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Criticism of the PACE Trial results
Tuesday 1 March 2011
PACE trial: ME Association letter to ‘The Lancet’, 3 March 2011
The disappointing results for adaptive pacing therapy (APT) in the PACE trial 1 do not reflect the feedback from the majority of published patient surveys, including ours 2, where pacing was reported to be one of the three most helpful strategies in managing ME/CFS.
The likeliest explanation is the difference between APT and the form of pacing advocated by most of the patient support groups around the world. Our version of pacing is evidence-based so it does not require patients to function well below their ability and adhere to the 70% rule, an important component of APT. It is based on clinical experience dating back to the 1950s and supported by several controlled trials showing that pacing limits post-exertional exacerbations and improves functioning over time 3. More significantly, it avoids the documented immunological and metabolic abnormalities following over-exertion 4 which are increasingly recognised as a contra-indication for graded exercise therapy (GET).
The fact that the findings of the PACE trial could result in pacing being removed as a treatment option within the NHS is just one of many concerns. The exaggeration of the outcomes, especially in the media 5, deserves to be challenged, particularly as the findings from the trials on GET are inconsistent with almost every patient group survey and audit conducted.
Dr Charles Shepherd
1 White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R 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. Lancet Feb 17 2011 [Epub ahead of print]
3 Brown M, Khorana N, Jason LA. The role of changes in activity as a function of perceived available and expended energy in non-pharmacological treatment outcomes for ME/CFS. Journal of Clinical Psychology 2011, 67, 253-260
4 White PD, Nye KE, Pinching AJ, Yap TM, Power M et al. JM. Immunological changes after both exercise and activity in chronic fatigue syndrome: A pilot study. Journal of Chronic Fatigue Syndrome 2004; 12: 51-66
5 Got ME? Just get out and exercise, say scientists. The Independent 18 February 2011
PACE Trials LANCET
"The treacherous swamp of confusion that is ME" and "Why doctors are failing ME sufferers."
The findings outlined in the Lancet PACE study (18 Feb 2011 P D White et al) were presaged in 1996.
In response to the 1996 Chronic Fatigue Syndrome UK Royal Colleges Report The Lancet Editorial staff reported "the committee's terms of reference included a brief to look at service provision; indeed, one member was a commissioner who buys health-care services, and a whole appendix is a special summary for commissioners. After emphasising management within primary care, the report then says that the secondary sector is "often inadequate", suggesting the low-cost option of setting up multidisciplinary teams".
The editorial concluded "Psychiatry has won the day for now. A decade hence, when an organic cause for at least some cases of CFS may have emerged, it would be tempting to ask the committee to reconvene. We believe that the report was haphazardly set-up, biased, and inconclusive, and is of little help to patients or their physicians". The outcomes of the UK Royal Colleges Report have guided UK attitudes to research and treatment of ME for the past 15 years.
With further reference to the Royal Colleges Report in March 1997 Richard Horton, Editor of the Lancet wrote an article in The Observer (UK) titled "Why doctors are failing ME sufferers". Horton acknowledged that "today, physicians do not take kindly to being challenged. They feel defensive and insecure.They have become accustomed to unqualified respect and genuflection. Nowhere is this trait more obvious than in the treacherous swamp of confusion that is myalgic encephalomyelitis (ME)". Outlining the objections of the Royal Colleges Committee to the term ME as an unsatifactory label, Horton noted "they used this semantic quarrel to establish a cardboard case against the idea that chronic fatigue syndrome is an organic brain disease".
In 2011 the overwhelming strength of biological evidence is determinedly ignored and semantics (not science) based medicine prevails in "the treacherous swamp of confusion that is ME".
Christine Hunter AM
Letter: ME Myths
There have been some outrageous headlines in the media recently, following publication in the Lancet of a five-year, £4.2 million study which compared different therapies for ME (your report, 18 February).
Let's be very clear on this: exercise and talking therapy cannot cure ME. The Pace trial does not say it can. What the study says is that some people who have fatigue as their primary symptom may gain moderate improvements in their physical functioning if they receive a cognitive behaviour or graded exercise programme in a specialist chronic fatigue syndrome/ME clinic.
Now, can the UK research community please start focusing on the biology of this illness?
Sir Peter Spencer
Action for ME
Letter: Pole-axed by ME
Anyone who has had glandular fever and has lived with recurrent mild re-runs of the illness (a form of ME) for years afterwards, will throw their hands up at your report about ME sufferers just needing "to get out and exercise" (18 February).
Doubtless there is a category of people who rock up at their GPs' surgeries complaining of constant fatigue and who perk up no end after running around a bit. It doesn't follow that they have been cured of ME. It suggests they didn't have it in the first place.
Many ME sufferers can manage several hours at the gym each week with no ill-effects. What distinguishes them from those without the condition is a limit to their exercise tolerance beyond which they relapse into debilitating exhaustion – pole-axed for days, often with accompanying sore throat and swollen neck glands. It can then take weeks for them to work up to functioning normally again.
Exercise is a good thing in moderation but what ME sufferers need is for the scientists to go back to their labs and do some proper research.
St Albans, Hertfordshire
(PACE Trial) What does a score of 60+ on the SF-36 Physical Functioning scale actually represent
[The major new/interesting part in this is **down the bottom** where the questions are given and the scoring explained. But I thought I should be thorough and give some context. Tom]
Regarding the PACE Trial, a few people have been asking me about what normal functioning represents and about the recovered group that is mentioned in the Knoop & Bleijenberg editorial.
Firstly a reminder that the published protocol promised us different data involving the SF-36 that has never materialised:
Primary outcome measures:
The SF-36 physical function sub-scale  measures physical function, and has often been used as a primary outcome measure in trials of CBT and GET. We will count a score of 75 (out of a maximum of 100) or more, or a 50% increase from baseline in SF-36 sub-scale score as a positive outcome. A score of 70 is about one standard deviation below the mean score (about 85, depending on the study) for the UK adult population [51,52].
Those participants who improve in both primary outcome measures [SF-36 criteria and Fatigue Scale criteria] will be regarded as overall improvers.
Secondary outcome measures
4. "Recovery" will be defined by meeting all four of the following criteria: (i) a Chalder Fatigue Questionnaire score of 3 or less , (ii) SF-36 physical Function score of 85 or above [47,48], (iii) a CGI score of 1 , and (iv) the participant no longer meets Oxford criteria for CFS , CDC criteria for CFS  or the London criteria for ME .
The highest score we having given data for is for those with a SF-36 score
"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 14.2 (+4.6) 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"
"25 (16%) of 153 participants in the APT group were within normal ranges for both primary outcomes at 52 weeks, compared with 44 (30%) of 148 participants for CBT, 43 (28%) of 154 participants for GET, and 22 (15%) of 152 participants for SMC. More participants were within normal ranges after CBT than APT (p=0.0057) or SMC (p=0.0014), and more were within normal ranges with GET compared with APT (p=0.0145) or SMC (p=0.0040); APT did not differ from SMC (p=0.65)."
This threshold of 60+ for the SF-36 physical functioning is an unusual one to have in these circumstances given that one could get into the trial with a score of 60 (and indeed later with a score of 65). So one could even deteriorate and still be classed in this group "within normal ranges"
Other eligibility criteria consisted of a bimodal score of 6 of 11 or more on the Chalder fatigue questionnaire15 and a score of 60 of 100 or less on the short form-36 physical function subscale.16 11 months after the trial began, this requirement was changed from a score of 60 to a score of 65 to increase recruitment.
This is threshold has led to media coverage like:
"Trudie Chalder, professor of cognitive behavioural psychotherapy at King's College, London, said that "twice as many people on graded exercise therapy and cognitive behaviour therapy got back to normal" compared with those in the other two treatment groups." ("back to normal" suggests (i) improvement (which wasn't necessary) and (ii) the person is able to lead their normal lives again when there is nothing inherence in the score to suggest this would necessarily happen).
The Daily Mail's article was headed: "Got ME? Fatigued patients who go out and exercise have best hope of recovery, finds study". It started, "It may seem counter-intuitive to patients suffering with fatigue, but scientists have found encouraging people with ME to push themselves to their limits gives the best hope of recovery."
The PACE newsletter didn't use the word, recovery, but did say: ""The number of patients returning to normal levels of fatigue and physical function was about three out of ten after CBT or GET". Given the sort of wording used, it is not surprising the word recovery was used by some. In the accompanying editorial, we are told:
"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.
Although the PACE trial shows that recovery from chronic fatigue syndrome is possible ..."
So I thought people might be interested to see what exactly is the requirement that is used.
Scores are 0-100 with 0 being the worst. Possible scores are 0, 5, 10, 15, 20, ... 85, 90, 95, 100 (unless somebody doesn't fill in all the questions).
Basically for the following 10 questions, you score 10 points if one says: "No, Not Limited At All" to a question and 5 points if one says: "Yes, Limited A Little".
4. The following items are about activities you might do during a typical day. Does your health now limit you in these activities? If so, how much?
Yes, Limited A Lot
Yes, Limited A Little
No, Not Limited At All
a. Vigorous activities, such as running, lifting heavy objects, participating in strenuous sports
b. Moderate activities, such as moving a table, pushing a vacuum cleaner, bowling, or playing golf
c. Lifting or carrying groceries
d. Climbing several flights of stairs
e. Climbing one flight of stairs
f. Bending, kneeling, or stooping
g. Walking more than a mile
h. Walking several hundred yards (US version has "several blocks")
i. Walking one hundred yards (US version has "one block")
j. Bathing or dressing yourself
So one could (say) put "Yes, Limited A Lot" to 2 of the questions and "Yes, Limited A Little" to 4 more and still satisfy their recovery-type definition (of a score of 60+).
Most healthy younger adults score 90-100. The average age in this trial was 38.
It should also be remembered when comparisons are made that a much higher percentage of the population in this study would not be working full-time compared to their peers. Healthy people can commute to and from work and then work full-time; if somebody with ME/CFS can walk several hundred yards a few times a day (or less) but are not able to do much else, the same score may not represent the same level of functioning. It does not mean, as this finding may be interpreted, that the ability to work has been restored to the people with ME/CFS. More interesting data would have been actometer (the researchers decided to drop using that at the end of the trial but are still using it at the start), hours worked (not published), etc.
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