PACE Trial and PACE Trial Protocol

[Esther12]

Given the harm that's been done to patients through the promotion the the psychosocial approach to CFS, they'd better come up with something damn near curative. Moderately alter questions for a fatigue questionnaire? I'd be pretty pissed.

 

[oceanblue]

Given the harm that's been done to patients through the promotion the the psychosocial approach to CFS, they'd better come up with something damn near curative. Moderately alter questions for a fatigue questionnaire? I'd be pretty pissed.

Doesn't sound like they've found the Holy Grail, I guess we'll have to see the paper for how much effect they've had - and how long it lasts. And now I really must log off and settle down...

 

[Snow Leopard]

Yes, that's all such studies show. If you condition patients to complain less about their symptoms, the questionnaire scores improve.

The problem is that the improvements of scores on fatigue questionnaires and the sf-36 have been demonstrated not to be well correlated with activity levels after non-pharmaceutical interventions (See Dr Jason etc).

additional edit:

"Even with the best therapies we have, four out of 10 people don't improve," said Peter White, a professor of psychological medicine at the Queen Mary University of London, who led the study.

So if you had 1% of the population meeting the Oxford Criteria and 0.4% meeting CCC. And then you find 4/10 not improving....
Sorry, thinking out loud.

The measures I am interested in (as per PACE protocol paper) are:

EQ-5D (I want to see how the reported QOL compares to other diseases)
The Client Service Receipt Inventory (CSRI) (apparently measuring hours worked etc).

I don't really care much about improvements on the questionaires in general.

Tom Kindlon's point about the lack of objective measures of activity are still very important.

 

[Bob]

"Even with the best therapies we have, four out of 10 people don't improve," said Peter White, a professor of psychological medicine at the Queen Mary University of London, who led the study.

Erm, I'm sorry, but why did a professor of psychological medicine lead a multi-thousand pound study into a neuro-immune disease? How is he qualified to do that? (Sorry, it's just a rhetorical question - I couldn't help saying it again!)
It's interesting that he says that CBT is the best therapy available for a neuroimmune disease. If there had been an immunologist leading the study, then maybe the study wouldn't have failed 4 out of 10 patients. (Sorry, I know i'm just going over old ground! - Just warming up for the results!)

 

[Snow Leopard]

Since when does direct qualifications matter? Anyone can lead a multi-million pound study. All you need is the right political affiliations to get funding.

 

[Bob]

Since when does direct qualifications matter? Anyone can lead a multi-million pound study. All you need is the right political affiliations to get funding.

Oh OK, just call me old fashioned... and naive!!!
Was it a multi-million pound study? That makes it even worse.
I wonder how much of that went into Wessely's and White's bank accounts.

 

[Dolphin]

Reference for 5.0m cost

Reference for UK5.0m cost

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);"

 

[Dolphin]

Breakdown of where most of the money came from

Breakdown of where most of the money came from (never saw a figure for DWP contribution but it's on the record):

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.

 

[Esther12]

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60096-2/fulltext

edit -only summary available for free.

 

[Dolphin]

Abstract

Here's the abstract
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60096-2/fulltext

The Lancet, Early Online Publication, 18 February 2011doi:10.1016/S0140-6736(11)60096-2Cite or Link Using DOI

Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial

Original Text

Prof PD White MD a , KA Goldsmith MPH b, AL Johnson PhD c d, L Potts MSc b, R Walwyn MSc b, JC DeCesare BSc a, HL Baber BSc a, M Burgess PhD e, LV Clark PhD a, DL Cox PhD f, J Bavinton BSc i, BJ Angus MD g, G Murphy MSc h, M Murphy FRCP i, H O'Dowd PhD j, D Wilks FRCP[Ed] k, Prof P McCrone PhD l, Prof T Chalder PhD m *, Prof M Sharpe MD n *, on behalf of the PACE trial management group†

Summary

Background

Trial findings show cognitive behaviour therapy (CBT) and graded exercise therapy (GET) can be effective treatments for chronic fatigue syndrome, but patients' organisations have reported that these treatments can be harmful and favour pacing and specialist health care. We aimed to assess effectiveness and safety of all four treatments.

Methods
In our parallel-group randomised trial, patients meeting Oxford criteria for chronic fatigue syndrome were recruited from six secondary-care clinics in the UK and randomly allocated by computer-generated sequence to receive specialist medical care (SMC) alone or with adaptive pacing therapy (APT), CBT, or GET. Primary outcomes were fatigue (measured by Chalder fatigue questionnaire score) and physical function (measured by short form-36 subscale score) up to 52 weeks after randomisation, and safety was assessed primarily by recording all serious adverse events, including serious adverse reactions to trial treatments. Primary outcomes were rated by participants, who were necessarily unmasked to treatment assignment; the statistician was masked to treatment assignment for the analysis of primary outcomes. We used longitudinal regression models to compare SMC alone with other treatments, APT with CBT, and APT with GET. The final analysis included all participants for whom we had data for primary outcomes. This trial is registered at http://isrctn.org, number ISRCTN54285094.

Findings
We recruited 641 eligible patients, of whom 160 were assigned to the APT group, 161 to the CBT group, 160 to the GET group, and 160 to the SMC-alone group. Compared with SMC alone, mean fatigue scores at 52 weeks were 34 (95% CI 18 to 50) points lower for CBT (p=00001) and 32 (17 to 48) points lower for GET (p=00003), but did not differ for APT (07 [−09 to 23] points lower; p=038). Compared with SMC alone, mean physical function scores were 71 (20 to 121) points higher for CBT (p=00068) and 94 (44 to 144) points higher for GET (p=00005), but did not differ for APT (34 [−16 to 84] points lower; p=018). Compared with APT, CBT and GET were associated with less fatigue (CBT p=00027; GET p=00059) and better physical function (CBT p=00002; GET p<00001). Subgroup analysis of 427 participants meeting international criteria for chronic fatigue syndrome and 329 participants meeting London criteria for myalgic encephalomyelitis yielded equivalent results. Serious adverse reactions were recorded in two (1%) of 159 participants in the APT group, three (2%) of 161 in the CBT group, two (1%) of 160 in the GET group, and two (1%) of 160 in the SMC-alone group.

Interpretation
CBT and GET can safely be added to SMC to moderately improve outcomes for chronic fatigue syndrome, but APT is not an effective addition.

Funding
UK Medical Research Council, Department of Health for England, Scottish Chief Scientist Office, Department for Work and Pensions.

 

[Esther12]

Link to a couple of sentances of the editorial: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60172-4/fulltext

Darn - I was hoping this would be free access. I'm off for a bit, but will have a quick look through before bed.

 

[Snow Leopard]

edit - reading it now.

 

[Dolphin]

It's available for free (or maybe not)

It's available for free (if one does free registration):
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60096-2/abstract

---
Currently it is no longer free - maybe it will change again?

 

[Dolphin]

Data on some of the interesting secondary outcome measures wasn't published

If one looks at the PACE Trial Protocol:

White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R; on behalf of the 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. BioMed Cent Neurol 2007; 7: 6.
http://www.biomedcentral.com/1471-2377/7/6
one sees that some of the more interesting data wasn't published:
e.g.

4. "Recovery" will be defined by meeting all four of the following criteria:
(i) a Chalder Fatigue Questionnaire score of 3 or less [27], (ii) SF-36 physical Function score of 85 or above [47,48], (iii) a CGI score of 1 [45], and (iv) the participant no longer meets Oxford criteria for CFS [2], CDC criteria for CFS [1] or the London criteria for ME [40].

11. The Client Service Receipt Inventory (CSRI), adapted for use in CFS/ME [31], will measure hours of employment/study, wages and benefits received, allowing another more objective measure of function.

Call me cynical but I think if the figures were good we would have seen them.

It might be worth highlighting this/pushing for the data.
Peter White has been claiming a full recovery rate of 25% but based on the data on the loser criteria used here, I don't think it was anything like it if the "recovery" definition had been used.

 

[Sean]

Yes, that's all such studies show. If you condition patients to complain less about their symptoms, the [subjective] questionnaire scores improve.

..., independent of improvement in objective scores.

(And the conditioning used is sometimes pretty unpleasant, dishonest, and unethical stuff too. Any fool with a bit of power can get somebody else in a less powerful position to change their immediate external behaviour by making threats of some sort, explicit or implicit. Doesn't mean the superficial behaviour change is real or sustainable, or even desirable.)

That pretty well sums up the 'evidence' for CBT in ME/CFS.


Although this paper and the furious spin that will accompany it will be a serious PITA to deal with, the other side of that coin is that this is their best shot, but all they could manage was a "moderate" improvement in a limited number of subjective measures. (And let's wait and see the actual numbers say. I think it is reasonable to assume that the available abstract gives the most favourable possible spin on it they can get away with. If they are only able to claim a moderate improvement, and if their spin (and methodology) is their usual standard, then I will bet a closer look at the numbers shows the actual outcomes to be less than even merely moderate.)

They almost totally dominate the politics and public relations in the field, get the lion's share of the funding, had almost total control over the study, and had first crack at spinning the results, at framing the debate. It is the most favourable possible set of conditions for them and their model, and so presumably this is the best they can do with it. But they have not delivered any substantial real-world outcome. And that is before we factor in the serious methodological problems with this study and its underlying model. Frankly, it is pathetic, especially given how extravagant and assertive the claims about the effectiveness of this approach has been over the years.

Definitely no killer blow in there for them.

I would suggest that this is their high point. They will not be able to do any better than this. It is all down hill from here.

(No, I don't think it will suddenly change policy or life on the ground for patients, it will take time to filter through. But they have simply failed to deliver their promised land, and that will not go unnoticed among the more hard nosed policy makers and purse string holders.)

I also think that the issue of lack of objective measures, especially when they were originally in the study protocol but were later removed (on very dubious grounds), will not sit well with real scientists. This issue will come back to haunt them.

 

[Sean]

Call me cynical but I think if the figures were good we would have seen them.

I have no doubt if those numbers had been good for their model then they would have been loudly proclaiming them at every possible opportunity. It would be the ultimate vindication for them (from their perspective). But... crickets (thus far, at least).

This was supposed to be their big moment, the definitive proof of their explanatory and therapeutic model, and of course the coup de grace to their critics, and, well, they blew it.

Like I said, I strongly suspect that when we get to look at the actual data (and all of it, not just selectively released bits of it), it will clearly fail to provide solid support for even for a "moderate" success.

 

[Snow Leopard]

Call me cynical but I think if the figures were good we would have seen them.

Reminds me of the Nijmegen research - they didn't publish the unimpressive actometer data until much later.

Note, the appendix states one case of "Deterioration in mobility and self-care". Guess which treatment this was associated with? (yes, GET!)

The amount of patients ruled out after basline screeing (over 2,200) is staggering. Apparently there were 745 that had been clinically diagnosed, but did not meet the Oxford criteria?

Is this a result of bad recruitment, or do three times as many people claim to have CFS than actually meet Oxford criteria?
I wish I knew the exact reasons why they were ruled out.

40% were taking antidepressants at baseline. Is this normal?

Note they also keep stressing 'postexertional malaise' improvements, as if their questionnaires can actually measure this objectively.

 

[Angela Kennedy]

Hi Sean

But they have not delivered any substantial real-world outcome. And that is before we factor in the serious methodological problems with this study and its underlying model. Frankly, it is pathetic, especially given how extravagant and assertive the claims about the effectiveness of this approach has been over the years.

Definitely no killer blow in there for them.

I would suggest that this is their high point. They will not be able to do any better than this. It is all down hill from here.

(No, I don't think it will suddenly change policy or life on the ground for patients, it will take time to filter through. But they have simply failed to deliver their promised land, and that will not go unnoticed among the more hard nosed policy makers and purse string holders.)

I also think that the issue of lack of objective measures, especially when they were originally in the study protocol but were later removed (on very dubious grounds), will not sit well with real scientists. This issue will come back to haunt them.

Thank you. I think these are very wise words.

 

[Cort]

A quick look at this suggests that the news overall is good. This was their best shot - right? I think we'll look and say....this where CBT/GET peaked as a therapy for CFS.......now.there MUST be a recognition that the research establishment must look elsewhere.

http://www.nytimes.com/2011/02/18/health/research/18fatigue.html?ref=science

We plan to report relative cost-effectiveness of the treatments, their moderators and mediators, whether subgroups respond differently, and long-term follow-up in future publications. Our finding that studied treatments were only moderately effective also suggests research into more effective treatments is needed. The effectiveness of behavioural treatments does not imply that the condition is psychological in nature.

Our findings were strengthened by the small numbers of dropouts, high rates of acceptance of the treatments, use of manual-defined treatments provided by competent clinicians, high rates of participant satisfaction, adherence to manuals, and therapeutic alliance. The PACE findings can be generalised to patients who also meet alternative diagnostic criteria for chronic fatigue syndrome12 and myalgic encephalomyelitis13 but only if fatigue is their main symptom.11

To repeat

Our finding that studied treatments were only moderately effective also suggests research into more effective treatments is needed.

Notice that in Table Five from 60-70% of all patients did reported only minimum or negative change. Only 41% at the most reported positive change - and that doesn't mean cure.

The idea of CBT/GET curing CFS is OVER! Let them have their 'moderate effect' in their 40% of the patients and lets get on with the real research...

 

[Cort]

I thought Tuller blew it in his rather small article. These were my comments to the NYTimes

Perhaps Mr Tuller should take a closer at this article. The findings didn't displease me at all - the article did though. The study states that "Our finding that studied treatments were only moderately effective also suggests research into more effective treatments is needed."

A closer look at the study (see Table 5) indicates that even in the most effective treatment arm (CBT) 61% of the people in the study received only minimum or negative effects. How is it that approach in which almost 2/3rds of the recipients received only minimum or negative effects is some hailed as as effective protocol for a disorder? I would expect that these therapies would have a similar effectiveness in virtually any chronic illness - given how devastating chronic illnesses are. In fact CBT has been effectively used in disorders ranging from rheumatoid arthritis to heart disease to asthma.

The bottom line from this study is that CBT/GET are nowhere near being cures for these heterogenous disorders, are hot helpful for most participants and have a limited effectiveness even in that portion of the population they are helpful for.

Somehow Mr. Tuller parlayed that information into this statement "The new study, conducted at clinics in Britain and financed by that countrys government, is expected to lend ammunition to those who think the disease is primarily psychological or related to stress."

How he managed to do that is entirely unclear to me.

It's statements like this that have such a chilling effect to people with CFS.

"In the long-awaited study, patients who were randomly assigned to receive cognitive behavioral therapy or exercise therapy, in combination with specialized medical care, reported reduced fatigue levels and greater improvement in physical functioning than those receiving the medical care alone"

A person with CFS might say...soooo? So what if extreme fatigue levels were moderately reduced? That's kind like cheering because 40% of diabetics insulin levels were somewhat reduced but they still had diabetics ( and the other sixty percent noticed no change)....Somehow the fact that some reduction is fatigue is achieved opens chronic fatigue syndrome patients open, once again, to the claim that the disorder is all their heads.

Hopefully Mr Tuller will read the next study on chronic fatigue syndrome a little more care and will refrain from perpetuating more of the same old stereotypes people with CFS have facing for decades now.

This study - the best CBT trial the UK government has or will be able to throw at CFS - should be seen as the point at which the unreasonable expectations for CBT are finally discarded and the practice is finally seen for what is....a moderately effective practice of symptom reduction that at best works in only a limited number of patients.

Let's start getting real about this disorder. It effects a million people in the US, receives almost no funding and according to CDC studies costs the US economy about $20 billion a year. Now that CBT/GET have had their day - its time for serious effort.