PACE Trial and PACE Trial Protocol

[Sasha]

I'm not sure what you mean exactly, but new papers can confuse issues: We thought some of the planned objective measures had been dropped but then they published the step test data recently, four or five years after the original paper. And the original 2011 Lancet commentary that was published alongside the main paper made erroneous claims about recovery, and it defined 'recovery', but that all changed when the recovery paper was published which used yet another (the third) definition of recovery. So there were two sets of recovery data published to analyse and question.

Sorry, Bob, I don't think I was very clear.

What I meant was that the protocol lists all the planned analyses (including how recovery was to be defined). So every time a paper comes out, we see which analyses are being reported and can compare them to the protocol to see which have changed and which are still per protocol. If an analysis is changed several times in later papers, great - that can also be noted.

 

[Bob]

Is there an up-to-date list of publications?

If you're referring to official PACE papers, then here's an up-to-date list. Happy reading!

Updated December 2015.

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2007 Published protocol:
White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R; PACE trial group.
Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy.
BMC Neurol. 2007; 7:6.
http://www.biomedcentral.com/1471-2377/7/6

2011 Main PACE trial paper:
White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL, Bavinton J, Angus BJ, Murphy G, Murphy M, O'Dowd H, Wilks D, McCrone P, Chalder T, Sharpe M; PACE trial management group.
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; 377:823-36.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60096-2/abstract

2012 Cost-effectiveness analysis (Includes employment and welfare benefits data):
McCrone P, Sharpe M, Chalder T, Knapp M, Johnson AL, Goldsmith KA, White PD.
Adaptive pacing, cognitive behaviour therapy, graded exercise, and specialist medical care for chronic fatigue syndrome: A cost-effectiveness analysis.
PLoS ONE 2012; 7:e40808.
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040808

2013 [Alleged] "Recovery" paper:
White PD, Johnson AL, Goldsmith K, Chalder T, Sharpe MC.
Recovery from chronic fatigue syndrome after treatments given in the PACE trial.
Psychological Medicine 2013; 43:2227-35.
http://journals.cambridge.org/abstract_S0033291713000020

2013 Statistical Analysis Plan:
Walwyn R, Potts L, McCrone P, Johnson AL, DeCesare JC, Baber H, Goldsmith K, Sharpe M, Chalder T, White PD.
A randomised trial of adaptive pacing therapy, cognitive behaviour therapy, graded exercise, and specialist medical care for chronic fatigue syndrome (PACE): statistical analysis plan.
Trials 2013; 14:386.
http://www.trialsjournal.com/content/14/1/386

2014 Adverse events and deterioration:
Dougall D, Johnson A, Goldsmith K, Sharpe M, Angus B, Chalder T, White P.
Adverse events and deterioration reported by participants in the PACE trial of therapies for chronic fatigue syndrome.
J Psychosom Res. 2014; 77:20-6.
http://www.sciencedirect.com/science/article/pii/S0022399914001883

2015 Secondary Mediation Analysis (contains the step test results - graph only):
Rehabilitative therapies for chronic fatigue syndrome: a secondary mediation analysis of the PACE trial.
Chalder T, Goldsmith KA, White PD, Sharpe M, Pickles AR.
Lancet Psychiatry 2015; 2:141–52
http://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(14)00069-8/abstract

2015 Two Year Follow Up:
Sharpe M, Goldsmith KA, Johnson AL, Chalder T, Walker J, White PD.
Rehabilitative treatments for chronic fatigue syndrome: long-term follow-up from the PACE trial.
Lancet Psychiatry 2015; 2:1067–74
DOI: http://dx.doi.org/10.1016/S2215-0366(15)00317-X
http://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(15)00317-X/fulltext


2015 Longitudinal Mediation Analysis - conference abstract only:
Goldsmith K, Chalder T, White P, Sharpe M, Pickles A.
Longitudinal mediation in the PACE randomised clinical trial of rehabilitative treatments for chronic fatigue syndrome: modelling and design considerations
Trials 2015; 16(Suppl 2):O43 doi:10.1186/1745-6215-16-S2-O43
http://www.trialsjournal.com/content/16/S2/O43


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Minor papers and PACE-related papers:

Lawn T, Kumar P, Knight B, Sharpe M, White PD. (2010)
Psychiatric misdiagnoses in patients with chronic fatigue syndrome.
JRSM Short Rep. 1:28.

Cella M, Sharpe M, Chalder T. (2011)
Measuring disability in patients with chronic fatigue syndrome: reliability and validity of the Work and Social Adjustment Scale.
J Psychosom Res. 71:124-8.

Cella M, White PD, Sharpe M, Chalder T. (2013)
Cognitions, behaviours and co-morbid psychiatric diagnoses in patients with chronic fatigue syndrome.
Psychological Medicine 43:375-380. doi:10.1017/S0033291712000979

Bourke JH, Johnson AL, Sharpe M, Chalder T, White PD. (2014)
Pain in chronic fatigue syndrome; response to rehabilitative treatments in the PACE trial.
Psychological Medicine 44:1545-52. doi:10.1017/S0033291713002201

Cox D, Burgess M, Chalder T, Sharpe M, White P, Clark L. (2013)
Training, supervision and therapists' adherence to manual-based therapy.
International Journal of Therapy and Rehabilitation 20:180-186.

White PD, Chalder T, Sharpe M. (2015)
The planning, implementation and publication of a complex intervention trial for chronic fatigue syndrome: the PACE trial.
BJPsych Bull. 39:24-7. doi: 10.1192/pb.bp.113.045005
http://www.ncbi.nlm.nih.gov/pubmed/26191420


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[Sasha]

Thanks, @Bob!

 

[Sasha]

Just taking a look at the first of the therapists' manuals for PACE (183pp). Only seven more to go!

Is there a convenient summary anywhere of what patients in each group were told to expect in terms of improvement/recovery? And of what therapists were told? And were told to tell patients?

 

[user9876]

Just taking a look at the first of the therapists' manuals for PACE (183pp). Only seven more to go!

Is there a convenient summary anywhere of what patients in each group were told to expect in terms of improvement/recovery? And of what therapists were told? And were told to tell patients?

As well as therapists manuals there were shorter patient manuals or leaflets I think.

http://www.pacetrial.org/trialinfo/
Has participant manuals.

One thing I remember is with CBT and GET patients were told these could lead to recovery but with APT and SMC they were told that they could help the body and perhaps lead to a natural recovery. I can't remember the exact phrases but I remember different expectations being set.

 

[Sasha]

Sorry if this has been tackled already by I'm confused by the PACE trial authors' taking a certain whole-adult-population mean score on the SF-36 physical function subscale and then subtracting 1 SD to define a threshold for "recovery" of patients in the trial.

Let's set aside that the SF-36 isn't normally distributed and that means and SDs aren't a good idea in this context.

Where has this idea of using a mean-minus-SD to define any sort of threshold?

@Jonathan Edwards, have you ever heard of this being done this way in a clinical trial or similar context?

 

[Jonathan Edwards]

Sorry if this has been tackled already by I'm confused by the PACE trial authors' taking a certain whole-adult-population mean score on the SF-36 physical function subscale and then subtracting 1 SD to define a threshold for "recovery" of patients in the trial.

Let's set aside that the SF-36 isn't normally distributed and that means and SDs aren't a good idea in this context.

Where has this idea of using a mean-minus-SD to define any sort of threshold?

@Jonathan Edwards, have you ever heard of this being done this way in a clinical trial or similar context?

No, it sounds completely arbitrary. I think a better way to define recovery would be to ask patients if they think they are fully recovered.

 

[Large Donner]

Is there such a thing as a false recovery belief as far as psychiatrists are concerned and is it to be trusted. If eveyone in the study claimed they had fully recovered what would that mean to them as the those types of studies are about testing the hypothesis of "false illness beliefs" aren't they?

Then if the psychiatrist believed the patient was suffering from a false recovery belief would he be ethically obliged to give him CBT to get him back to false illness belief status.

Perhaps they should have one psych fully trained in false illness beliefs and one trained in false recovery beliefs and they could bounce the patient back and forwards between them until they stop believing anything at all apart from that Anna from Frozen is a real princess and she lives next door.

 

[worldbackwards]

I think a better way to define recovery would be to ask patients if they think they are fully recovered.

It'll never catch on

 

[Sasha]

No, it sounds completely arbitrary. I think a better way to define recovery would be to ask patients if they think they are fully recovered.

I think @charles shepherd said they should have done that in a letter but I'm not sure if it was published. Probably too sensible.

 

[Sasha]

Do we have a reference for the trial costing £5m?

 

[Scarecrow]

Do we have a reference for the trial costing £5m?

Here's a reliable for source for just now.
http://www.meassociation.org.uk/2011/02/me-association-press-statement-on-the-pace-trial-results/

The PACE trial
* The randomised controlled trial compared CBT, GET, adaptive pacing therapy and specialised medical care.
* The assessments took place in hospitals in Bristol, Edinburgh, Oxford and London.
* The trial was largely funded by the Medical Research Council and cost over £4million.
* The MEA has been opposed the PACE from the onset.
* NICE are currently considering whether they should review their guideline on ME/CFS to take account of the PACE trial results.

I've seen a breakdown showing the amount of all funding sources for PACE. I'll keep looking.

 

[Jonathan Edwards]

Is there such a thing as a false recovery belief as far as psychiatrists are concerned and is it to be trusted. If eveyone in the study claimed they had fully recovered what would that mean to them as the those types of studies are about testing the hypothesis of "false illness beliefs" aren't they?

Then if the psychiatrist believed the patient was suffering from a false recovery belief would he be ethically obliged to give him CBT to get him back to false illness belief status.

Perhaps they should have one psych fully trained in false illness beliefs and one trained in false recovery beliefs and they could bounce the patient back and forwards between them until they stop believing anything at all apart from that Anna from Frozen is a real princess and she lives next door.

I think maybe you have forgotten that you would need a patient to assess the false beliefs the psychiatrists that the (other) patients beliefs that they had recovered were false. It could go on for ever indeed. Do you mean Anna next door?

 

[Dolphin]

Do we have a reference for the trial costing £5m?

Here are two sources for the £5m or so.

=====Source 1 =====

http://tinyurl.com/ydsv857
i.e.
http://www.rae.ac.uk/submissions/ra5a.aspx?id=176&type=hei&subid=3181

You are in: Submissions > Select unit of assessment > UOA 9 Psychiatry,
Neuroscience and Clinical Psychology > University of Edinburgh > RA5a UOA 9 -
Psychiatry, Neuroscience and Clinical Psychology University of Edinburgh

[..]

"the PACE trial (7 UK centres) of chronic fatigue syndrome (CFS) treatments
(MRC; £5.0M);"

=====Source 2 =====

From figures below:
£2,076,363
£1,800,600
£702,975
£250,000
------
£4,829,938 + DWP money (unknown)


(Yes this is the same web page but it is a summary of a different entry)

http://tinyurl.com/ydsv857
i.e.
http://www.rae.ac.uk/submissions/ra5a.aspx?id=176&type=hei&subid=3181

You are in: Submissions > Select institution > Queen Mary, University of
London > UOA 9 - Psychiatry, Neuroscience and Clinical Psychology > RA5a Queen
Mary, University of LondonUOA 9 - Psychiatry, Neuroscience and Clinical
Psychology
RA5a: Research environment and esteem

[..]

White showed that recovery from CFS is possible following CBT (Knoop et al,
2007). The MRC funded PACE trial, led by White , evaluates CBT, graded
exercise, adaptive pacing and usual medical care in the treatment of CFS, and
is over half-way completed (http://www.pacetrial.org/) (PACE trial MRC
04-09 £2,076,363, DH Central Subvention 04-09 £1,800,600; MRC PACE trial
extension 09-10 £702,975).
=========
==================

SCOTTISH PARLIAMENT - WRITTEN ANSWER

2 December 2005

Health Department

Janis Hughes (Glasgow Rutherglen) (Lab): To ask the Scottish Executive what
funding it has awarded for chronic fatigue syndrome/myalgic encephalomyelitis
(CFS/ME) services or research since the CFS/ME short-life working group
reported in 2002.

(S2W-20924)
Lewis Macdonald:

NHS Boards are given unified budgets, increased by an average of 7.6% in the
current financial year, from which they are expected to meet the costs of
services for people with CFS/ME and all other chronic conditions. It is for
NHS Boards to decide how their unified budgets should be distributed, based on
their assessments of local needs.

The Chief Scientist Office (CSO), within the Scottish Executive Health
Department, has responsibility for encouraging and supporting research into
health and health care needs in Scotland. CSO is currently contributing
£250,000 to the Medical Research Council project 'Pacing, Activity and
Cognitive behaviour therapy: a randomised Evaluation (PACE)' which compares
different approaches to the clinical management of patients with CFS/ME.

 

[Large Donner]

I think maybe you have forgotten that you would need a patient to assess the false beliefs the psychiatrists that the (other) patients beliefs that they had recovered were false. It could go on for ever indeed. Do you mean Anna next door?

Wow, you live next door to a magical castle. How cool!!

 

[Scarecrow]

@Sasha

Oh, good. Dolphin to the rescue. I can stop looking now but this is what I found.

I think that the trial was originally projected to cost £4.2M:
http://www.actionforme.org.uk/get-i...r-news/2011/pace-surprising-and-disappointing

The MRC grant was £2,779,280
http://gtr.rcuk.ac.uk/project/7EC0DBA0-0FC2-44F1-8708-8676EBEDA4C9
which was comprised of the two figures quoted by Dolphin. That accounts for the difference between the original and eventual cost.

Just out of interest, I came across this FOIA request while I was looking. Somebody asked the DWP to explain their involvement
https://www.whatdotheyknow.com/request/part_funding_of_the_pace_trial_b

 

[Dolphin]

In case it's of interest, three people who took part in the PACE Trial posted on the ME Association Facebook page yesterday on this thread:
https://www.facebook.com/permalink.php?story_fbid=928793400511652&id=171411469583186

Lois Addy I was on the pace trial at kings in London. During it I went from full to part time. Anecdotal evidence, I remember my CBT therapist commenting most of the participants who were working at the start weren't at the end. To me that makes sense cos it was moderately affected people who participated and were struggling with life and had been recently diagnosed, so the treatments involved stabilising which in that scenario to me means doing less. I can't quite remember but I may have been that particular therapists only patient who had managed to keep working. But I had a very understanding boss, which is unusual.

I don't remember working being a criteria. They did lots to exclude mental illnesses type fatigue and other symptoms illnesses have in common. And asked that I didn't join me\cfs groups etc I wasn't a member of. But tbh I had to work to stay in my home so for me it was a given.

Lois Addy I can't remember if the periodic questionnaires asked you about work. But there was a trial nurse session where you were asked about working hours and earnings a couple of times during the year. Cos mine messed up his tidy stats, I did fewer hours but payrises so not the income drop one would normally expect. Thankfully, cos I needed that money when the recession hit!!!! I saved it.

Dani St I was also in the pace trial, at was at university at the time, the conclusions Prof. White made about how I could "cure" my illness has pretty much been disproven now. Feel free to inbox me if you have any questions smile emoticon

Siân Ledger I took part in the trial and was working part time right the way through. Employment status wasn't a factor in recruitment on to the trial but they definitely collected data from me about how many hours I worked and the economic annual cost of me-Cfs to me which included 'lost' earnings because of my part time status. I don't know what they did with this data though.

Also:

Sylvia Greybe I was asked to be part of the PACE trial just after I was diagnosed. I had just started a new job with the NHS but couldn't get time off during the day to attend the trial appointments. I asked if I could come after work but they told me I would be allocated a time slot during the day and would have to attend at that time. So in the end I was not able to be part of the trial, but knowing that I could have ended up having to do graded exercise or cbt put me off as well. I had already tried cbt by then, as it was the only treatment the nhs would offer me, and even then it was just 6 homework-writing type sessions through my gp, which I found frustrating, useless anbd totally irrelevant.

 

[Large Donner]

@Sasha

Oh, good. Dolphin to the rescue. I can stop looking now but this is what I found.

I think that the trial was originally projected to cost £4.2M:
http://www.actionforme.org.uk/get-i...r-news/2011/pace-surprising-and-disappointing

The MRC grant was £2,779,280
http://gtr.rcuk.ac.uk/project/7EC0DBA0-0FC2-44F1-8708-8676EBEDA4C9
which was comprised of the two figures quoted by Dolphin. That accounts for the difference between the original and eventual cost.

Just out of interest, I came across this FOIA request while I was looking. Somebody asked the DWP to explain their involvement
https://www.whatdotheyknow.com/request/part_funding_of_the_pace_trial_b

Wow that DWP FOI response is just astonishing.

We believe that the findings of the trial will contribute to the
continually growing evidence base, which informs the development of
health and work related policy, policy based on the large body of
evidence showing that work is good for physical and mental wellbeing and
that being out of work can lead to poor health and other negative
outcomes.

However Peter White claimed after the trial that employment/study status could not be used to asses the effectiveness of the "treatment" didnt he?

I think he actually meant lack of reintroduction to employment/study etc because the figures just didn't suit him. Either way hasn't the DWP disproved their bold assertion made before the findings where even published? If its good enough to fund a trial on the basis that the outcome would almost certainly be "that work is good for physical and mental wellbeing and
that being out of work can lead to poor health and other negative
outcomes", why isn't the data readily available.

Also they make the age old cart before the horse assumption that being out of work leads to poor health and other negative outcomes rather than the other way around. Its also astonishing that this is supposed to be a study on treatments for a neurological disease and they are acting as if its a study on the needlessly unemployed who then catch ME as a result of being unemployed.

I think they need to be challenged further and asked if they now consider the neurological disease ME to be caused by unemployment and if the PACE trial proves such.

How many of us where unemployed when we got ill and how many where employed or studying or raising a family when they got ill and had to cut out or down such activities.

So now the PACE trial wasn't even about a loosely defined "CFS cohort using the operational defintion of fatigue and not CFS/ME" but it was actually a study on people who where not ill until they where out of work and then that "lead to poor health and other negative outcomes."

This bit is bizarre.....

........policy based on the large body of
evidence showing that work is good for physical and mental wellbeing and
that being out of work can lead to poor health and other negative
outcomes.

...because whatever the DWP financial contribution was to this part of the study where are the two subsets, one who didn't return to work and one who did in order to make any comparison.

They also missed out the subset of people who have died weeks after being told they are fit for work. If returning to work is the cure for debilitating diseases how come some people die in the interim period before they are even forcibly returned to work.

Just what measures did the study design have built in to ensure some people would return to work to be assessed after such. I don't recall any. Also how ethical would this be deciding in advance that there would be a cohort of people that they could return to work in an attempt to make any judgments.

How astonishing!!

 

[Dolphin]

@Large Donner (and others)

Just in case you're not aware, the employment data and some benefits data were published in the PACE Trial cost effectiveness paper in 2012:


http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0040808

 

[Sasha]

No, it sounds completely arbitrary. I think a better way to define recovery would be to ask patients if they think they are fully recovered.

There's another thing in the "recovery" paper that seems a bit odd. They didn't plan this in the protocol (that I can see, anyway), but they report two "recovery" outcomes:

Composite definitions of recovery
We operationalized two composite definitions of recovery: (1) trial recovery from CFS, and (2) clinical recovery from the illness, however it was defined. To provide a definition of trial recovery, we calculated a hierarchical, cumulative definition that included the following domains mentioned earlier: normal range in fatigue, normal range in physical function, not meeting the Oxford case definition of CFS, and CGI scores of 1 or 2 (‘very much’ or ‘much’ better). To fulfil the criteria for clinical recovery from the illness, participants had to meet all the criteria for trial-defined recovery (described earlier), in addition to not meeting either the International (CDC) criteria for CFS or the London criteria for ME.​

Is that usual, to have two definitions like this? I don't know that I've ever seen this distinction (trial vs clinical recovery) made in a clinical trial before.

I'm not sure I understand the implied reasoning. What sort of recovery are the two things meant to represent?

Does anybody get this?