PACE Trial and PACE Trial Protocol

[Snow Leopard]

And more importantly, could they repeat that distance over the next few days...

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

I'm not a big believer in conspiracies, but!?!

By the way, I hope someone else discusses the problems of the cohort definitions in depth in their letter, because I won't be. Damn 250 word limit.
Dr Jason has many good articles to read and reference. http://condor.depaul.edu/ljason/leonard.html#pubs

 

[Esther12]

The only objective measure is the 6 minute walking ability test. Can anyone get some data from healthy controls from anywhere or normative data. One could do a t-test and compare against the results. The "best" result was 379m which doesn't seem that far - it's less than 1 lap of a 400m athletics track (it translates to an average speed of 3790m/hour - it's not saying they could do that amount of course in 1 hour).

Instinctively, I'd assume that this would be a test which many CFS patients could be shown to be 'normal' on, even if they were not at all healthy. I walk at normal speed... six minutes would be pushing it but I could possibly get within the normal range, I'd just be destroyed afterwards. I'm not sure what level of cynicism is appropriate here either... it could be that CBT and GET do have some real but limited benefits for patients, and help them walk in a more natural manner. It does seem a very strange test to use though, especially considering that patients with serious mobility problems were excluded by the nature of the trial. (CBT improvement were pretty limited too)

re withdrawals: One problem with the strange and restrictive approach to pacing ... those who were recovering as part of the natural course of their illness could see pacing as a burden, and withdraw. For CBT and GET, those whose condition worsened could see treatment as more of a burden, and withdraw. I don't think this is a significant point, and withdrawels weren't that big a problem (11% from CBT though), but thought I'd mention it. It could be these slight biases would affect the data collected from a randomly fluctuating patient population.

The Work and Social adjustment scale is just another questionnaire: http://bjp.rcpsych.org/cgi/content/full/180/5/461
I was hoping for some more objective data on hours worked etc... but given the lack of sub-dividing, I'm not sure how interesting it would have been.

I'm really disappointed by the appendix. I thought we would see a serious attempt to assess all these patients as individuals, and try to understand who would be most/least likely to benefit from different treatment approaches. Devoting yourself to GET for limited/no improvement has a really high cost for patients, and even accepting the most positive of spins to their work, this is what happens for nearly half their patients. They seem to have no interest in recognising the innate burden of engaging with these sorts of therapies when they're ineffective. Or with CBT... teaching patients who do not have control over their symptoms that they do is a terrible thing, even if this is not picked up in worsening scores on the Chalder fatigue scale.

Overall: I've only given it a quick look. To me, the worst thing about the paper is that so much was spent on a study that presented so little worthwhile data. Because some of the results have clearly been dishonestly presented, it means that we really can't trust the rest of it. I didn't really find much to pick apart, other than what others have already mentioned, and the innate limitations of using these sorts of RCTs to assess psychosocial approaches to CFS. I'm tempted to agree with Cort's appraisal... it's conclusions are so weak it might even be good for us. But given how the study has been promoted and reported, and how similarly weak studies have been used misleadingly in the past, I'm afraid that's probably a rather panglossian view of things.

 

[Dolphin]

Instinctively, I'd assume that this would be a test which many CFS patients could be shown to be 'normal' on, even if they were not at all healthy. I walk at normal speed... six minutes would be pushing it but I could possibly get within the normal range, I'd just be destroyed afterwards. I'm not sure what level of cynicism is appropriate here either... it could be that CBT and GET do have some real but limited benefits for patients, and help them walk in a more natural manner. It does seem a very strange test to use though, especially considering that patients with serious mobility problems were excluded by the nature of the trial. (CBT improvement were pretty limited too)

Thanks. But data might show they were still walking slower.

Here are the numerical results again on this:
APT: increased by 20 steps (314 to 334)
CBT: increased by 21 steps (333 to 354)
Control group: increased by 22 steps (326 to 348)

Only difference is with the GET group:
GET: increased by 67 steps (312 to 379).

But not the best as you say. Exercise testing often involves measuring gases etc to see the biological demands the exercise is putting on somebody.

 

[Dolphin]

The Work and Social adjustment scale is just another questionnaire: http://bjp.rcpsych.org/cgi/content/full/180/5/461
I was hoping for some more objective data on hours worked etc... but given the lack of sub-dividing, I'm not sure how interesting it would have been.

In case you missed it, they did measure it - it was one of their secondary outcome measures, they just didn't report it.
This is what they had said themselves in the trial protocol:

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.

http://www.biomedcentral.com/1471-2377/7/6

 

[Dolphin]

Overall: I've only given it a quick look. To me, the worst thing about the paper is that so much was spent on a study that presented so little worthwhile data. Because some of the results have clearly been dishonestly presented, it means that we really can't trust the rest of it. I didn't really find much to pick apart, other than what others have already mentioned, and the innate limitations of using these sorts of RCTs to assess psychosocial approaches to CFS. I'm tempted to agree with Cort's appraisal... it's conclusions are so weak it might even be good for us. But given how the study has been promoted and reported, and how similarly weak studies have been used misleadingly in the past, I'm afraid that's probably a rather panglossian view of things.

I think the point in bold is worth mentioning in a letter. At the moment, that's what I'm thinking of using but they might not like my wording but might like how somebody else said it.

We need quite a few people writing in, either making the same or different points so that they at least publish one or two letters. Although there are disadvantages in more than one person making the same point, at the same time, a few people may turn the editor around to the point while maybe if only one person said it, they might not have been convinced. It's a pain that the journal doesn't allow e-letters - trials in the BMJ for example can get a bashing from lots of people. Complaining about the outcome measures wouldn't require many references or knowledge of the literature - they can be "self-evident".

 

[Cort]

Forgot to say: the participants still wore them before the trial. So there was no extra costs involved. Using 5m (US$8m) of taxpayers' money and they avoid using something which would give some hard data.

You are good Dolphin- you navigate these waters with ease . That's $8,000 US dollars that were spent. ?

 

[Cort]

Thanks. But data might show they were still walking slower.

Here are the numerical results again on this:
APT: increased by 20 steps (314 to 334)
CBT: increased by 21 steps (333 to 354)
Control group: increased by 22 steps (326 to 348)

Only difference is with the GET group:
GET: increased by 67 steps (312 to 379).

But not the best as you say. Exercise testing often involves measuring gases etc to see the biological demands the exercise is putting on somebody.

This is what I have on this so far....

Baseline Walking Test - was another measure of functionality. It simply asked the participants to ‘walk as far as they can’ in six minutes and then measured in meters how far they went. The best outcome was in GET but once again one has to ask how much meaningful improvement the participants saw.

Pacing CBT GET Specialist
Baseline 314 333 312 326
52 weeks 334 354 379 348

According to Walking.About.com http://walking.about.com/od/measure/f/howfastwalking.htm these therapies moved the participants from walking at a ‘puttering around the house’ rate to just above a puttering around the house rate. None of them assisted the participants to come close to even maintaining an ‘easy health walk’ for all of six minutes. Functionally the participants improved only marginally.

• Puttering around the house - 320
• Easy Health Walk - 500 meters
• Brisk Walk - 650 meters
• Fast Walking - 800-1,000 meters.

 

[Esther12]

Does their 'normal range' include seriously ill people?

"In another post-hoc
analysis, we compared the proportions of participants
who had scores of both primary outcomes within the
normal range at 52 weeks. This range was defi ned as
less than the mean plus 1 SD scores of adult attendees
to UK general practice of 142 (+46) for fatigue (score
of 18 or less) and equal to or above the mean minus 1 SD
scores of the UK working age population of 84 (–24) for
physical function (score of 60 or more).32,33"


32 Cella M, Chalder T. Measuring fatigue in clinical and community
settings. J Psychosom Res 2010; 69: 17–22.
33 Bowling A, Bond M, Jenkinson C, Lamping DL. Short form 36
(SF-36) health survey questionnaire: which normative data should
be used? Comparisons between the norms provided by the
Omnibus Survey in Britain, The Health Survey for England and
the Oxford Healthy Life Survey. J Publ Health Med 1999, 21: 255–70.

I'm afraid my partner's just come down with a migraine, so I'm probably not going to be able to spend much time on this for the next few days (I'm a poorly carer!), but will be happy to look in to little things like that when we're back to normal here. I might try and write a letter then too - I won't be able to come up with anything that solid, but in 250 words, I'm not sure many will.

 

[Cort]

I'm going to put my paper up on the Forums today. We can move it to the WIKI and work on it more to produce a more detailed response if anyone wants to do that.

 

[oceanblue]

Does their 'normal range' include seriously ill people?

"In another post-hoc
analysis, we compared the proportions of participants
who had scores of both primary outcomes within the
normal range at 52 weeks. This range was defined as
less than the mean plus 1 SD scores of adult attendees
to UK general practice of 142 (+46) for fatigue (score
of 18 or less) and equal to or above the mean minus 1 SD
scores of the UK working age population of 84 (24) for
physical function (score of 60 or more).32,33"

33 Bowling A, Bond M, Jenkinson C, Lamping DL. Short form 36
(SF-36) health survey questionnaire: which normative data should
be used? Comparisons between the norms provided by the
Omnibus Survey in Britain, The Health Survey for England and
the Oxford Healthy Life Survey. J Publ Health Med 1999, 21: 25570.

Sorry to hear your partner is not well, we'll miss your contribution.

Clearly using adult attenders to GPs is no way to measure fatigue levels in the healthy population! It is self-evident nonsense and it's hard to see how this got through the reviewers (ok, we know how it did that...)

For the SF-36 data surely the relevant measure for measuring 'recovery' is that for healthy people, not the whole population which will inevitably include everyone who is ill too. And I'm not too sure that SF-36 PF scores are normally distributed on the 0-100 scoring (athletes don't score higher than moderately fit people so the scores are bunched up at 80+) and if that's the case using mean minus one SD might not be appropriate.

But I think getting to the bottom of these numbers is crucial. Exposing them as flawed would be a huge blow against the way the results have been spun.

 

[oceanblue]

6 minute walking test

I was also a bit sceptical about walking tests as a measure of physical activity, perhaps because I walk at a normal pace (but not for very far).

But those figures from Cort about puttering around the house are interesting: what was the source?

That said, the walking test was done in hospital corridors (so lots of walking up and down a short stretch) rather than outdoors, so that may have affected speed/total steps.

 

[Dolphin]

You are good Dolphin- you navigate these waters with ease .?

That's $8,000 US dollars that were spent. ?

US$8,000,000 (although better to put it as US$8m as it's not like it's exactly US$8,000,000.

 

[Esther12]

Thanks OB.

Clearly using adult attenders to GPs is no way to measure fatigue levels in the healthy population! It is self-evident nonsense and it's hard to see how this got through the reviewers (ok, we know how it did that...)

The editorial from Bleijenberg & Knoop came close to openly promoting deception as treatment. I think there's a good case for tying the way the Pace results were produced and promoted to the notion that patients need to be positively deluded for their own good. It would be difficult to make it in 250 words though.

"Both graded exercise therapy and cognitive behaviour therapy assume that recovery from chronic fatigue syndrome is possible and convey this hope more or less explicitly to patients. Adaptive pacing therapy emphasises that chronic fatigue syndrome is a chronic condition, to which the patient has to adapt. Although PACE was not intended to compare cognitive behaviour therapy and graded exercise therapy with each other, there was actually no difference between the two. Both were more effective than adaptive pacing.

Graded exercise therapy and cognitive behaviour therapy might assume that recovery from chronic fatigue syndrome is possible, but have patients recovered after treatment? The answer depends on one’s definition of recovery.3 PACE used a strict criterion for recovery: a score on both fatigue and physical function within the range of the mean plus (or minus) one standard deviation of a healthy person’s score. In accordance with this criterion, the recovery rate of cognitive behaviour therapy and graded exercise therapy was about 30%—although not very high, the rate is significantly higher than that with both other interventions."

 

[Dolphin]

PACE Trial: Participant newsletter February 2011 Issue 4

"The number of patients returning to normal levels of fatigue and physical function was about three out of ten after CBT or GET; about twice as many as those who received APT or SMC."

Funny definition of "normal levels of fatigue and physical function" they use given having a SF-36 physical functioning score of 60 and Chalder Fatigue Scale of 18 would also mean one was eligible to take part in the trial!

http://www.pacetrial.org/docs/participantsnewsletter4.pdf

PACE Trial: Participant newsletter

Results
Pacing, graded Activity, and Cognitive behaviour therapy; a randomised Evaluation February 2011 Issue 4

You were one of the 640 patients who kindly took part in the PACE trial between March 2003 and January 2010. The trial was conducted in six hospitals in England and Scotland and compared the safety and effectiveness of four treatments: Specialist medical care
(SMC) alone, and SMC plus one of the following therapies: adaptive pacing therapy (APT), cognitive behaviour therapy (CBT), and graded exercise therapy (GET). The results are now available and summarised below.
We would like to take this opportunity to thank you very much for taking part.

What were the treatments?

Cognitive behavioural therapy (CBT) - A clinical psychologist or specialist nurse helped the patient to understand how their symptoms were affected by the way that they think about and cope with them, and encouraged them to try out increasing their activity.

Graded exercise therapy (GET) - A physiotherapist or exercise physiologist helped the patient to try a gradually increasing tailored exercise programme which took into account the individual patient's symptoms, fitness, and current level of activity.

Adaptive pacing therapy (APT) - An occupational therapist helped the patient to match their activity level to the amount of energy they had, and aimed to help the patient adapt to the illness rather than assuming they could gradually do more.

Specialist medical care (SMC) - A hospital doctor with experience in CFS gave general advice about managing the illness and prescribed medicines for symptoms such as insomnia and pain.
When given alone, self-help management of the patients' choice was encouraged.

What did the trial show?
We found that patients with CFS were more likely to improve their fatigue and physical function if they were given CBT or GET as well as seeing a hospital specialist, than if they just saw the specialist.
APT was not found to reduce fatigue or improve physical function any more than SMC alone.

How many patients improved and how many were back to normal?
Around six out of ten patients made an improvement in both fatigue and physical ability after CBT or GET, compared to four out of ten patients who improved with APT or SMC.
The number of patients returning to normal levels of fatigue and physical function was about three out of ten after CBT or GET; about twice as many as those who received APT or SMC.

Did the results apply to patients with ME?
The PACE trial classified participants using different ways of diagnosing both CFS and ME to test whether the results applied to both groups. The results were similar however the illness was diagnosed, as long as the primary symptom was fatigue (something all patients required to enter the trial).

Were the treatments found to be safe?
In any trial, some participants may not respond or have adverse reactions to treatment. In the PACE trial adverse reactions to treatment were monitored closely by independent experts. We found that serious adverse reactions to treatment were rare (less than 2% for all treatments) and the number of reactions did not differ between treatments. Patients can therefore have confidence in the safety of APT, CBT, GET and SMC.

Why did you find that APT was less effective when patients report it to be helpful?
We know the treatment was delivered as planned and that patients were satisfied with it, but it didn't help as much as CBT and GET. Although we do not know for sure, it may be because adapting to CFS is less effective than being helped to return towards normal health and abilities.

Do these findings bring us any closer to a cure for CFS?
When added to the knowledge from previous studies, we now have very strong evidence that CBT and GET can help. But like you we hope that even more effective treatments will become available.

Where can full details of the PACE trial results be found?
The results have been published in the Lancet and further details are available on the PACE trial website www.pacetrial.org. This website will be kept up to date with any further news and results coming from the PACE trial.

What will happen now?
As you know we are continuing to collect long-term follow up data for the trial to give us more information about whether the benefits of receiving GET and CBT are long lasting. We are also interested to look at what characteristics determine how patients respond to treatment and how treatments work, as well as the cost effectiveness of treatments.

I have a question about the trial or results, whom should I speak to?
Please refer to the PACE trial website for further information and if this does not answer your question please email the PACE trial team at pace@qmul.ac.uk or contact your local specialist doctor who treated you.
ISRCTN54285094

The PACE Trial was a Multi-Centre study run across six UK Centres, and was jointly funded by:

 

[Dolphin]

Sorry to hear your partner is not well, we'll miss your contribution.

Clearly using adult attenders to GPs is no way to measure fatigue levels in the healthy population! It is self-evident nonsense and it's hard to see how this got through the reviewers (ok, we know how it did that...)

I recall something vague in my head that 25% of GP attendees present with fatigue. I'm not going to swear on that figure but sometimes high figures are thrown around when justifying fatigue papers.

 

[Dolphin]

For the SF-36 data surely the relevant measure for measuring 'recovery' is that for healthy people, not the whole population which will inevitably include everyone who is ill too. And I'm not too sure that SF-36 PF scores are normally distributed on the 0-100 scoring (athletes don't score higher than moderately fit people so the scores are bunched up at 80+) and if that's the case using mean minus one SD might not be appropriate.

But I think getting to the bottom of these numbers is crucial. Exposing them as flawed would be a huge blow against the way the results have been spun.

Agreed.

Here are some population norms for South Australia: http://www.health.sa.gov.au/PROS/portals/0/sa-pop-norm-SF-36.pdf . It's the PF (Physical Functioning) scale.

So if one looks at 35-44 year olds, the 25th percentile is 90 with 45% scoring 100/100.
And they want to tell us 60 is a normal score!
----
At http://www.sf-36.org/nbscalc/index.shtml , one can see the population norms for Sweden: (Mean, SD) Physical Function(ing) (87.9, 19.6), Role-Physical (83.2, 31.8), Bodily Pain (74.8, 26.1), General Health (75.8, 22.2) Vitality (68.8, 22.8), Social functioning (88.6, 20.3), Role-Emotional (85.7, 29.2), Mental Health (80.9, 18.9), Physical Composite Score (PCS) (50.0, 10) and Mental Composite Score (MCS) (50.0, 10).

Also the US, Norway and Canada (I had copied the Swedish ones before which is why I did them).

Note population norms for healthy people and/or working age adults would be more interesting - including people in their 80s (say) shouldn't count. I think I've seen them before for the SF-36.

 

[Dolphin]

SF-36: some UK normative data

Here's some UK normative data:

Short form 36 (SF36) health survey questionnaire: normative data for adults of working age. BMJ. 1993 May 29;306(6890):1437-40. Jenkinson C, Coulter A, Wright L. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1677870/pdf/bmj00022-0017.pdf

 

[Snow Leopard]

Thanks Dolphin. Are you going to cite one of those?

Five reference limit.

Actually, you could substitute the reference of the trial protocol for one of those. Hmm..

 

[Dolphin]

Thanks Dolphin. Are you going to cite one of those?

Five reference limit.

Actually, you could substitute the reference of the trial protocol for one of those. Hmm..

My first draft letter doesn't cite any of them. Would be nice but ran out of words. Others can feel free to use them.

 

[oceanblue]

Comments of thresholds for 'recovery'

Not much time to do this but i see Dolphin has been doing some great digging - here are a few comments from me

Using GP attenders as a sample of a healthy population is patently ridiculous, but it's worse than that: PACE set the threshold as one Standard Deviation below the mean, which statistically is equal to the 15th percentile. This means they took 15% most fatigued patients attending GP surgeries and said any fatigue less than that counts as 'recovered'.

The Oxford criteria require that "c) The fatigue is severe and disabling". However, the PACE trial went futher than this, requiring that the disability (activity) element of a SF-36 PF subscale score of 65 or less. Thus the PACE trial recruitment criteria sets a disability threshold of 65 or less.

Using this threshold, 12% (251 ex 2,080 diagnosed as meeting the Oxford Criteria, from Figure 1) were excluded from the trial due to a PF score of 70 or more (let's assume it was 70 exactly). Yet these excluded patients had already been diagnosed by trial clinicians as suffering from 'severe & disabling fatigue'.

So we know that, according to PACE clinicians, a PF score of 70 counts as disabling fatigue.
Yet, when it comes to assessing recovery, a PF score of 60, ie 10 points lower , counts as 'normal'.

Black is white, the moon's a balloon and we're a bunch of malingerers.