin Rheumatol. 2011 Mar;30(3):381-9.

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The continuing trials and tribulations of PACE

I honestly hadn't intended talking about the PACE trial - "pacing, graded activity, and cognitive behaviour therapy: a randomised evaluation" in relation to chronic fatigue syndrome (CFS) - quite so much on this blog. Others have done it so much better than I ever could.

My interest however keeps being piqued in relation to the results originally produced suggesting that: "CBT [cognitive behaviour therapy] and GET [graded exercise therapy] can safely be added to SMC to moderately improve outcomes for chronic fatigue syndrome" and the subsequent myriad of voices quite unanimously suggesting that one perhaps needs to be a little careful with such sweeping generalisations (see here).

OK, for anyone new to this topic, below are a few of the previous occasions that it has been discussed on this blog in chronological order:

• Chronic Fatigue Syndrome and various factors (2014) (see here)
• Chronic fatigue syndrome and the detrimental application of the 'biopsychosocial model' (2016) (see here)
• PACE-gate! (2016) (see here)
• PACE trial recovery data and chronic fatigue syndrome (2017) (see here)
• PACE trial recovery data and chronic fatigue syndrome - a reply (2017) (see here)

I want to add a few more 'science references' to this issue because some important things are being discussed in the peer-reviewed domain, in the context that CBT and GET at the moment, are considered 'best practice' here in the UK and beyond when it comes to CFS. That may change in future times (see here) as it has in other parts of the world (see here) but that's where we are at the time of writing. I might add that the addition of new references to this post is a rather more descriptive thing minus too much additional commentary from me, and that the views represented are those of the authors. I wrote this post on 9 April 2017 so it is accurate up to that point.

OK, starting with the editorial from Keith Geraghty [1] mentioned in that PACE-gate! post, we have an authors reply to some of the points raised [2]. The main crux of the reply is to correct "misunderstandings and misrepresentations of the PACE trial." Next up was a paper by Leonard Jason [3] (someone with quite an impressive research track record when it comes to CFS) and some comments on the pacing intervention (adaptive pacing therapy, APT) used and "patient selection ambiguity." This is a particularly interesting paper because APT - "based on the envelope theory of chronic fatigue syndrome" where the symptoms of CFS are "not reversible by changes in behaviour" - did not hit the 'research spot' according to the original PACE trial results.

I want to next include the paper by Luis Nacul and colleagues [4] into proceedings, and a role for "selection bias and disease misclassification" when it comes to studies on CFS (and myalgic encephalomyelitis, ME). To quote from them: "When studies using the broad Oxford criteria... were excluded, a virtual disappearance of effect for graded exercise therapy (GET), cognitive behaviour therapy (CBT) and other psychological therapies recommended by the NICE guidelines (National Institute for Health and Care Excellence.. was revealed." Guess which criteria (among the many available) were used in the original trial?

Onward. The paper by Steven Lubet [5] titled: 'Investigator bias and the PACE trial' sets out quite an 'accusation' in that: "the PACE investigators “impartiality might reasonably be questioned”." This is a theme that crops up again shortly. The paper by Tom Kindlon [6] asked whether graded exercise in particular, could be thought of as 'safe and risk-free'? I set this question within the context that the original PACE trial did find that: "Non-serious adverse events were common" and GET did seem to produce the largest number of 'serious adverse effects' in number if not in participants.

Nearly there. Next up is the paper from Carolyn Wishire [7] who, when talking about "lively discussion", reports on various potential forms of bias in behavioural intervention studies using the PACE study as a kind of template. This author was the lead on the recent peer-reviewed commentary (open-access) re-analysing the 'recovery' data subsequently published in relation to the PACE trial. Then, we have the paper by Jonathan Edwards [8] who notes that the PACE trial represents a lesson in how research design needs to develop further when it comes to science in general. To quote: "The failure of the academic community to recognise the weakness of trials of this type suggests that a major overhaul of quality control is needed." And finally Charles Shepherd [9] provides further commentary on the PACE trial and a call for independent review.

And rest.

There is quite a lot to take in from those various publications and I don't doubt that this is not the last we are going to hear about the PACE trial. Allied to articles such as this one describing how: "Physicians used to dismiss the disease as psychosomatic" (past tense) it certainly would not out of place to suggest that there are still questions that need to be answered about the design and results obtained from the PACE trial and their applicability to the (very) wide CFS/ME population. To quote again from the paper by Edwards [8]: "If they are still ill [those diagnosed with CFS/ME], presumably these approaches have failed and the priority is to find something more effective." Wise words indeed.

To close, it's here... the first glimpse of The Last Jedi.

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[1] Geraghty KJ. ‘PACE-Gate’: When clinical trial evidence meets open data access. J Health Psychology. 2016. Nov 1.

[2] White PD. et al. Response to the editorial by Dr Geraghty. J Health Psychology. 2017. Jan 24.

[3] Jason LA. The PACE trial missteps on pacing and patient selection. J Health Psychology. 2017. Feb 1.

[4] Nacul L. et al. How have selection bias and disease misclassification undermined the validity of myalgic encephalomyelitis/chronic fatigue syndrome studies? J Health Psychology. 2017. March 1.

[5] Lubet S. Investigator bias and the PACE trial. J Health Psychology. 2017. March 7.

[6] Kindlon T. Do graded activity therapies cause harm in chronic fatigue syndrome? J Health Psychology. 2017. March 20.

[7] Wilshire C. The problem of bias in behavioural intervention studies: Lessons from the PACE trial 2017. J Health Psychology. March 23.

[8] Edwards J. PACE team response shows a disregard for the principles of science. 2017. J Health Psychology. March 28.

[9] Shepherd CB. PACE trial claims for recovery in myalgic encephalomyelitis/chronic fatigue syndrome – true or false? It’s time for an independent review of the methodology and results. J Health Psychology. April 9.

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Edwards, J. (2017). PACE team response shows a disregard for the principles of science Journal of Health Psychology DOI: 10.1177/1359105317700886





White, P., Chalder, T., Sharpe, M., Angus, B., Baber, H., Bavinton, J., Burgess, M., Clark, L., Cox, D., DeCesare, J., Goldsmith, K., Johnson, A., McCrone, P., Murphy, G., Murphy, M., O’Dowd, H., Potts, L., Walwyn, R., & Wilks, D. (2017). Response to the editorial by Dr Geraghty Journal of Health Psychology DOI: 10.1177/1359105316688953

PACE trial recovery data and chronic fatigue syndrome - a reply

I'd encourage readers interested in the background to the response paper by Michael Sharpe and colleagues [1] to have a look at a previous blogging occasion when the topic of the PACE trial, chronic fatigue syndrome (CFS) and 'recovery' were discussed (see here).

Suffice to say that this latest paper is a reply to one published by Carolyn Wilshire and colleagues [2] who concluded that: "The claim that patients [with CFS] can recover as a result of CBT [cognitive behaviour therapy] and GET [graded exercise therapy] is not justified by the data, and is highly misleading to clinicians and patients considering these treatments." Said discussions linking back to some quite extensive debates on how one should (and shouldn't) treat/manage conditions like CFS (see here).

I wanted to highlight the latest Sharpe paper because (a) I anticipated a reply from these authors following the Wilshire paper criticism of their recovery paper [3], and (b) although the debates in this area have been quite extensive already, the use of the scientific peer-reviewed medium to discuss and even argue is an important avenue. The authors have a right to scientific reply.

So how did Sharpe et al respond? Well the words 'recovery', 'threshold' and ''no generally agreed measure of recovery" when it comes to CFS form the crux of the response to the Wilshire paper. They address the issue of recovery thresholds that have been a real source of discussion in relation to the PACE trial secondary analysis concluding that: "No participant met our full criteria for recovery at baseline." They point out that whilst "13% of participants met the recovery criterion of being within the normal range... for physical functioning when entering the trial" physical functioning was but one measure they used to determine recovery.

They also approach the topic of 'changing thresholds' when it came to the definition of recovery in the PACE trial. To quote: "We changed these thresholds for our detailed analysis plan because after careful consideration and consultation, we concluded that they were simply too stringent to capture clinically meaningful recovery." They also report that elements of their assessment - the PACE walking test - are "not comparable with data collected in other studies" as a function of their reliance on personal motivation/ability over and above the use of encouragement as in other studies.

Finally, authors also talk about 'what other studies have found regarding recovery' when it comes to CFS. They note that their findings in relation to the use of standard medical care (SMC) for CFS in the PACE trial were similar to other reports [4]. They also point to research suggesting that the use of CBT in independent study for CFS show similar rates of recovery [5] to theirs originally reported. In other words, they make a case for their findings fitting in with some of the other literature on this topic.

A quick trawl of PubMed with the terms 'chronic fatigue syndrome' and 'recovery' reveals that there is indeed quite a bit more to do in this area of science. To quote from one paper (a critical review) [4]: "Estimates of recovery ranged from 0 to 66 % in intervention studies and 2.6 to 62 % in naturalistic studies." What this tells us is that (a) how recovery is reported in relation to CFS is still in need of some clarification [6] and perhaps more importantly, agreed uniformity is still required in its assessment; (b) some of the measures used to form judgements of recovery when it comes to CFS are not necessarily fit for purpose [7] (bearing in mind not everyone agrees with this); and (c) further efforts need to go into looking at many more aspects of CFS recovery outside of just a reliance on the fatigue parameter (see here and see here for examples). In short, science does not really know what recovery looks like in relation to CFS [8] despite it seemingly happening for all manner of reasons...

Where do we go from here? This is a difficult question to answer. It is doubtful that the response from Sharpe and colleagues is going to change too many opinions about PACE given the strength of feeling on the topic and the various goings-on that have occurred around debate in this area (see here). Still today, other comments on the PACE trial continue to emerge in the peer-reviewed domain [9] from notable CFS researchers and there are even calls to retract the original recovery paper (see here). Yes, there are lessons to be learned from the PACE trial (e.g. stick to your "original protocol thresholds", make your data 'open-access' and think about how to do this in the planning/recruitment stages of your trial, be mindful that short-term gains don't necessarily translate into long-term ones, work with the ME/CFS community (rather than labelling elements of them 'vexatious' or worse when they ask questions or request data) but I can't see how these factors will immediately and positively affect the lives of people living with CFS/ME here and now. That recommendations on the use of CBT for CFS have already altered in some parts of the world (see here) - "The strength of evidence on global improvement is downgraded from moderate to low when considering CBT separately from other counseling and behavioral interventions" - and are potentially likely to change here in Blighty perhaps signifies that science and medicine is moving on when it comes to this topic. Science should be doubling its efforts to expand its research boundaries when it comes to managing CFS outside of just a reliance on the [outdated?] psychosomatic model and indeed, it is...

And on the topic of other CFS research avenues, I've already talked about a few interesting avenues on this blog (see here and see here and see here) mindful that when we talk about CFS/ME, we're probably not talking about just one entity (see here). Also alongside, that there seems to be an awful lot of 'over-represented' comorbidity accompanying quite a lot of CFS/ME (see here for example) to also contend with...

Music: Lush Life (even if you don't know the song title, you might recognise the tune).

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[1] Sharpe M. et al. Do more people recover from chronic fatigue syndrome with cognitive behaviour therapy or graded exercise therapy than with other treatments? Fatigue: Biomedicine, Health & Behavior. 2017. Feb 15.

[2] Wilshire C. et al. Can patients with chronic fatigue syndrome really recover after graded exercise or cognitive behavioural therapy? A critical commentary and preliminary re-analysis of the PACE trial. Fatigue: Biomedicine, Health & Behavior. 2016. Dec 14.

[3] White PD. et al. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychol Med. 2013 Oct;43(10):2227-35.

[4] Cairns R. & Hotopf M. A systematic review describing the prognosis of chronic fatigue syndrome. Occup Med (Lond). 2005 Jan;55(1):20-31.

[5] Flo E. & Chalder T. Prevalence and predictors of recovery from chronic fatigue syndrome in a routine clinical practice. Behav Res Ther. 2014 Dec;63:1-8.

[6] Twisk FN. A definition of recovery in myalgic encephalomyelitis and chronic fatigue syndrome should be based upon objective measures. Qual Life Res. 2014 Nov;23(9):2417-8.

[7] Matthees A. Assessment of recovery status in chronic fatigue syndrome using normative data. Qual Life Res. 2015 Apr;24(4):905-7.

[8] Brown B. et al. 'Betwixt and between'; liminality in recovery stories from people with myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS). Sociol Health Illn. 2017 Feb 27.

[9] Jason LA. The PACE trial missteps on pacing and patient selection. Journal of Health Psychology. 2017. Feb 1.

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M Sharpe, T Chalder, AL Johnson, KA Goldsmith, & PD White (2017). Do more people recover from chronic fatigue syndrome with cognitive behaviour therapy or graded exercise therapy than with other treatments? Fatigue: Biomedicine, Health & Behavior, 1-5 : 10.1080/21641846.2017.1288629

PACE trial recovery data and chronic fatigue syndrome

PACE mentioned in the title of this post refers to the PACE trial [1] which concluded that: "CBT [cognitive behaviour therapy] and GET [graded exercise therapy] can safely be added to SMC [specialist medical care] to moderately improve outcomes for chronic fatigue syndrome, but APT [adaptive pacing therapy] is not an effective addition."

The recent paper by Carolyn Wilshire and colleagues [2] who drew on "relevant normative data and other research" continues a peer-reviewed research theme focused on some of the details included in the original and subsequent PACE trial publications specifically that discussing the topic of recovery [3]. To quote from that 2013 paper [3] on the topic of the PACE trial: "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."

OK, anyone that knows anything about chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) will probably have seen or heard about the debates around the PACE trial; the trial now having it's own -gate suffix (see here). The ups-and-downs, twists-and-turns, surrounding this trial have rumbled on for years now; merging with more general criticism of the biopsychosocial (BPS) model (see here), moving into debates about data-sharing, including Information Commissioner legal stuff and allowing the word 'vexatious' to be banded around quite a few times. The term 'bad science' has also been used on occasion (see here) albeit not necessarily in the peer-reviewed domain context...

Quite a few of the authors on the Wilshire paper have been central to many of the discussions around the PACE trial, also including the respondent who is credited with getting the raw trial data released alongside the UK Information Commissioner. They set out to examine the recovery definition used in that 2013 PACE trial add-on paper and "whether these recovery claims are justified by the evidence". Their answer: "None of the changes made to PACE recovery criteria were adequately justified. Further, the final definition was so lax that on some criteria, it was possible to score below the level required for trial entry, yet still be counted as ‘recovered’." The sorts of recovery figures they arrived at were "only single-digit rates of “recovery” for all four groups in the study" according to another write-up of the study in comparisons to the 22% offered in the 2013 paper. Whilst this is important research, this is not the first time that the recovery criteria included in the PACE trial has been discussed. Indeed, this latest publication really just gets the whole thing into the peer-reviewed domain.

"The claim that patients can recover as a result of CBT and GET is not justified by the data, and is highly misleading to clinicians and patients considering these treatments." Strong words indeed from the authors and I expect there will eventually be a reply from the original PACE authors on this matter too. PACE-gate is set to rumble on into 2017...

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[1] White PD. et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011 Mar 5;377(9768):823-36.

[2] Wilshire C. et al. Can patients with chronic fatigue syndrome really recover after graded exercise or cognitive behavioural therapy? A critical commentary and preliminary re-analysis of the PACE trial. Fatigue: Biomedicine, Health & Behavior. 2016. Dec 14.

[3] White PD. et al. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychol Med. 2013 Oct;43(10):2227-35.

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Wilshire, C., Kindlon, T., Matthees, A., & McGrath, S. (2016). Can patients with chronic fatigue syndrome really recover after graded exercise or cognitive behavioural therapy? A critical commentary and preliminary re-analysis of the PACE trial Fatigue: Biomedicine, Health & Behavior, 1-14 DOI: 10.1080/21641846.2017.1259724

PACE-gate!

With all rights reserved for Keith Geraghty and his publication in the Journal of Health Psychology [1] (open-access) I want to reproduce his abstract relevant to the PACE trial commenting on the ups-and-downs of this study looking at the use of CBT (cognitive behaviour therapy) and GET (graded exercise therapy) for chronic fatigue syndrome (CFS) (also known as myalgic encephalomyelitis, ME):

"Science is not always plain sailing and sometimes the voyage is across an angry sea. A recent clinical trial of treatments for chronic fatigue syndrome (the PACE trial) has whipped up a storm of controversy. Patients claim the lead authors overstated the effectiveness of cognitive behavioural therapy and graded exercise therapy by lowering the thresholds they used to determine improvement. In this extraordinary case, patients discovered that the treatments tested had much lower efficacy after an information tribunal ordered the release of data from the PACE trial to a patient who had requested access using a freedom of information request."

For those familiar with PACE [2] and the 'angry sea' saga following its publication (see here for some of that saga), this paper represents one of the the first 'peer-reviewed' discussions that makes reference to the reanalysis of 'trial improvers' vs. that included in the original PACE trial publication (see here). Indeed, combined with other (as yet unpublished in the peer-reviewed domain) re-analyses (see here), there seem to be some pretty stark differences noted between the different 'versions' in terms of the effectiveness of different arms of the intervention tested during the PACE trial. Even before these latest re-analyses, some agencies were already adjusting the strength of their recommendations when it came to CBT and/or GET for CFS/ME (see here). Does this mean other organisations might follow suit?

The other issue central to the Geraghty discussions is that of 'enforced data release' and data transparency. This has been a focal point when it comes to PACE (including that with reference to other papers on the trial) and perhaps something that has significantly added to the sometimes bitter discussions about the trial. As Geraghty notes: "The PACE-Trial stands out as a showcase example of why data transparency is needed in contemporary science. Patients suffering from health conditions like CFS, and independent scientists, should have the right to see the evidence behind the claims of any scientific study, especially if this evidence is used to direct health policy or promote certain treatments – as was the case for the PACE-Trial." In light of how PACE has been contributory to public policy, and indeed was part funded by agencies such as "the UK Department for Work and Pensions", I don't think many people would argue against suitable data transparency in this case.

I say nothing more at this point in time but will no doubt be returning to this topic as the peer-reviewed literature allows (which should be quite soon). If there are however, some lessons that can already be learned from PACE-gate (e.g. stick to your "original protocol thresholds", make your data 'open-access' and think about how to do this in the planning/recruitment stages of your trial, be mindful that short-term gains don't necessarily translate into long-term ones, work with the ME/CFS community rather than labelling elements of them 'vexatious' or worse) one would hope that they would be applied to future research projects related to CFS/ME (see here) as well as their anticipated long-term follow-up [3]...

Music: The King and what wise men (might) say (easily recognisable to any Black Cats fan).

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[1] Geraghty KJ. 'PACE-Gate': When clinical trial evidence meets open data access. J Health Psychol. 2016 Nov 1. pii: 1359105316675213.

[2] White PD. et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011 Mar 5;377(9768):823-36.

[3] Nijhof SL. et al. Internet-based therapy for adolescents with chronic fatigue syndrome: long-term follow-up. Pediatrics. 2013 Jun;131(6):e1788-95.

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Geraghty KJ (2016). 'PACE-Gate': When clinical trial evidence meets open data access. Journal of health psychology PMID: 27807258