PACE Trial and PACE Trial Protocol

[urbantravels]

I noticed a lot of these letters describe the 6MWD as an objective test but is it truly objective in the way that for example a machine measured specific blood count would be ? There must be factors such as reckless determination, willingness to risk relapse, or blind denial of ramifications that could affect the result independently of any actual objective change.

In a sense it is factual they did walk X meters in 6 minutes, but in a sense it is also an opinion, it is a demonstration of the participants opinion of how far they believe they can safely walk in 6 minutes.

What if there had been 1million 500 meters away which they could keep if they made it there in 6 minutes, would it have changed the results ? would it have improved anyone's health ?

Watch the presentation by Christopher Snell of the Pacific Fatigue Lab from the State of the Knowledge conference - he's on toward the end of Day 1. Toward the end of his presentation he discusses PACE a little bit. He is pretty scathing about how manipulable/influenceable the 6 minute walk test is (I forget the exact word he used, even though I just rewatched it yesterday.)

Dr. Snell's conclusion: Metabolic data (i.e., the kind of data the PFL collects in its exercise test) or GTFO.

 

[anciendaze]

...In a sense it is factual they did walk X meters in 6 minutes, but in a sense it is also an opinion, it is a demonstration of the participants opinion of how far they believe they can safely walk in 6 minutes...

There's still an elephant in the room, statistically. If 31% of participants did not take both 6MWT, you have a selection effect large enough to explain the entire improvement in the GET group, (even though I do not believe this is clinically significant.)

This still ignores the 21 meters which appear to be due to retest familiarity. Competent researchers intending to use the 6MWT would have had three runs: one for practice, one for initial values and one for final values. The carelessness here indicates they weren't very concerned with objective data, which fits with the unused data from Actometers.

An alternative interpretation is that patients were sicker than believed, and the sickest were not able to complete both 6MWT. If you deny both of these, we can get into conspiracy theories. Anyone care to present these alternatives to those who ran PACE?

The bottom line from this trial comes down to a particularly weak endorsement: few of those participating ended up in hospital. It's a pity they didn't have a real control group, so we could judge that aspect fairly.

My own view is that there is enough self-deception and incompetence already apparent to explain all results. The hard bit is explaining the press release, unless this is standard scientific spin control to avoid charges of p*ssing away 5M pounds. If you don't believe this happens, consider this SNAFU. One of the critics quoted in that article, Michael Griffin, was allegedly in charge of NASA!

 

[Sean]

I noticed a lot of these letters describe the 6MWD as an objective test but is it truly objective in the way that for example a machine measured specific blood count would be ? There must be factors such as reckless determination, willingness to risk relapse, or blind denial of ramifications that could affect the result independently of any actual objective change.

In a sense it is factual they did walk X meters in 6 minutes, but in a sense it is also an opinion, it is a demonstration of the participants opinion of how far they believe they can safely walk in 6 minutes.

All this is true. But 1) it is a damn sight more objective than every other measure reported so far, 2) it is objective in that it sets a kind of upper limit for patients pushing yourself only works so far, and 3) even allowing for all this the results were clearly still abysmal for the CBT/GET lovers.

But I agree that we can do better than this for objective evidence, like actigraphs and metabolic studies, etc.

Like anceindaze said, the only thing PACE can really push about the results is the safety angle, which is why they are making such a big deal about it, though even there it seems they are on pretty soft ground.

 

[Dolphin]

Doubts about the walking test were alluded to in these two (extracts from) letters:

Objective outcome measures are preferable due to the potential for response bias, and
the protocol mentioned several but only one, the six-minute walking distance, was
reported.3 Graded Exercise Therapy (GET) performed better on this test than the other
interventions which all had similar results.1 However, even for GET, the mean of 379m is
unimpressive compared to reference values of approximately 600m for healthy men and
women aged 45 years; the improvement could even theoretically be due to a learning
effect (given GETs content, participants would have had more experience walking
continuously than, say, the Adaptive Pacing Therapy (APT) group) and possibly a greater
willingness on the part of GET participants (compared to those using APT) to push
themselves for the test.1,3,4

Furthermore, the degree of improvement on the only objective physical measure reported at follow up (6 minute walking distance test 6MWD) was well below clinical significance in three of the four trial arms,2 and barely reached significance in the fourth and most successful arm (Graded Exercise Therapy),2 with patients (average age 38) still scoring worse than healthy 70-80 year olds,3 and most categories of cardiopulmonary
patients.4 Such marginal improvements, coming off a very low base, mean any practical functional gains for patients will be minimal at best, even if sustained.

There was also no repeat 6MWD test 24-48 hours later to objectively measure post-exertional malaise, with only a single subjective measure being used for this significant symptom, and follow up data weren't reported for the objective Self-Paced Step test, or Client Service Receipt Inventory.

It's worth remembering that people writing letters only had 250 words to play with so you don't get a chance to fully expand on lots of points. Also, one only had 5 references which was really 4 as one was used up referring to the Lancet paper. If you referred to the Protocol paper, you were down to 3 references. That's why this was really a case where we needed lots of people writing in as even a few people couldn't cover all or most of the points.

 

[Dolphin]

There's still an elephant in the room, statistically. If 31% of participants did not take both 6MWT, you have a selection effect large enough to explain the entire improvement in the GET group, (even though I do not believe this is clinically significant.)

This still ignores the 21 meters which appear to be due to retest familiarity. Competent researchers intending to use the 6MWT would have had three runs: one for practice, one for initial values and one for final values. The carelessness here indicates they weren't very concerned with objective data, which fits with the unused data from Actometers.

An alternative interpretation is that patients were sicker than believed, and the sickest were not able to complete both 6MWT. If you deny both of these, we can get into conspiracy theories. Anyone care to present these alternatives to those who ran PACE?

This letter in the Irish Medical Times raises the issue:

In the PACE Trial, actometers were not used. The only objective outcome measure was the six-minute walk test, which only increased for CBT participants by 21m to 354m, a change that was actually slightly smaller than that of the control group. The GET group increased by a bit more, to 379m after 12 months.

However, this still is a very low absolute walking distance for a group with a mean age of 40. By comparison, a group of older adults (mean age: 65) covered an average distance of 631m (Troosters et al., 1999). In addition, data was unavailable for 31 per cent of GET participants and 24 per cent of those who undertook CBT; it may be the case that sicker patients were less likely to try the test.

These data could be explained by only a small fraction of the participants actually engaging in increased activity or exercise; the only reported measure of treatment adequacy was the number of appointments attended, not the type, intensity, or duration of activity/exercise performed each week.

Lack of objective outcome measures, the possible biasing effects of missing data and the uncertainty regarding whether trial subjects actually implemented CBT/GET as planned severely limit conclusions about efficacy and safety that can be drawn from PACE. Thus the results may not be truly inconsistent with the high rates of adverse effects from graded activity/exercise programmes reported by CFS patients in surveys across the world

http://www.imt.ie/opinion/2011/04/caution-is-still-required-on-get-and-me.html

 

[Sean]

But I agree that we can do better than this for objective evidence, like actigraphs and metabolic studies, etc.

My personal interest is in basic movement studies (neuro-sensory-motor), IMHO there are some tantalising clues in our gait patterns, etc, beyond the obvious fact that we are having trouble moving properly.

 

[Jenny]

Oceanblue and I have sent a the following letter to The Psychologist commenting on their piece on the PACE trial:

Your summary of the findings of the PACE trial (White et al., 2011), which evaluated the effectiveness of CBT and graded exercise therapy as treatments for ME/CFS (Fatigue evidence gathers PACE, April 2011), gave a somewhat misleading impression of the outcomes of this study. You said that self-reports on measures of fatigue and physical function showed that 30% of CBT patients and 28% of exercise patients had returned to normal function. This suggests that nearly one-third had recovered with these treatments. Unfortunately this is far from the case.

First, the thresholds for normal were set so low they could include those with considerable disability. The authors defined within the normal range as a Short Form-36 Physical Function (SF-36) score of 60 or more (0-100 scale), yet the problems with physical functioning that characterise CFS were defined by a SF-36 score of up to 65 - which overlaps with normality. The situation with fatigue scores is similar, so that a participant may have met the trial fatigue criteria for CFS yet simultaneously have met the criteria for normal. Consequently the figures you quoted tell us little meaningful about the PACE trials effectiveness.

Secondly, it is of some concern that the authors inexplicably changed the criteria for positive primary outcomes originally proposed by them in the protocol for the study
(White et al., 2007). On the Chalder Fatigue Scale, for example, they stated that a positive outcome would be a 50% reduction in self-reported fatigue, or a score of 3 or less. And on the SF-36 scale of physical function a score of 75 or more, or a 50% increase from baseline would be required. So the figures you reported are misleading.

Thirdly, you omitted to mention the disappointing outcomes on more objective measures of functioning. For example, after a year of treatment, patients receiving graded exercise therapy had on average increased the distance they were able to walk in 6 minutes from 312 to 379 metres. Even patients suffering from serious chronic cardiopulmonary diseases can manage more than this (in a sample of over 1,000 such patients the mean distance walked was 393 metres [Ross, Murthy, Wollak, & Jackson, 2010]), and at normal walking speed people typically cover around 500 metres. CBT treatment had no significant effect on walking distance.

Perhaps these results are unsurprising, given that the treatments focused on reducing patients assumed fear of engaging in activity, and completely failed to acknowledge the complexity of this illness. We are much concerned that exaggerated claims for these treatments will create a false impression of the effectiveness of PACE amongst psychologists, and will continue to divert scarce resources away from effective medical treatments for this devastating condition.

References
Ross, R.M., Murthy, J.N., Wollak, I.D., & Jackson, A.J. (2010). The six-minute walk test accurately estimates mean peak oxygen uptake. BMC Pulmonary Medicine, 10.31. http://www.biomedcentral.com/1471-2466/10/31

White P.D., Sharpe M.C., Chalder T., DeCesare J.C., Walwyn R., and the PACE Trial Group (2007). 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 Central Neurology, 2007;7:6. http://www.biomedcentralcom/1471-2377/71/6

White, P.D., Goldsmith, K.A., Johnson, A.L, Potts, L., Walwyn, R., DeCesare, J.C, Baber, H.L., Burgess, M., Clark, L.V., Cox, D.L., Bavinton, J., Angus, B.J., Murphy, G., Murphy, M., ODowd, H., Wilks, D., McCrone, P., Chalder, T., Sharpe, M.C., on behalf of the PACE trial management group (2011). Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE). The Lancet, published online February 2011. DOI:10.1016/So140-6736(11)60006-2.

Our letter hasn't been included in the May issue of The Psychologist. Still a chance for a later issue though.

Jenny

 

[Dolphin]

Letter in Therapy Today, journal of British Assoc. for Counselling & Psychotherapy

Well done and thanks to whoever wrote this:
http://www.meassociation.org.uk/?p=5710

Treating ME: what works?, letter in Therapy Today

Letter in Therapy Today, journal of the British Association for Counselling and Psychotherapy, April 2011

Treating ME: what works?

I was alarmed to read your news item titled Hope for ME sufferers as study results support effective therapy (Therapy Today, March 2011) which was based on the report of the PACE trial recently published in The Lancet.1 Unfortunately the results of this research are very strongly contested by the ME community at large by which I mean people who have ME.

I am writing to you as a member of BACP and a practising counsellor, but also as someone who has had the illness for approximately 14 years, and who is an active member of my local ME support group, as well as a member of the two main national organisations supporting adults with ME.

The PACE trial reports that CBT and GET (graded exercise therapy) can safely be added to SMC (specialist medical care) to moderately improve outcomes for chronic fatigue syndrome, but APT (Adaptive Pacing Therapy) is not an effective addition. Strangely this research contradicts both the reported experiences of members of our local group, and the results of a number of national readership surveys carried out by the ME Association and Action for ME.2, 3

The results of the Action for ME Survey 20084 found that 82 per cent of respondents found pacing helpful, 15 per cent experienced no change, and three per cent were made worse; 45 per cent found graded exercise helpful, 15 per cent experienced no change, and 34 per cent were made worse; and 50 per cent found CBT helpful, 38 per cent experienced no change, and 12 per cent were made worse.

The ME Association Survey 20102 found that 71 per cent of respondents improved after pacing, 24 per cent experienced no change, and 5 per cent were made worse; 22 per cent improved after graded exercise, 21 per cent experienced no change, and 57 per cent were made worse; and 26 per cent improved after CBT, 55 per cent experienced no change, and 20 per cent were made worse. (Other smaller surveys by the same organisations have produced very similar results.)

Pacing was the intervention judged to be the most helpful by members of the two largest membership organisations of adults with ME, but it has been described by the PACE trial as doing little more than help sufferers manage their illness. Conversely, interventions judged by members of these organisations to be less helpful, and in some cases positively harmful (GET 57 per cent, CBT 26 per cent) are stated by PACE to be able to be safely added to treatment options.

In our local group we have held several meetings at which members hold unstructured discussions about what has helped them most. Many ideas come up that are sadly not available on the NHS, but the one intervention that the NHS does offer that is found to be helpful is pacing, yet this is the approach that the PACE study states does little more than help sufferers manage their illness (incidentally this is an outcome that many of our members would welcome!). In contrast our group members have never mentioned GET as being helpful, and some members have been quite severely harmed by it. Similarly CBT has been found to be helpful by a few members, but it does seem to depend very much on the CBT therapist, and some are experienced as severely lacking in understanding of the illness, and potentially harmful.

Dr Charles Shepherd, the medical advisor to the ME Association, has commented: We find the trial results extremely worrying because pacing, in the form that the MEA recommends, may as a result no longer be offered as a treatment option in NHS clinics. And at the same time, NICE may well strengthen its inflexible and unhelpful recommendations regarding CBT and GET.

We also fear that the way in which the results are already being reported in media headlines eg Got ME? Just get out and exercise, say scientists will lead some doctors to advise inappropriate exercise regimes that will cause a serious relapse. This is not a good day for people with ME/CFS. They have a complex multisystem illness that requires a range of treatment options based on their individual symptoms as well as the stage and severity of their illness.4

Both charities are preparing detailed responses to the PACE report, which will hopefully clarify why there is such a disparity between PACE and the lived experience of people with ME. In the meantime my fears are similar to Dr Shepherds, and my reason for writing to you is to urge counsellors and therapists not to recommend exercise regimes to their clients and risk causing a serious relapse. This applies particularly to CBT therapists, who may be tempted, on the basis of the PACE report, to describe the cautious approach to exercise of a client with ME as being based on an irrational belief about the illness, rather than respecting the clients own lived experience.

ME is a very variable illness, in the degree of severity, the nature of the symptoms, in precipitating factors, and in what is helpful to manage and/or cure the disease. When our local group meets we are always careful to remind each other that what works for one may not work for another. If this letter makes all your readers aware of this very significant aspect of the illness then it will have achieved its object.

Anon

References:

1. Sharpe M et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. The Lancet. 2011; 377(9768):823-836.

2. The ME Association. Managing my ME: What people with ME/CFS and their carers want from the UKs health and social services. The ME Association; 2010.

3. ME Association. Press statement about the results of the PACE study. 18 February 2011.

4. Action for ME. Initial findings of a national survey of over 2,760 people with ME focusing on their health and welfare. Action for ME; 2008.

Links:

www.meassociation.org.uk/?page_id=1345

www.meassociation.org.uk/?p=4607

http://www.afme.org.uk/default.asp

www.afme.org.uk/campaigning.asp?table=contenttypethree_detail&title=NHS Services&id=168

 

[urbantravels]

Please excuse me if this has already been mentioned and I missed it, but - now that the rejections on letters have started coming from the Lancet, do we know when the *accepted* letters are due to be published?

 

[Dolphin]

Please excuse me if this has already been mentioned and I missed it, but - now that the rejections on letters have started coming from the Lancet, do we know when the *accepted* letters are due to be published?

I looked around a month ago and over various editions over a few months, letters were usually in around 3 months or a bit longer following publication in the print edition (which was March 4/5). So I'd be guessing June.

 

[Graham]

If a defective definition of the illness caused them to include a few subjects who did not have ME/CFS, these would naturally show large gains over the course of a year, possibly without any treatment at all. Including a small percentage of these, and dropping a small number of subjects who were too ill the complete the trial, could produce all the change seen. Of course, if this happened, it would be easy to tell what was going on if you looked at raw data. Therefore, I don't expect to see data which addresses such questions.

Does this qualify as a conspiracy theory? Researchers are just as capable of self-deception as patients. Published work on confirmation bias is abundant.

Sorry about the delay in responding - I'm slow. But that's it exactly! It is even possible that the ones who did improve would have improved more if the GET and CBT hadn't held them back. Without subgroups and clinically defined expectations for each subgroup, then it is possible for us to end up with a treatment that appears to help a little bit on average, but actually harms all. OK, that's unlikely, but a good scientist would anticipate this problem and analyse the subgroups. I don't think it is conspiracy, but looking at all the psychological studies that I have been able to manage over the years, I'm of the firm impression that their grasp of scientific, statistical or even logical thought processes are weak.

 

[Dolphin]

BMJ coverage of the PACE Trial

BMJ coverage of the PACE Trial

http://www.bmj.com/content/342/bmj.d1168

BMJ 2011; 342:d1168 doi: 10.1136/bmj.d1168 (Published 23 February 2011)
Cite this as: BMJ 2011; 342:d1168
Short Cuts
All you need to read in the other general journals

CBT and graded exercise are safe and effective treatments for chronic fatigue syndrome

Lancet 2011; doi:10.1016/S0140-6736(11)60096-2

Cognitive behavioural therapy (CBT) and graded exercise are the best treatments for chronic fatigue syndrome, according to a rigorous trial of four different options. Both treatments looked safe when added to specialist medical care and worked better than adaptive pacing therapy or specialist care alone. The 641 participants were treated for six months and followed up for a further six months. All groups improved, but by the end of the trial patients treated with CBT or graded exercise had significantly less fatigue and significantly better function than any of the other groups. All secondary outcomes pointed in the same direction, including patients own impressionsCBT and graded exercise therapy both doubled the odds of being much or very much improved, relative to specialist care alone (odds ratios 2.2, 95% CI 1.2 to 3.9; and 2.0, 1.2 to 3.5)?.


Adaptive pacing was the least successful active treatment in this trial, despite patients high expectations. Some patient groups favour adaptive pacing because it teaches patients to live within their capabilities (adaptation) rather than risk exacerbating fatigue by increasing activity. Graded exercise therapy and CBT, both of which encourage patients to do more, did not worsen symptoms in this trial, and serious adverse events were rare in all groups. Only a handful of patients got much worse during or after any treatment.

Patients with chronic fatigue syndrome have nothing to fear from CBT or graded exercise, say the authors. Both work as a bolt on to specialist care, although their overall effects looked modest. Less than a third of patients were cured by either treatment (30% (44/148) after CBT and 28% (43/154) after graded exercise therapy).

------
People could post a comment at: http://www.bmj.com/content/342/bmj.d1168

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Those figures don't relate to anything close to a "cure" (requires 60 or more on the SF-36 physical functioning scale and 18 or less on Likert Chalder fatigue scale):

One could be at the same level or even be slightly worse than at the entry point to the trial and satisfy those criteria!

 

[oceanblue]

BMJ coverage of the PACE Trial
People could post a comment at: http://www.bmj.com/content/342/bmj.d1168
One could be at the same level or even be slightly worse than at the entry point to the trial and satisfy those criteria!

can't get past the paywall.

 

[Dolphin]

can't get past the paywall.

I posted the full text.

If one goes to: http://www.bmj.com/content/342/bmj.d1168.extract , one can click: "Submit a rapid response". You may have to get free bmj.com membership to submit - not sure about that. Lots of people who haven't had full personal membership have submitted comments over the years.

 

[Sean]

Can't get past the propaganda wall.

 

[Dolphin]

Can't get past the propaganda wall.

 

[Dolphin]

The direct link if anyone wants to send a comment (it would be good) is: http://www.bmj.com/letters/submit/bmj;342/feb23_1/d1168 . I'm too busy.

 

[anciendaze]

Coming Attractions

My last nap resulted in disturbed dreams which might presage future psychosocial discoveries trumpeted by BMJ.
I vividly imagined this headline: CBT and GET Cure Aging!

While you could say many things about admitted defects in my subconscious, you can't deny the logic. If walking 389 meters in 6 minutes means you are cured of ME/CFS, then there must be a herd of elderly malingerers pulling scams about this business of aging. Economic implications are hard to overstate. Pension savings alone could support any amount of bureaucratic and professional foolishness. If that isn't the purpose of government, what is?

 

[Graham]

My last nap resulted in disturbed dreams which might presage future psychosocial discoveries trumpeted by BMJ.
I vividly imagined this headline: CBT and GET Cure Aging!

While you could say many things about admitted defects in my subconscious, you can't deny the logic. If walking 389 meters in 6 minutes means you are cured of ME/CFS, then there must be a herd of elderly malingerers pulling scams about this business of aging. Economic implications are hard to overstate. Pension savings alone could support any amount of bureaucratic and professional foolishness. If that isn't the purpose of government, what is?

Nice one, anciendaze! How could you be so cynical?

But I don't think you have gone far enough. What about "GET and CBT cure death"? All you need is a slightly flexible definition of death - say an Oxford Criterion that specifies persistent lack of breathing for 3 minutes, then as long as a couple of patients defined as dead spring back to life, you can average it out over all the ones that did not, and hey presto, you have a cure.

 

[Dolphin]

My last nap resulted in disturbed dreams which might presage future psychosocial discoveries trumpeted by BMJ.
I vividly imagined this headline: CBT and GET Cure Aging!

While you could say many things about admitted defects in my subconscious, you can't deny the logic. If walking 389 meters in 6 minutes means you are cured of ME/CFS, then there must be a herd of elderly malingerers pulling scams about this business of aging. Economic implications are hard to overstate. Pension savings alone could support any amount of bureaucratic and professional foolishness. If that isn't the purpose of government, what is?

Since becoming ill, I've noticed an attitude in society where for some people "if you exercise you're a good person, if you don't, you're a sinner" - if somebody becomes ill, it's probably weren't living a healthy enough lifestyle (I loved sports myself before become ill (aged 16) and perhaps might have ended up like that myself). So it is awkward the treatment we can't do. To me, Peter White's views http://bit.ly/d46IET seem quite similar to the way one would talk about very obese people (you don't give them supports, it's for their own good to "kick them in the butt"/"tell them to get off their lazy a$$" (not exact words used by anybody); "you have to be cruel to be kind").