PACE Trial - letters that were not accepted by the Lancet

Dolphin

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I thought I would start a thread for letters in reply to the PACE Trial that were not accepted by the Lancet.

It might act as a sort of summary of some observations people made.

People can PM their letters if they prefer (I can include it either with or without their name - it doesn't matter to me).

Best to keep comments on letters to another thread (you can link to the posts) I think.

ETA: There are now 30 letters from 25 people/groups in this thread.
 

Dolphin

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This was posted on Co-Cure http://listserv.nodak.edu/cgi-bin/wa.exe?A2=ind1104C&L=CO-CURE&P=R1953&I=-3 which has a public archive:

Dear All,

here are my letters rejected by The Lancet editorial.

Best Wishes,
Peter Kemp

The PACE Trial Walking Test



The PACE Trial Protocol (1) projected using a 6 minute walking test at baseline assessment and as an outcome measure. The Protocol does not provide for a practice walk test which is required to gain reproducible data.



The reference given in the PACE Trial Protocol for the walking test is Butland et al (2) which followed McGavin et al (3). Both require a practice walk to compensate for a training effect; i.e., "The important increase in distance walked on the second occasion may have been due to practice, although no similar improvement occurred in the values of the progressive exercise test. The walking test must be carried out twice, therefore, to achieve reproducible results"(3).



Unless the practice walk was included or White et al have data showing that a single walking test can provide reproducible data, in contradiction of Butland et al, McGavin et al and others, the PACE Trial data for this test must be considered unreliable and should be withdrawn.





REFERENCES



1. PACE Trial Protocol. 2007. BMC Neurology. 7:6doi:10.1186/1471-2377-7-6 [Online PDF]. Available at: http://www.biomedcentral.com/1471-2377/7/6. Accessed Feb 24th 2011.



2. Butland RJA, Pang J, Gross ER, Woodcock AA, Geddes DM: 1982. Two, six, and 12 minute walking test in respiratory disease. BMJ 1982 , 284:1607-1608.



3. McGavin CR, Gupta SP, McHardy GJR. 1976. Twelve minute walking test

for assessing disability in chronic bronchitis. Br MedJ. 7 1976;i:822-3







The PACE Trial Results



The authors provide figures for "improved by at least 2 points for fatigue and at least 8 points for physical function at 52 weeks" as follows:



Specialist Medical Care (SMC), 45% (the control group)

Cognitive Behavioral Therapy (CBT) 59%

Graded Exercise Therapy (GET) 61%



Therefore only 14% of participants in the CBT group improved over and above the control group. For GET the figure is 16%.



The figures for "within normal ranges for both primary outcomes at 52 weeks" show:



Specialist Medical Care (SMC), 15% (the control group)

Cognitive Behavioral Therapy (CBT) 30%

Graded Exercise Therapy (GET) 28%



Therefore only 15% of participants in the CBT group improved over and above the control group. For GET the figure is 13%.



Substantial numbers of PACE Trial participants receiving none of the treatments under investigation, spontaneously improved (45%) or recovered to 'normal ranges' (15%). The measures above show that CBT and GET had a effect for only a small percentage of participants (less than 16%).



CBT and GET appear to be ineffective for most Chronic Fatigue Syndrome patients.



Peter Kemp





The PACE Trial and Infectious Mononucleosis (IM)



Professor White, Principal Investigator of the PACE Trial (The Lancet. Feb 19th), was a co-author of Candy et al (2002) which states, "The prevalence of prolonged illness after IM varies, from 1.5% to 56%. The symptom consistently reported to have longest duration was fatigue. One of the two largest prospective studies found that, six months after onset of IM, physical fatigue was present in 40% of subjects and 9% to 22% had a CFS." Candy et al also remark, "Physical deconditioning may play a key role in causing prolonged symptoms".



According to Thompson et al (1969, cited by Candy et al), 56% IM cases reported fatigue at 6 months, and 16% at 11 months. Thus many chronic IM patients spontaneously improve and might be expected to respond to rehabilitation.



The inclusion of chronic IM patients could confound research of interventions in CFS by biasing results towards improvement. The PACE Trial should have identified such patients for exclusion or sub-grouping.





References:

Candy, B., Chalder, T., Cleare, A., Wessely, S., White, P.D., Hotopf, M. 2002. Recovery from infectious mononucleosis: a case for more than symptomatic therapy? A systematic review. British Journal of General Practice. October.



Thompson, DS., Godleski, J., Herman, S. 1969. Prognosis post infectious mononucleosis. Journal of American College Health. 17:453-457.





The PACE Trial and Objective Measures



The PACE Trial (The Lancet, Feb 19th 2011) employed a therapeutic relationship to deliver CBT. The research also relied heavily on subjective questionnaires such as the Chalder Fatigue Scale and SF-36 to measure symptoms. How such questionnaires are completed may be influenced by how a client feels about their therapist, whether they like, dislike or even fear them.



In "Clients' Deference in Psychotherapy", Rennie (1994) analysed 16 therapy sessions and identified 348 instances of client deference to the therapist. These most commonly related to the client's, "Concern about the therapist's approach", closely followed by "Fear of criticising the therapist".



This demonstrates the influence therapists can have over clients and is one of the important reasons why objective measures should be used whenever possible in research. Using objective measures in the PACE Trial should have been straightforward as distinct change is one of the factors that has made CBT so popular with health professionals. Failure to employ this approach means that the PACE Trial provides inadequate objective evidence for patients and professionals to make rational choices about the therapies under investigation.



REFERENCE

Rennie, David, L. 1994. Client's Deference in Psychotherapy. Journal of Counseling Psychology. 41.4.427-437.
Also:
Dear Editor,



re: The Lancet Feb 19th 2011.



Subjective Measures in the PACE Trial - A Rational Choice?



The PACE Trial (The Lancet, Feb 18, 2011) led by Professor Peter White, researched rehabilitative therapies for Chronic Fatigue Syndrome (CFS). Two of the therapies used in the trial explain CFS symptoms with theories of deconditioning and fear avoidance (White et al, 2007); abnormal illness beliefs and secondary gains etc. Yet the PACE Trial used almost entirely subjective measures such as quality of life, symptom and fatigue questionnaires to assess participants and treatment effect.



On the one hand, the theories underpinning the interventions on trial imply that people with CFS are incompetent to judge their own symptoms. On the other hand the PACE Trial uses these same people's assessment of their symptoms as evidence in a controlled clinical trial. This seems irrational.



I would have thought that objective measurement of any treatment effect was essential in the PACE Trial. Failure to do this has made it appear that White et al are having their cake and eat it. The subjective nature of the evidence is unlikely to satisfy researchers and clinicians who have identified physiological abnormalities in CFS such as mitochondrial dysfunction, oxidative stress, chronic infections and widespread inflammation.



Peter Kemp MA
 

Dolphin

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Dr. Charles Shepherd (MEA)

Dr. Charles Shepherd (ME Association):
http://www.meassociation.org.uk/?p=4900
PACE trial: ME Association letter to The Lancet, 3 March 2011

Editor

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
Hon Medical Adviser, The ME Association
7 Apollo Office Court, Radclive Road, Gawcott, Bucks MK18 4DF

References
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]
2 ME Association. Managing my ME. What people with ME/CFS and their carers want from the UKs health and social services. http://www.meassociation.org.uk?page_id=1345
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
 

Dolphin

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Invest in M.E.

Invest in M.E.
http://www.investinme.org/IIME Statement 2011-03-01.htm
IiME Submission to Lancet

Response to PACE Trials


March 2011

Invest in ME responded to the publication in the Lancet of -

"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, Volume 377, Issue 9768, Pages 823 - 836, doi:10.1016/S0140-6736(11)60096-2

The response content was limited by the Lancet to a maximum of 250 words.

Below is the submission from IiME to the Lancet-




The trial investigators did not use objective outcome measures apart from a six minute walking test in which patients in the CBT arm were able to walk an extra 21 metres in 6 minutes (354m) compared to baseline [1] - a distance well below that of healthy elderly subjects (631m) [2]. The clinical benefit is insignificant in relation to the trials cost.

It would be more consistent if the researchers had adhered to their initial intention of using actigraphy at the end as well as the beginning of the trial [3] to see if patients traded their other daily activities for exercise. The hypocrisy of the researchers is demonstrated by their comments [4] especially as patients chosen for the trial had to be well enough to attend clinics.

Of the 3158 patients screened for eligibility for the trial from secondary fatigue clinics 1011 did not meet the inclusion criteria, the Oxford criteria [2]. These criteria exclude those with neurological signs and symptoms so by definition this trial had nothing to do with myalgic encephalomyelitis (ME) as classified by WHO [5].

It is therefore important that the trial results are not extrapolated to justify effectiveness of CBT/GET for patients diagnosed with ME.

The purpose of medical research should be to benefit patients.

It is not in patient groups interests in mixing patient cohorts and trying to find a one-size-fits-all management technique.

The PACE trials lack credibility, do not benefit ME patients, are flawed and the result of poor and unprofessional research.



References:

1/. Prof PD White MD,KA Goldsmith MPH,AL Johnson PhD,L Potts MSc,R Walwyn MSc,JC DeCesare BSc,HL Baber BSc,M Burgess PhD,LV Clark PhD,DL Cox PhD,J Bavinton BSc,BJ Angus MD,G Murphy MSc,M Murphy FRCP,H O'Dowd PhD,D Wilks FRCP[Ed],Prof P McCrone PhD,Prof T Chalder PhD,Prof M Sharpe MD,on behalf of the 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. The Lancet - 18 February 2011 DOI: 10.1016/S0140-6736(11)60096-2.

2/. Butland RJA, Pang J, Gross ER, Woodcock AA, Geddes DM: Two-, six-, and 12-minute walking tests in respiratory disease. BMJ 1982; 284:1607-8.

3/. White PD, Sharpe MC,Chalder T, DeCesare JC and Walwyn R for 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. BMC Neurology 2007, 7:6.

4/ .. we decided that a test that required participants to wear an actometer around their ankle for a week was too great a burden at the end of the trial. PD White, MC Sharpe, T Chalder, JC DeCesare, R Walwyn, for the PACE trial management group. Response to comments on Protocol for the PACE trial. BMC Neurol. 2007, 7:6doi:10.1186/1471-2377-7-6.

5/ WHO Diseases of the nervous system (G00-G99) http://apps.who.int/classifications/apps/icd/icd10online/?gg90.htm+g933
 

Dolphin

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One person sent me theirs and asked that it being posted without their name:

In what appears to be the only objective outcome measure reported on by White et al.,1 the Six-Minute Walking Distance (6MWD), the results appear to be, at best, modest: the cognitive behaviour therapy (CBT), adaptive pacing therapy (APT) and specialist medical care (SMC) groups all increased by approximately 20m, with the graded exercise therapy (GET) cohort reaching 379m, an improvement of 67m over 12 months. This remains well short of what one might expect from a set of individuals with a mean age of 39 (+/-12) when they undertook the test. By comparison, a group of healthy older adults of mean age 65 (+/-10) walked an average of 631 (+/-93) metres.2

In order to properly evaluate whether even these small increases in activity were gained at a price, it would be helpful if the authors were to report on the secondary outcome measures referred to in the PACE protocol,3 in particular hours of employment, before and after treatment.


References:

1. White PD, Goldsmith KA, Johnson AL, et al., on behalf of the 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; published online Feb 18. DOI:10.1016/S0140-6736(11)60096-2.

2. Troosters T, Gosselink R, Decramer M. Six minute walking distance in healthy elderly subjects. Eur Respir J. 1999 Aug;14(2):270-4. Eur Respir J. 1999 Aug;14(2):270-4.

3. White PD, Sharpe MC, Chalder T, et al. 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.
 

Marco

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Here's my attempt :


Are the PACE trial results 'well anchored'?


A common consideration in clinical trials is determining the degree to which any objectively measured changes may be considered to be clinically significant, particularly when such changes are small.

A widely used concept is to 'anchor' such changes with participants' subjective assessment of the degree to which measured changes have impacted more generally on their perceived sense of well being and functioning.1 The PACE authors define 'clinically useful differences' in relation to the Chalder Fatigue questionnaire and the SF 36 physical function sub-scale, both of which rely on participants' self-rated responses.2 It would seem reasonable to conclude from the results that, while the improvements seen in the only objective measure reported (the six minute walking test) were modest, they were considered clinically useful by a proportion of participants.

Such conclusions are however problematic in trials such as PACE where the therapy arms under investigation actively target participants' subjective experience and reporting of symptoms and understanding of prognosis. In the case of CBT and GET, participants are encouraged to believe that recovery is possible and that symptoms are not clinically meaningful, while in the APT arm they are encouraged to believe that the illness is not reversible and that they must operate within a 'energy envelope'.

I would submit that, contrary to usual practice, subjective responses are not a reliable indicator of a clinically useful difference where therapies aim to change subjective experiences and that further objective measures of functioning would be a more appropriate 'anchor'.


1. Guyatt GH, Osoba D, Wu, AW, Wyrwich KW, Norman GR, and the clinical significance consensus meeting. Methods to Explain the Clinical Significance of Health Status Measures Mayo Clin Proc. 2002;77:371-383

2. White PD, Goldsmith KA, Johnson AL, et al, on behalf of the 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; published online Feb 18. DOI:10.1016/S0140-6736(11)60096-2.
 

Dolphin

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Somebody asked me to post this for them:

Submitted Version

PACE fails to deliver substantial or objective gains.

All but one of the outcomes published by the PACE trial are from subjective self-report measures,1 which claim "...30% of participants were within normal ranges for both [the main outcome measures]", and "...41% rated themselves as much better or very much better in their overall health."

However, all trial arms received standard medical care, and subtracting this contribution (15%) leaves no more than 15% of patients reporting normal range outcomes in any treatment arm.

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.

Lastly, the PACE trial didn't noticeably improve on the already modest, limited therapeutic results from previous clinical trials of the behavourial model of chronic fatigue syndrome.5

It is clearly time to look elsewhere for answers to this debilitating, distressing, and stigmatised disorder.


References
1 White PD, Goldsmith KA, Johnson AL, et al, on behalf of the 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; published online Feb 18. DOI:10.1016/S0140-6736(11)60096-2.

2 Wise RA, Brown CD. Minimal clinically important differences in the six-minute walk test and the incremental shuttle walking test. COPD, 2005;
2(1): 1259.

3 Enright PL, Sherrill DL. Reference equations for the six-minute walk in healthy adults. Am. J. Respir. Crit. Care Med., 1998; 158: 13841387

4 Ross RM, Murthy JN, Wollak ID, Jackson AS. The six minute walk test accurately estimates mean peak oxygen uptake. BMC Pulmonary Medicine, 2010, 10: 3

5 Price JR, Mitchell E, Tidy E, Hunot V. Cognitive behavioural therapy for chronic fatigue syndrome in adults. Cochrane Database Syst Rev., 2008;
16(3): CD001027.


Revised Version


Pace fails to deliver substantial or objective gains

All but one of the outcomes published by the PACE trial are from subjective self-report measures, which claim "...30% of participants were within normal ranges for both [the main outcome measures]", and "...41% rated themselves as much better or very much better in their overall health." [1]

However, all trial arms received "standard specialist medical care", and subtracting this contribution (15%) leaves no more than 15% of patients reporting a 'normal' range outcome in any active treatment arm, with serious questions over how that 'normal' was arbitrarily and more broadly re-defined at the analysis stage of the study.

The degree of improvement on the only objective physical measure reported at outcome (6-minute walking distance test 6MWD) was well below clinical significance (minimal clinically important difference) in three of the four trial arms, and barely reached significance in the fourth and most successful arm (Graded Exercise Therapy). [2] Patients average age 38 still scored worse than healthy 70-80 year olds, and most categories of cardiopulmonary patients. [3, 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 no repeat 6MWD test 24-48 hours later to objectively quantify post-exertional malaise, with only a single subjective measure used for this important symptom, and outcome data were not reported for the objective Self-Paced Step test, Client Service Receipt Inventory, or actigraph. [5, 6]

Lastly, the PACE trial failed to significantly improve on the already modest and limited therapeutic results from previous clinical trials of the behaviour model of chronic fatigue syndrome. [7]

It is clearly time to look elsewhere for answers to this refractory, troubled, and distressing disorder.


References

1 White PD, Goldsmith KA, Johnson AL, et al, on behalf of the 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; published online Feb 18. DOI:10.1016/S0140-6736(11)60096-2.

2 Wise RA, Brown CD. Minimal clinically important differences in the six-minute walk test and the incremental shuttle walking test. COPD, 2005;
2(1): 1259.

3 Enright PL, Sherrill DL. Reference equations for the six-minute walk in healthy adults. Am. J. Respir. Crit. Care Med., 1998; 158: 13841387

4 Ross RM, Murthy JN, Wollak ID, Jackson AS. The six minute walk test accurately estimates mean peak oxygen uptake. BMC Pulmonary Medicine, 2010, 10: 3

5 VanNess JM, et al. Postexertional malaise in women with chronic fatigue syndrome. J Womens Health (Larchmt). 2010 Feb; 19(2): 239-44.

6 White PD, Sharpe MC,Chalder T, DeCesare JC and Walwyn R for 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. BMC Neurology 2007, 7:6. See also author's reply to comments in the letters section here:

http://www.biomedcentral.com/1471-2377/7/6/comments#306608

7 Price JR, Mitchell E, Tidy E, Hunot V. Cognitive behavioural therapy for chronic fatigue syndrome in adults. Cochrane Database Syst Rev., 2008;
16(3): CD001027.
 

Dolphin

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This seems to be the standard message from the Lancet:
Thank you for submitting your letter. After in-house review, I'm afraid we have decided not to accept it for publication. We regret that we are unable to write a personal note for every letter we turn down, but the following common reasons for rejection may help you with future submissions: lateness (ie, more than 2 weeks after publication of the article on which you are commenting), inclusion of original research (the section is not peer reviewed, so we cannot publish such work here), submission of case reports (we have a separate section for these), reiteration of points made by another correspondent, and inappropriate length (limits are 250 words and 5 references). If none of these apply to your letter, please be assured that we have nevertheless considered it carefully and probably had to refuse it because we have simply received too much good material.
 

Dolphin

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I've now heard of 16 people whose letters were not accepted.
Hopefully more of these letters will be added here in time.
 

Sean

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Was asked to post this up:

The results of the PACE Trial contrast with another Chronic Fatigue Syndrome (CFS)
study that tested four non-pharmacological therapies.1,2 The latter study found that,
across 25 outcome measures, an intervention involving a form of pacing obtained more
significant improvements than a Cognitive Behaviour Therapy (CBT) program (similar to
that assessed in the PACE Trial), an exercise program and a relaxation/stretching
program.2 If some of those measures had been used in the PACE Trial, the results might
have been different.

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

It would have been interesting if actometer data had been collected: a review of three CBT
studies found that despite significant subjectively-reported improvements in fatigue (and
indeed functioning), the objectively-measured total activity levels were only marginally
different to baseline scores, with no difference being recorded compared to the control
group.5

References:

1. White PD, Goldsmith KA, Johnson AL, et al., on behalf of the 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;
published online Feb 18. DOI:10.1016/S0140-6736(11)60096-2.

2. Jason LA, Torres-Harding S, Friedberg F, et al. Non-pharmacologic interventions for CFS: a
randomized trial. J Clin Psych Med Settings. 2007; 14:275-296.

3. 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.

4. Enright PL, Sherrill DL. Reference equations for the six-minute walk in healthy adults. Am J
Respir Crit Care Med.;158(5 Pt 1):1384-7.

5. Wiborg JF, Knoop H, Stulemeijer M, Prins JB, Bleijenberg G. How does cognitive behaviour
therapy reduce fatigue in patients with chronic fatigue syndrome? The role of physical activity.
Psychol Med. 2010; 40:1281-1287.
 

Dolphin

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Here's another person's letter:

The PACE trial is founded on the baseless hypothesis that CFS is a behavioural disorder which is perpetuated by wrong thoughts, fear avoidance and deconditioning and the assumption that these are reversible with CBT and GET. (1)

This hypothesis, in defiance of basic scientific principles, completely ignores the extensive biomedical research literature which invalidates it, and which clearly shows that ME/CFS is a multi-system organic disease. (2)(3)

The paper fails to mention or discuss this biomedical evidence and participants were not informed of the organic basis of their disease and thus could not give informed consent.

PACE Trial authors are in breach of:

1. The Declaration of Helsinki (4)

Medical research involving human subjects must conform to generally accepted scientific principles, be based on a thorough knowledge of the scientific literature, other relevant sources of information...

2. Department of Health, co-funders of PACE, Research Governance Framework (5):

All existing sources of evidence...must be considered carefully before undertaking research. Research...which is not of sufficient quality to contribute something useful to existing knowledge, is unethical.

The Lancet editors and publishers are also in breach of the Declaration of Helsinki(4):

Authors, editors and publishers all have ethical obligations with regard to the publication of the results of research...Reports of research not in accordance with the principles of this Declaration should not be accepted for publication.

This trial, based on a scientific falsehood, has wasted 5 million of public money and should never have been published by the Lancet.



1. 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, Early Online Publication, 18 February 2011 doi:10.1016/S0140-6736(11)60096-2


2. MRC CFS/NME literature review
http://www.mrc.ac.uk/Utilities/Documentrecord/index.htm?d=MRC006509

3. Magical Medicine:How to Make a Disease Disappear, section 2,110-214
http://www.meactionuk.org.uk/magical-medicine.htm
http://www.meactionuk.org.uk/magical-medicine.pdf

4. The Declaration of Helsinki, Ethical Principles for Medical Research Involving Human Subjects, Basic Principles of Medical Research http://www.wma.net/en/30publications/10policies/b3/index.html

5. Department of Health, Research Governance Framework for Health and Social Care, Second Edition, Standards, Science, 2.3.1 http://www.dh.gov.uk/dr_consum_dh/g...@dh/@en/documents/digitalasset/dh_4122427.pdf
 

Dolphin

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Here's another person's letter. Thanks for everyone who took the time to write.

As the largest study into the efficacy of Cognitive Behavioural Therapy (CBT) and Graded Exercise Therapy (GET) for Chronic Fatigue Syndrome (CFS) yet carried out, it is disappointing to see that White et al. decided it would be too great a burden to ask patients to use actometers at the end of the trial [1,2]. Actometers, which were used to assess patients at the start and were originally planned as an outcome measure, may have provided information which could help us understand the data from previous studies indicating that psychosocial treatments for CFS are able to improve self-rating questionnaire scores, but do not allow an increase in sustained activity levels [3].


There is a danger that if such interventions alter the way in which patients express their disability levels without necessarily improving their level of disability, then researchers could develop and promote a misleading understanding of these therapies usefulness.


In their commentary Bleijenberg and Knoop point out that both CBT and GET encourage patients to presume they can recover [4]. While this may be a healthy cognition for patients to have, we should not allow that to affect our examination of the evidence: in the Pace trial protocol recovery required a SF-36 physical function score of 85 or above, and a score of under 65 was part of the inclusion criteria for patients suffering from disabling fatigue that required treatment; by the time of the Pace trials press conference those scoring just 60 were being classed as back to normal [5].


1. White PD, Goldsmith KA, Johnson AL, et al, on behalf of the 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; published online Feb 18. DOI:10.1016/S0140-6736(11)60096-2.


2. White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R; on behalf of the PACE trial group. Response to comments on Protocol for the PACE trial http://www.biomedcentral.com/1471-2377/7/6/comments Accessed February 27, 2011


3. Wiborg JF, Knoop H, Stulemeijer M, Prins JB, Bleijenberg G. How does cognitive behaviour therapy reduce fatigue in patients with chronic fatigue syndrome? The role of physical activity. Psychological Medicine. 2010 Aug;40(8):1281-7.


4. Knoop H, Bleijenberg G. Chronic fatigue syndrome: where to PACE from here? Lancet 2011; published online Feb 18. DOI:10.1016/S0140-6736(11)60172-4 1


5. 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.
 

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Joan Crawford's letter: Effect size overstated

Joan Crawford's letter

Effect size overstated.

I read with interest that the PACE trial defines 05 of a SD as clinically useful change versus baseline1. With regard to the trials primary outcome measure of improved physical functioning, a large change of the order of 30 SD would equate to a return to normal healthy levels2, 3. To be in the moderate range an increase of greater than 20 SDs would be necessary. Changes lower than this should therefore be regarded as small or modest at best. Hence the 12 to 13 SD of improved functioning reported for CBT and GET in this trial cannot be reasonably reported as a moderate difference over baseline.

Overstating the benefits of CBT and GET (CBT and GET can safely be added to SMC to moderately improve outcomes....... 1) could lead to patients and clinicians disagreeing whether the consequences of participating in such interventions is acceptable given the effort involved in taking part by people who are profoundly sick and disabled2.

To refer to CBT and GET as treatments communicates that such interventions have the power to confer healing and offer a cure. At best this appears overly optimistic. At worst this is potentially misleading. Pacing is not defined as a treatment by support groups, charities, patients or professionals nor does it require to be described as a therapy. The very modest benefits of CBT or GET over and above simpler approaches such as pacing, which do not require 13 therapy sessions to explain, are unlikely to attract the confidence of policy makers and patients.

Yours faithfully,
Joan Crawford
Chair Chester ME Self Help (MESH)


1 White PD, Goldsmith KA, Johnson AL, 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 2011; 377(9766) 611690.
2 Komaroff A L, Fagioli LR, Doolittle TH, et al. Health Status in Patients with Chronic Fatigue Syndrome and in General Population and Disease Comparison Groups. Am J Med. 1997;101:281-290.
3 White PD, Sharpe MC, Chalder T, et al. 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.
 
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Trial's definition of 'within the normal range' is flawed

It is notable that the PACE Trial did not report recovery as defined by the original protocol,1,2 instead conducting a post-hoc analysis [note 1] of the proportion of participants within the normal range on both primary outcomes after therapy. Crucially, these post-hoc thresholds were much lower than those defined for recovery, with up to 30% of participants being classed as normal. The rates for normality were referred to as recovery rates both in the media and in the accompanying Lancet editorial.3

However, the post-hoc thresholds a short form-36 Physical Function (SF-36) score of 60 and a Chalder Fatigue questionnaire (CFQ) score of 18 in no way represent normal health. The PACE trial defined the severe and disabling fatigue that characterises Chronic Fatigue Syndrome as a SF-36 score of 65 (i.e. above that required for normality) or less, and a bimodal CFQ score of 6 or more (which could meet the Likert-scored normal threshold of 18). The trial thus may nonsensically define a participant as having severe and disabling fatigue yet simultaneously as being within the normal range.

The normal range was defined as one standard deviation from the mean, (despite the data being highly skewed),4 setting the threshold at around the 16th percentile [note 2], which is very low when 22% of the general population report a long-standing illness.5

As the Trial definition of within the normal range does not seem to accurately define normal health, it would be helpful if the authors now published recovery rates according to the original protocol.

Notes (not in the original letter)
Note 1. Post-hoc means after the researchers got their hands of the data. Good practice is to define in a protocol how the research will be analysed before seeing the data (as was the case for the original definition of recovery). Post-hoc analyses are always seen as slightly suspect since researchers have been able to torture the data until it tells them what they want to hear.
Note 2. Setting the threshold at the 16th percentile means that 16% of the normal population have this score or less (so 84% score higher than this, which makes it a very low definition of normal).

1. White PD, Goldsmith K, Johnson A, Potts L, Walwyn R, DeCesare J, 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 [Internet]. Lancet 2011; published online Feb 18. DOI:10.1016/S0140-6736(11)60096-2.
2. White P, Sharpe M, Chalder T, DeCesare J, Walwyn R, 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.
3. Bleijenberg G, Knoop H. Chronic Fatigue Syndrome: where to PACE from here? Lancet 2011; published online Feb 18. doi:10.1016/S0140-6736(11)60172-4
4. Prieto L, Alonso J, Ant JM. Estimating sample sizes for studies using the SF-36 health survey. J Epidemiol Commun H 1996; 50 (4): 473474.
5. Jenkinson C, Coulter A, Wright L. Short form 36 (SF36) health survey questionnaire: normative data for adults of working age. BMJ 1993; 306(6890): 14371440.
 
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Another unpublished letter someone asked me to post:

White and colleagues claim to have shown cognitive behavioural therapy (CBT)
and graded exercise therapy (GET) are "safe" for Chronic Fatigue Syndrome
(CFS).1 If the outcome measures had been presented as originally
published,2 one wonders whether the conclusion might have been different.

We were told "[a]n adverse outcome will be considered to have occurred if
the physical function score of the SF-36 [SF-36 PF] has dropped by 20 points
from the previous measurement".2 In the final report, this changed to "a
decrease of 20 or more between baseline and any two consecutive assessment
interviews".1 A similar stipulation [i.e. at two consecutive assessment
interviews] was also added for the Clinical Global Impression (CGI).1,2 Also
adverse outcomes for the latter had been defined as a "score of 5-7 of the
self-rated CGI" but we are not given any data on scores of 5.1,2

I do not believe such definitions of adverse outcomes have face validity.
For example, given the baseline scores, the threshold for the SF-36 PF is an
average score of 15, more than 50% below their initial scores and a very low
score for somebody of working age.1

It also should not be forgotten that a large number of so-called
"non-serious adverse events" occurred.1

Given the large percentages of patients who have previously reported being
made worse by CBT and GET programs for CFS,3,4 it would be good if
facilities such as the Yellow Card Scheme existed for reporting adverse
events associated with non-pharmacological interventions outside of clinical
trials.5




References:

1. 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.

2. White PD, Goldsmith KA, Johnson AL, 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. 2011;377(9768):823-36. Epub 2011 Feb 18.

3. Kindlon T, Goudsmit EM: Graded exercise for chronic fatigue
syndrome: too soon to dismiss reports of adverse reactions. J Rehabil
Med 2010; 42: 184.

4. Koolhaas MP, de Boorder H, van Hoof E: Cognitive behaviour therapy
for chronic fatigue syndrome from the patient's perspective. Medisch
Contact, 2008. ISBN: 978-90-812658-1-2.

5. Medicines and Healthcare products Regulatory Agency (MHRA) Yellow Card
Scheme
http://www.mhra.gov.uk/Safetyinformation/Howwemonitorthesafetyofproducts/Med
icines/TheYellowCardScheme/index.htm [Accessed: Friday 4, 2011]
 

Dolphin

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"Graded exercise not safe for individuals with post-exertional malaise"

Somebody asked me to post this for them:

Graded exercise not safe for individuals with post-exertional malaise

White c.s. compared Adaptive Pacing, Cognitive Behavioral Therapy (CBT) and Graded Exercise (GET) for chronic fatigue syndrome (CFS) with medical care, finding that 31%-41% of patients reported positive change. Small proportions reported negative changes or adverse effects. They conclude that CBT and GET can be safely added to specialist medical care.

This contrasts not only with patient perspectives but also with scientific evidence that people with CFS, or myalgic encephalomyelitis (ME), experience a serious and often long-lasting deterioration of their illness in response to light physical and mental exertion, and that CBT/GET can be harmful (1-3).

In 1959, Acheson called for a strict definition of ME because otherwise it would become a convenient dumping ground for non-specific illnesses including depression (4). The latter is demonstrated by White c.s. Including all patients with disabling fatigue as the main symptom leads to a sample with 47% psychiatric diagnoses, and 33% depressive disorder.

In addition, the most severely affected patients who are bedridden are not able to follow the study protocol. Others with invalidating forms of post-exertional malaise (PEM) may be part of the large group (n= 602) that declined informed consent, knowing that CBT or GET may be harmful.

As Kuhn noticed (5), the paradigm that researchers hold determines how they approach reality and what measures they apply: White c.s. did not adequately define or measure PEM.
Whether CBT and GET are safe, respectful, and fruitful treatments for individuals with PEM cannot be concluded from this study.

References
1. Carruthers B, Jain A, De Meirleir K, Peterson D, Klimas N, Lerner A, et al. Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols. J Chronic Fatigue Syndrome. 2003;11(1):7-115.
2. Nez M, Fernndez-Sol J, Nuez E, Fernndez-Huerta J-M, Gods-Sieso T, Gomez-Gil E. Health-related quality of life in patients with chronic fatigue syndrome: group cognitive behavioural therapy and graded exercise versus usual treatment. A randomised controlled trial with 1 year of follow-up. Clinical Rheumatology. 2011:1-9.
3. Twisk F, Maes M. A review on cognitive behavorial therapy (CBT) and graded exercise therapy (GET) in myalgic encephalomyelitis (ME) / chronic fatigue syndrome (CFS): CBT/GET is not only ineffective and not evidence-based, but also potentially harmful for many patients with ME/CFS. Neuro Endocrinol Lett. 2009;30(3):284-99.
4. Acheson E. The Clinical Syndrome Variously Called Benign Myalgic Encephalomyelitis, Iceland Disease and Epidemic Neuromyasthenia. American Journal of Medicine. 1959;26(4):569-95.
5. Kuhn T. The structure of scientific revolutions. Chicago: The University of Chicago Press; 1969.
 

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"CBT/GET is not an effective treatment for ME/CFS"

Another letter I was asked to post. This had more than one author I think:

Cognitive behaviour therapy/graded exercise therapy is not an effective treatment for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

According to White et al. (1) "either cognitive behaviour therapy (CBT) or graded exercise therapy (GET), when added to specialist medical care (SMC), are effective treatments for chronic fatigue syndrome (CFS)".

The size of this effect is however very moderate, while 60% reported they did not see a positive result in Global Impression of Health Scale benefit.

The Work and Social Adjustment scale indicated the average CBT/GET patient was still at the borderline of being 'very severely impaired'.

The conclusion is that these treatments cannot be considered to be effective (1) or curative (2).

More importantly, due to the selection criteria, the participants cannot be considered to be CFS patients, e.g. 47% met criteria for psychiatric disorders, while the two subjective measures fatigue and physical function are largely insufficient to establish recovery: cut-off scores on these measures do not correspond with a CFS diagnosis.

Moreover, an improvement in "fatigue" is not reflected by a significant objective improvement, e.g. in physical activity (3).

When looking at the only objective measure (1), i.e., meters walked in 6 minutes (CBT: 354; GET: 379; compared to 349 for SMC after treatment), CBT and GET hardly qualify as "moderately effective".

As recently has been confirmed (4), CBT and GET are not effective and even potentially harmful for many ME/CFS patients (5).

According to (1) non-serious adverse events for CBT (89%) and GET (93%) are very common.

Therefore the claim that "CBT and GET can safely be added to SMC" (1) cannot be substantiated.



References:
1. White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, 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 Feb 17. doi:
10.1016/S0140-6736(11)60096-2.
2. Wessely, S. Chronic fatigue syndrome - trials and tribulations. JAMA
2001; 286; 1378-9. doi: 10.1001/jama.286.11.1378.
3. Wiborg JF, Knoop H, Stulemeijer M, Prins JB, Bleijenberg G. How does
cognitive behaviour therapy reduce fatigue in patients with chronic fatigue syndrome? The role of physical activity. Psychol Med 2010; 40: 1-7. doi:
10.1007/s10067-009-1339-0.
4. Nez M, Fernndez-Sol J, Nuez E, Fernndez-Huerta JM, Gods-Sieso
T, Gomez-Gil E. Health-related quality of life in patients with chronic fatigue syndrome: group cognitive behavioural therapy and graded exercise versus usual treatment. A randomised controlled trial with 1 year of follow-up. Clin Rheumatol 2011 Jan 15. doi: 10.1007/s10067-010-1677-y.
5. Twisk FNM, Maes M. A review on cognitive behavorial therapy (CBT) and
graded exercise therapy (GET) in myalgic encephalomyelitis (ME) / chronic fatigue syndrome (CFS): CBT/GET is not only ineffective and not evidence-based, but also potentially harmful for many patients. Neuro Endocrinol Lett 2009; 30: 284-99.
 

Dolphin

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Susanna Agardy's letter

Susanna Agardy said I could post her letter with her name on it

Improved CBT/GET sought: All we need is a better whip to flog a dead horse with, so it will run.

Response to The Lancet editorial of 18 February 2011.

Susanna Agardy


The modest and oversold results of the PACE study demand that the physical abnormalities of ME/CFS be urgently confronted by the medical establishment. Even the loosely defined, highly selected, less debilitated sample of participants reached their limits following the star CBT and GET interventions.

People with properly defined ME/CFS with characteristic post-exertional malaise and lower tolerance of exercise would have sent improvement scores crashing and drop-out rates soaring. Such people were excluded and would have in any case refused to take part in PACE.

For me, a severely disabled sufferer, a few extra metres of walking triggers a bewildering array of symptoms, the third day of such exertion being the worst and needing about six days for any improvement. I wish I was just fatigued! GET treatment is not safe for us and must not be recklessly forced on us.

The word recovery has been given an abstract statistical definition and gives the media licence to make further exaggerations. There is no report of how many people who could not previously work returned to work, for example.

Dr Bleijenberg casts a euphoric glow over the results. His speculation about supposed CBT-related mechanisms of change sound to sufferers as appropriate as saying: All we need is a better whip to flog a dead horse with, so it will run.

It is time The Lancet regularly published and encouraged scientific research on the many serious physical abnormalities in this maligned illness. That would help patients.
 

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"Disclosure may aid interpretation of PACE Trial Results"

Another one I've been asked to post:

Disclosure may aid interpretation of PACE Trial Results

Editor,

Interpretation of the PACE Article (1) is a matter for readers.

With regard to conflicts of interest Young and Solomon (2) stated : The reader must [then] decide whether the declared factors are important and might have influenced the validity of the studys findings.

Two BMJ articles reported that P White and T Chalder resigned from the 2002 Chief Medical Officer CFS/ME Report over pacing.

In one of these articles, White acknowledged his resignation as a conflict of interest and expressed gratitude to M Sharpe for comments on an earlier draft.

Although the CMO Report featured throughout the PACE Protocol Introduction (5), there is no mention of this important Report which recommended pacing, in the current Article (1).

Without this information, readers may not be able to assess the validity of the studys findings.


1 PD White 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 February 18, 2011

2 How to critically appraise an article: J Young and M Solomon: Clinical Practice, Gastroenterology & Hepatology 2009;6(2):82-91. Nature Publishing Group

3 Chronic fatigue report delayed as row breaks out over content: BMJ Lynne Eaton : 2002;324 7328.7

4 Editorial: Chronic unexplained fatigue P D White Post Graduate Medical Journal 2002;78:445-446

5 Protocol for the PACE trial BMC Neurology 2007 7:6