Rehabilitative treatments for chronic fatigue syndrome: long term follow up from PACE trial

Dolphin

Senior Member
Messages
17,555
Likes
28,239
Was this posted anywhere?


For the record

Response to headlines suggesting ME 'is all in the mind'
Articles on Wednesday 28th October in the Daily Mail, the Daily Telegraph and others reported that new research on ME/CFS showed it to be a disease that was “all in the mind”, and that the research contradicted the view that ME/CFS is “chronic and cannot be alleviated”.

The study, published in The Lancet Psychiatry, was a long-term follow-up to a study that suggested that cognitive behaviour therapy and graded exercise therapy were moderately effective ways of treating some people with ME/CFS.

Lead author of the study, Michael Sharpe, Professor of Psychological Medicine, University of Oxford:

"The study did not find that ME/CFS is ‘all in the mind’ – in fact it didn’t look at causes of the disease at all. People think that if these kinds of treatments help, it is saying something about the nature of the illness, which of course isn’t true. This study tells us nothing about the cause of the illness, just how to help people who have it. 'All in the mind' is also a hugely misleading description of conditions that might be associated with psychological and social factors.

"The study did not contradict the view that ME/CFS is a chronic illness. These treatments, which we have found previously to be moderately helpful, are not a cure, and they do not benefit everyone. But the good news is, the benefit of these treatments is still apparent two years later, and they do not lead to a relapse of the illness. This new finding should reassure patients who want to try these treatments."

Document type: For The Record

Published: 28 October 2015


New For The Record search

- See more at: http://www.senseaboutscience.org/fo...ng-me-is-all-in-the-mind#sthash.QemuaiHS.dpuf
Two points:
(i)
These treatments, which we have found previously to be moderately helpful, are not a cure
If this is the case, why did they publish a study claiming 22% recovered.

(ii)
The study did not find that ME/CFS is ‘all in the mind’ – in fact it didn’t look at causes of the disease at all. People think that if these kinds of treatments help, it is saying something about the nature of the illness, which of course isn’t true. This study tells us nothing about the cause of the illness, just how to help people who have it. 'All in the mind' is also a hugely misleading description of conditions that might be associated with psychological and social factors.
The CBT and GET models suggest any problems can be reversed by the therapies. It would be interesting if these therapies led to recovery: it would say the models are correct and that the illness is maintained by maladaptive illness beliefs and behaviours.

However, with a rigid recovery definition (even their original one is still a bit loose e.g. 85 on SF-36 doesn't represent full functioning esp. if not working/studying full-time), it looks like the figures for recovery in the PACE trial would be very small suggesting the model doesn't fit for most people with the illness.

It is a great shame that we can't get the recovery definition in the protocol to get an idea what percentage the model works for (my guess is it's a very low figure). The revised recovery definition doesn't tell us anything on this issue.
 

Dolphin

Senior Member
Messages
17,555
Likes
28,239
BMJ e-letter replying to: Tackling fear about exercise produces long term benefit in chronic fatigue syndrome

http://www.bmj.com/content/351/bmj.h5771/rr

01 November 2015
Esmeralda Green
Patient
London


Re: Tackling fear about exercise produces long term benefit in chronic fatigue syndrome

There has been considerable concern expressed about the methodology behind this trial which should lead to huge caveats around the reliability of the results. David Tuller has written an excellent long article [1]on the issues as well as a corresponding reply from the PACE investigators [2] and David's follow up response [3]. I would recommend those looking to recommend or make decisions about these treatment read these articles first along with the latest ME Association patient survey [4] that documents may instances of harm caused by GET (one of the treatments recommended in this article).

To summarize two particular points of concern about the trial

1) There are many changes from the published protocol which is particularly serious given the trial was not blinded. Changes apparently occurred after the trial had finished but prior to looking at the data. But given the non-blinded nature of the trial it is likely that the investigators had an idea of the results. Detailed reasons beyond 'we believe this was better' statements were not given. Equally the effects of the changes could have been mitigated by publishing the original data along side the changes so that readers could see the effects. However, there has been a refusal to publish data as defined in the original protocol.

2) The results quoted rely on subjective measures of improvement. Part of the basis and rational of the CBT and GET protocols is to change how patients thing about symptoms. So improvements in subjective scores should not be considered reliable. The improvements were not demonstrated across more objective measures. At the start of this year, some 4 years after the first results were published, a graph showing the results of a fitness test was published. This showed very similar results for all groups with patients in the CBT and GET group performing slightly worse. Unfortunately the figures behind the graph are kept secret [5].

From the coverage of this latest long term follow up readers would believe that the trial suggested CBT and GET were the best long term treatments. However, the results of the primary long term hypothesis comparing the different groups showed no significant difference between all four treatments. This should be the main headline of this article anything else is misleading. Coyne has published a detailed analysis of this paper [6] - again I would suggest this is essential reading for anyone making decisions about these treatments.

Given the BMJ has called for better reporting of clinical trials, publishing of protocols and ensuring that they are enforced it is a pity they do not enforce such standards in their news stories.

[1] D. Tuller - TRIAL BY ERROR: The Troubling Case of the PACE Chronic Fatigue Syndrome Study - http://www.virology.ws/2015/10/21/trial-by-error-i/

[2] P.D. White et al - PACE trial investigators respond to David Tuller -http://www.virology.ws/2015/10/30/pace-trial-investigators-respond-to-david-tuller/

[3] D. Tuller - David Tuller responds to the PACE investigators -http://www.virology.ws/2015/10/30/david-tuller-responds-to-the-pace-investigators/.

[4] ME Association - ME/CFS Illness Management Survey results -http://www.meassociation.org.uk/wp-content/uploads/2015-ME-Association-Illness-Management-Report-No-decisions-about-me-without-me-30.05.15.pdf

[5] G. McPhee - Fitness Data for PACE trial -https://www.whatdotheyknow.com/request/fitness_data_for_pace_trial

[6] J. Coyne - Uninterpretable: Fatal flaws in PACE Chronic Fatigue Syndrome follow-up study http://blogs.plos.org/mindthebrain/...ace-chronic-fatigue-syndrome-follow-up-study/
 

Hutan

Senior Member
Messages
1,086
Likes
6,442
Location
New Zealand
Here's a bigger version of the same image:
@Anna Wood

This is a really valuable graph, thanks. To me it summarises the results of the PACE trial (without even having to go in to the problems with participant selection; participant drop out rate; enhanced placebo effects; subjective vs objective measures and more).

If participants did no CBT or GET after the trial:
There is no difference at all between treatment arms (SMC, APT, GET, CBT) in self-reported (subjective) fatigue and physical functioning.

If participants did CBT or GET after the trial (regardless of initial treatment arm)
Compared to those who did not do such treatment after the trial, their reported fatigue was about the same but their reported physical functioning was worse.
This is probably because the participants who sought further treatment were sicker than those who did not and so were desperately trying any treatment. It may also be because the CBT or GET caused harm (with the full impact of this possibility blurred by the exclusion of data from people who dropped out of the trial before completion).

Ah, yes. So the data come straight from a table with all 4 treatment arms. Data for 0, 5 and 10 are in pairs for SMT and APT, Data for 15, 20 and 25 are for CBT and GET. I didn't want to average them, to give the data the best chance, but as you see it really doesn't matter much. For PF - 5 sessions the high point is CBT, for 20 sessions the high point is GET.
Anna, did you mean to write 'For PF = 5 sessions the high point is APT'? given that for the CBT treatment arm, participants would have had more than 5 sessions?

Would it be possible to separate out the treatment arms in the graph by using different shaped markers?

That would be the graph I would be giving to the PACE researchers (and all who defend them and CBT/GET as a treatment for ME) with a 'please explain' note. Much more could be queried about their trial procedures but this alone shows that CBT and GET fail to produce any improvement when participants' data is averaged (and any improvement in an individual patient is balanced by a deterioration in another).
 

Valentijn

Senior Member
Messages
15,786
Likes
45,626
One of them has also posted some abusive nonsense about patients on Wessely's opinion-piece on the mental elf blog. They're not doing any favours for the NHS. The nastiness isn't a good look.
I'm pretty shocked that the NHS has medical summaries written by someone with that public attitude toward any patients. Why is this tolerated at all?
 

SOC

Senior Member
Messages
7,849
Likes
16,357
It's going to be tough extending amnesty to this one. Misled is one thing. Actively publicly abusive is another.
 

Esther12

Senior Member
Messages
13,774
Likes
28,353
I've just given the LTFU paper a proper read. tbh, I didn't follow a lot of the stats they referred to, but still have some thoughts.

1 Recovery and their use of this Cairns paper:

6. Cairns, R and Hotopf, M. A systematic review describing the prognosis of chronic fatigue syndrome. Occup Med (Lond). 2005; 55: 20–31

The prevalence of chronic fatigue syndrome is between 0·2% and 2·6% of people worldwide,5 and, if untreated, prognosis for recovery is poor.6
Several naturalistic follow-up studies have assessed outcomes in patients with chronic fatigue syndrome. A 2005 systematic review6 found 14 studies of people meeting operational criteria for chronic fatigue syndrome with a range of follow-up durations and outcome measures and concluded that prognosis was generally poor; improvement was reported by a median of 40% of participants and recovery by only 7%.6
So in the LTFU paper they're using Cairns to show how poor prognosis for recovery is if CFS is left untreated.

Now lets look at how they (mis)used the same Cairns paper to justify their new recovery criteria, and their failure to release results for the recovery criteria laid out in the trial's protocol:

We changed some of the thresholds for measuring recovery from those of the original protocols (White et al. 2007); we made the changes before analysis and to more accurately reflect recovery. Our finding that only 7% recovered after the minimal treatment of SMC, exactly the same proportion as the median recovery rate found without treatment (Cairns & Hotopf, 2005), supports these revised thresholds.
The 7% and 8% recovered after both APT and SMC were similar to the 7% reported in a systematic review after no treatment, suggesting a lack of efficacy of these treatments (Cairns & Hotopf, 2005).
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776285/

As their LTFU paper now indicates that the addition of CBT and GET to SMC led to no additional benefits at 2.5 years, which is closer to the average follow up of the Cairns paper, that would seem to place them in a bit of a bind.

Also, their recovery paper had stated:

We considered scores of 1 (‘very much better’) or 2 (‘much better’) as evidence of the process of recovery, rather than our original protocol threshold of a score of 1 only, because we considered that participants rating their overall health as ‘much better’ represented the process of recovery.
It seems that SMC alone was as effective at initiating the 'process of recovery' as when CBT and GET were added.

Their recovery paper was always such a joke - other PACE papers just serve to highlight that fact.

2 Their use of Powell 2004, while ignoring FINE:

No follow-up study of GET has been done, although a 2 year follow-up of a randomised trial of an educational intervention that included advice on graded activity showed benefits to be maintained.10
10. Powell, P, Bentall, RP, Nye, FJ, and Edwards, RH. Patient education to encourage graded exercise in chronic fatigue syndrome. 2-year follow-up of randomised controlled trial. Br J Psych. 2004; 184: 142–146

It was not mentioned this trial was followed by the larger FINE trial, which found that this approach led to no improvement over a poor control. Despite this trial being so much more expensive, it seems unlikely that we will see LTFU data - which would be likely to only further embarrass the trial's researchers. David Tuller wrtoe a piece on the way in which the results from FINE are routinely overlooked: http://www.virology.ws/2015/11/09/t...-sister-trial-been-disappeared-and-forgotten/

3 Pre-specified? Employment status?:

They state:

We report the findings of a pre-specified long-term (minimum 2 years after randomisation) follow-up of the PACE trial participants.
Does anyone know where these were pre-specified?

The trial's full protocol (the searchable version that's was gained through an FOI) stated:

9.2.1 Long term follow-up
Permission will be sought from the participant to be contacted annually for follow-up
information regarding the participant's health and employment status. The participant will
also be invited to remain in contact so that.the results may be disseminated to them once
published.
I've not found any more details than that, and we've not been provided with data on participant's employment status.

In their response to concerns about their recovery claims the PACE authors stated:

In addition, follow-up at 6 months after the end of therapy may be too short a period to affect either benefits or employment. We therefore disagree with Shepherd (2013) that such outcomes constitute a useful component of recovery in the PACE trial.
http://www.meassociation.org.uk/201...ournal-of-psychological-medicine-august-2013/

I've seen this argument used by others too. That being the case, it would be nice to have data from LTFU, which they had said they would collect.

4 Wish it was open peer review:

In an exploratory post-hoc subgroup analysis requested by a reviewer, the within-group improvements were observed whether participants had received additional CBT or GET or not; however, this finding must be interpreted with great caution, as we discuss later.
I would love to see their initial submission too, and how they tried to use the argument about follow-up CBT/GET before they included this data.

There was some evidence from an exploratory analysis that improvement after the 1 year trial final outcome was not associated with receipt of additional treatment with CBT or GET, given according to need. However this finding must be interpreted with caution because it was a post-hoc subgroup analysis that does not allow the separation of patient and treatment factors that random allocation provides.
This is cheeky, and Coyne was good on this:

However, why is this analysis singled out has exploratory and to be interpreted with caution because it is a post-hoc subgroup analysis when similarly post-hoc subgroup analyses are recommended without such caution?

The investigators finally get around to depicting what should be their primary finding, but do so in a dismissive fashion.

Between the original groups, few differences in outcomes were seen at long-term follow-up. This convergence in outcomes reflects the observed improvement in those originally allocated to SMC and APT, the possible reasons for which are listed above.
The discussion then discloses a limitation of the study that should have informed earlier presentation and discussion of results
http://blogs.plos.org/mindthebrain/...ace-chronic-fatigue-syndrome-follow-up-study/

I don't think it stood out to me so much on my first quick read through, and I wonder if my standards for PACE are now so low that I forget to be concerned by this sort of spin.

5 Arguably:


They ran a non-blinded trial with subjective self-report outcomes to assess two interventions intended to alter how patients viewed and thought about their symptoms, and the trial's objective outcomes failed to support their claims about CBT/GET's value to patients. You'd think that they'd have come up with some vaguely plausible sounding excuses for this, but instead we get this:

Third, the outcomes were all self-rated, although these are arguably the most pertinent measures in a condition that is defined by symptoms.
They keep referring to an argument on this rather than making it, eg:

First, recovery from chronic fatigue syndrome (CFS), which is defined by a patient’s reported symptoms, is arguably best measured by multiple patient-reported outcome measures, rather than a single performance test.
http://www.meassociation.org.uk/201...ournal-of-psychological-medicine-august-2013/

Whilst some correspondents have complained that the primary outcomes of the trial were self-rated, we argue that these are the most appropriate measures to judge improvement in an illness that is currently defined by symptoms.
http://www.bmj.com/content/350/bmj.h227/rr-24

If it's so arguable, why don't they present the argument?

6 What does it all mean?! (I don't know - worthless speculation, feel free to join me):

In some ways, the failure of CBT/GET to lead to improvements in self-reported fatigue and physical function slightly challenges my own assumptions that claims made as a part of CBT/GET lead to patients positively biasing self-report outcomes. If this biasing were to 'wear off' as patients became more sceptical over time, with the positive claims made by therapists not being supported by their own experiences, then wouldn't scores decline? Instead, we saw scores for APT/SMC increase. Could a desire to be a part of the trial and receive 'evidence based' interventions lead to patients exaggerating symptoms at baseline - as a way of emphasising that they need help? Those receiving CBT/GET had it made clear to them that this was as good as it gets for CFS treatments, which could reduce the need to 'call for help'? Did the passing of time lead to improvements in self-reported symptoms at roughly the same rate that the positive biasing resulting from CBT/GET diminished?

Something weird has happened here and I don't have a satisfying explanation, but I guess I don't have to provide one. PACE and claims about the value of CBT/GET are a mess, and that's not satisfying.

I re-read Keith Law's second blog on this, and appreciated it more this time. I think that a lot of patients have become so cynical about the value of PACE's subjective self-report outcomes that we can try less hard to interpret them.

http://keithsneuroblog.blogspot.co.uk/2015/11/song-for-siren.html

CBT seeming 'ineffective' post GET could reflect them having a shared mechanism of action? But then GET was associated with improvement post CBT.

This is making my head hurt. I'm going to eat a yoghurt. I'd like to think that this paper is the death-knell of CBT/GET/PACE-spin and I'll never have to read another medical paper again. Suspect that may not be the case.
 
Last edited:

user9876

Senior Member
Messages
4,556
Likes
18,065
In some ways, the failure of CBT/GET to lead to improvements in self-reported fatigue and physical function slightly challenges my own assumptions that claims made as a part of CBT/GET lead to patients positively biasing self-report outcomes. If this biasing were to 'wear off' as patients became more sceptical over time, with the positive claims made by therapists not being supported by their own experiences, then wouldn't scores decline? Instead, we saw scores for APT/SMC increase. Could a desire to be a part of the trial and receive 'evidence based' interventions lead to patients exaggerating symptoms at baseline - as a way of emphasising that they need help? Those receiving CBT/GET had it made clear to them that this was as good as it gets for CFS treatments, which could reduce the need to 'call for help'? Did the passing of time lead to improvements in self-reported symptoms at roughly the same rate that the positive biasing resulting from CBT/GET diminished?
I have a vague memory about differences in sf36 scores when done at home as opposed to at the doctors. So where the questionnaires are done could matter. Also I think there could be a timing thing so when forms are sent out people tend to wait for a good day before they fill them in - especially if there are a lot of them.
 

daisybell

Senior Member
Messages
1,613
Likes
7,384
Location
New Zealand
I think there is a tendency for people to score themselves as less impaired over time, simply as a result of adapting to life being ill. The frustration of the early years becomes acceptance/resignation, and we get better at pacing ourselves and being more resilient to the opinions of others.. So I would expect more positive bias over time, I think.
 

user9876

Senior Member
Messages
4,556
Likes
18,065
I think there is a tendency for people to score themselves as less impaired over time, simply as a result of adapting to life being ill. The frustration of the early years becomes acceptance/resignation, and we get better at pacing ourselves and being more resilient to the opinions of others.. So I would expect more positive bias over time, I think.
It would be interesting to see if improvements correlated with length of illness.
 

Esther12

Senior Member
Messages
13,774
Likes
28,353
There are so many potential problems with these outcome measures that it's a bit overwhelming.

Wessely chucked this into his mental Elf blog:

But frankly, it all seems far fetched. If a few encouraging anonymous sentences are all it takes to improve outcomes in CFS, then one wonders why we are bothering with all these complex treatments anyway. It is more plausible that there would have been a negative impact from some of the relentless negative publicity out there, some of it backed by one of the UK patient associations, and which was explicitly aimed against CBT and GET, and in favour of pacing, and some of it also specifically directed against PACE.
There are so many way in which these questionnaires can be distorted, especially by the relatively minor amounts that PACE is claiming are clinically significant, that it's difficult to use them to say anything.
 

anciendaze

Senior Member
Messages
1,841
Likes
4,789
In addition to previous material in which PACE authors accused other doctors of a 30% error rate in diagnosing CFS, I've turned up a review with Michael Sharpe as an author reporting that rates of diagnostic error for "conversion disorders" have been reduced to "only" 4% since 1970. Applied to a cohort of 640 patients this would mean we could expect 25 misdiagnoses, or about 6 in each arm of the study. This is quite enough to account for everything reported as a positive result in terms of group means.

Of course if you call it "somatization" it is entirely different, and the error rate drops to zero, right?
 

Tom Kindlon

Senior Member
Messages
1,634
Likes
8,656

Dolphin

Senior Member
Messages
17,555
Likes
28,239
https://www.facebook.com/permalink....1334574529933535&comment_tracking={"tn":"R2"}

An example of the possible short-term effect with GET that wasn't maintained long-term. Not a PACE participant as far as I know.
X said:
GET and CBT worked for me but no I was not cured nor did I expect a cure when doing them.
Y said:
Steve Boyle If you were not cured, how did GET and CBT benefit you ?

X said:
With GET I worked my steps up to about 8000 per day within 4 months which ment I was able to lose half a stone. I was also trying to drink 2 litres of water a day. Its the most well ive ever felt but life situations happened and i couldnt keep the routine up...i then went back to my 'normal' M.E state. Im pretty much house bound like i was prior to GET. Witj CBT im quite mindful any way. I worked on parts of my anxiety which obvious doesnt help the flight or fight response...i feel calmer but nothing has fixed the exhaustion.
Z said:
CBT and GET /GAT might work for some individuals at certain stages of illness. It's not a cure though, and the numbers substantially helped are probably quite small, given the decades that people have been going down with ME and probably having entrenched forms.

The people behind the PACE trial have argued that people with CFS are largely kept ill because of our attitudes and behaviour and fear of exercise which has negated the need for biomedical research and placed the emphasis on cheap self management services, instead of proper medical care. They have framed it as if we are being negative or resistant if we won't engage in their therapies and aim for recovery with them which is absurd given how sick many with ME are. They don't recognise our bodies can have ceilings and organic illness which can't just be overcome with increased activity.