PACE Trial - letters that were published and authors' response (and editorial)

Dolphin

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PACE Trial - letters that were published and authors' response

The correspondence on the PACE Trial has just been published at various links found at: http://bit.ly/j9cEoD or http://www.thelancet.com/search/res...Name=AllFields&journalFromWhichSearchStarted= .

I'll post the letters and replies here.

N.B.: I've given the editorial accompanying the correspondence its own thread: http://forums.phoenixrising.me/show...torial-accompanying-PACE-Trial-correspondence) . I can't seem to change the mention in the title - maybe a moderator can remove it?
 

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Jane Giakoumakis' letter

Jane Giakoumakis' letter

The Lancet, Early Online Publication, 17 May 2011
doi:10.1016/S0140-6736(11)60689-2

The PACE trial in chronic fatigue syndrome
Jane Giakoumakis a

In their randomised trial of treatments for patients with chonic fatigue syndrome, Peter White and colleagues (March 5, p 823)1 define a clinically useful difference between the means of the primary outcomes as 05 of the SD of these measures at baseline, equating to 2 points for Chalder fatigue questionnaire and 8 points for short form-36. They cite achieving a mean clinically useful difference in the graded exercise therapy or cognitive behaviour therapy groups, compared with specialist medical care alone, as evidence that these interventions are moderately effective treatments.

The source for this definition of clinically useful difference states that such a method has a fundamental limitation: estimates of variability will differ from study to studyif one chooses the between-patient standard deviation, one has to confront its dependence on the heterogeneity of the population under study.2 In White and colleagues' study, we do not have heterogeneous samples on the Chalder fatigue questionnaire and short-form 36 physical function subscale, since both are used as entry criteria.1

Patients had to have scores of 65 or less on short-form 36 to be eligible for the study.1 However, most, in practice, would probably need to have scores of 30 or more to be able to participate in this clinic-based study. Indeed, only four of 43 participants in a previous trial of graded exercise therapy scored less than 30.3, 4 Guyatt and colleagues2 suggest that an alternative is to choose the standard deviation for a sample of the general population, which White and colleagues have given as 24.1 An SD of 24 gives a clinically useful difference of 12; both graded exercise therapy and cognitive behaviour therapy fail to reach this threshold. Whether they moderately improve outcomes, as claimed,1 is therefore questionable.


I am chair of a myalgic encephalomyelitis support and advice groupan unpaid voluntary position.

References

1 White PD, Goldsmith KA, Johnson AL, et alon 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; 377: 823-836. Summary | Full Text | PDF(309KB) | CrossRef | PubMed

2 Guyatt GH, Osaba D, Wu AW, et al. Methods to explain the clinical significance of health status measures. Mayo Clinic Proc 2002; 77: 371-383. PubMed

3 Fulcher KY. Physiological and psychological responses of patients with chronic fatigue syndrome to regular physical activity. Loughborough: Loughborough University of Technology, 1997. http://hdl.handle.net/2134/6777. (accessed March 4, 2011).

4 Fulcher KY, White PD. Randomised controlled trial of graded exercise in patients with the chronic fatigue syndrome. BMJ 1997; 314: 1647-1652. PubMed

a xxxxxxxxxxxxxx, Glasgow xxxxxxxxx, UK
 

Dolphin

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John T Mitchell's letter

John T Mitchell's letter

The Lancet, Early Online Publication, 17 May 2011

doi:10.1016/S0140-6736(11)60683-1

The PACE trial in chronic fatigue syndrome

John T Mitchell a

Much has been made of the recovery achieved by some participants in Peter White and colleagues' PACE trial,1 one of the authors having stated to the media that twice as many people on graded exercise therapy and cognitive behaviour therapy got back to normal2 and the accompanying Comment stating that, by use of a strict criterion for recovery, the recovery rate of cognitive behaviour therapy and graded exercise therapy was about 30%.3

Although the trial protocol4 does give a strict definition for recovery, this information is omitted from the published paper, which instead refers to physical function and fatigue in the normal range. Whether the values given are indicative of normal function is open to question, however. For instance, although a score of 60 or more on the short-form 36 (SF-36) physical function subscale and of 18 or less on the Chalder fatigue questionnaire are characterised as being in the normal range by White and colleagues, and as recovery in the accompanying Comment, an SF-36 physical function score of 65 was low enough for a patient to be included in the trial to begin with. Additionally, the above definitions for recovery and normal range would not even have qualified as being a positive outcome (75 or more on SF-36, bimodal fatigue scale score 3 or less) as published in the original protocol. Data on increases in baseline scores, the other positive outcome measure, are not given.

Also in question is how White and colleagues arrived at their reduced thresholds, since the trial protocol states that an SF-36 score of 70 is one SD below the mean of the UK adult population, but in the published paper this figure drops to 60 without explanation.

I am a CFS patient.

References

1 White PD, Goldsmith KA, Johnson AL, et alon 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; 377: 611-690. Full Text | PDF(70KB) | CrossRef | PubMed

2 Boseley S. Study finds therapy and exercise best for ME. The Guardian Feb 18, 2011. PubMed

3 Knoop H, Bleijenberg G. Chronic fatigue syndrome: where to PACE from here?. Lancet 2011; 377: 786-788. Full Text | PDF(378KB) | CrossRef | PubMed

4 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. CrossRef | PubMed

a xxxxxxxxxxxxxxxxx, Lincoln, AR xxxxx, USA
 

Dolphin

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Sarah M Feehan's letter

Sarah M Feehan's letter

The Lancet, Early Online Publication, 17 May 2011

doi:10.1016/S0140-6736(11)60688-0

The PACE trial in chronic fatigue syndrome

Sarah M Feehan a, on behalf of the Liverpool ME Support Group

Peter White and colleagues1 say that normal fatigue is represented by a figure of 18 or less on the Chalder fatigue questionnaire (Likert scoring), rather than the validated definition of fatigue caseness (4 or more, bimodal scoring) used in the trial's protocol.2, 3 A score of 18 represented the mean plus 1 SD (142 + 46) for a control group who had attended their general practitioner in the previous 12 months.4 This figure almost certainly would have been lower if those who had not attended their general practitioner had also been included when deriving population data. Indeed, normative data from a Norwegian study gave a mean of 122 (SD 40).5 Interestingly, the Norwegian data were stratified by health condition (unfortunately, only means were published): No disease/current health problem: 112; Past or current disease: 121; Current health problem: 125, and Disease and current health problem: 142.

Furthermore, 176% of chronic fatigue syndrome patients diagnosed at the Chronic Fatigue Unit (South London and Maudsley NHS Trust) had a score of 18 or less before they were treated.4 This suggests either that the Chronic Fatigue Unit diagnoses and treats fatigue problems in patients with normal levels of fatigue or, alternatively, that the threshold of 18 to represent normal fatigue is not suitable.

Given this information, and the fact that those with a Chalder fatigue questionnaire Likert score of 18 could still meet the trial's entry criteria (bimodal score of 6 or more),1, 3 it would be good if White and colleagues would now recalculate the data using the original definition of fatigue caseness.2, 3

I declare that I have no conflicts of interest.

References

1 White PD, Goldsmith KA, Johnson AL, et alon 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; 377: 823-836. Summary | Full Text | PDF(309KB) | CrossRef | PubMed

2 Chalder T, Berelowitz G, Pawlikowska T, et al. Development of a fatigue scale. J Psychosom Res 1993; 37: 147-153. CrossRef | PubMed

3 White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn Ron 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. BMC Neurol 2007; 7: 6. CrossRef | PubMed

4 Cella M, Chalder T. Measuring fatigue in clinical and community settings. J Psychosom Res 2010; 69: 17-22. CrossRef | PubMed

5 Loge JH, Ekeberg O, Kaasa S. Fatigue in the general Norwegian population: normative data and associations. J Psychosom Res 1998; 45: 53-65. CrossRef | PubMed

a Liverpool ME Support Group, Bootle, Liverpool L20 9LD, UK
 

Dolphin

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Andrew James Kewley's letter

Andrew James Kewley's letter

The Lancet, Early Online Publication, 17 May 2011

doi:10.1016/S0140-6736(11)60681-8

The PACE trial in chronic fatigue syndrome

Andrew James Kewley a

I am concerned by the change in assessment method between the published results of the PACE trial1 and the trial protocol.2 Seven secondary outcomes were not reported and there were changes in several of the measures that were reported.1, 2

In particular, the protocol stated that those with short-form 36 physical function subscale scores of 65 or less would be deemed ill enough to participate, and that those with scores of 85 or more would be regarded as recovered.2 However, the authors have questionably defined normal as a score of 60 or more,1 based on general population scores which did not exclude those reporting chronic illnesses. In the cited study of working-age adults,3 the mean physical function score for respondents without long-term health problems was 927 (SD 131). The mean physical function scores for those aged 7584 years, including those with long-term health problems, was 579.3

The lack of objective data, such as hours employed or actometer results, is problematic, since Wiborg and colleagues4 showed that improvements on questionnaires are not reflected in an increase in activity, as would be expected if the patients had more energy.4

The only significant difference between treatments for the 6-min walking test was for graded exercise therapy. But the increase in walking distance is small when compared to the distance walked by healthy elderly people (mean age 65 years), which was shown to be 631 m (SD 93).5

Unfortunately, the overall results of the PACE treatments were unimpressive, and with only 41% of patients reporting positive change after cognitive behavioural therapy or graded exercise therapy, further biomedical research is imperative.

I declare that I have no conflicts of interest.

References

1 White PD, Goldsmith KA, Johnson AL, et alon 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; 377: 611-690. Full Text | PDF(70KB) | CrossRef | PubMed

2 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. CrossRef | PubMed

3 Bowling A, Bond M, Jenkinson C, Lamping DL. Short form 36 (SF-36) health survey questionnaire: which normative data should be used? Comparisons between the norms provided by the Omnibus Survey in Britain, the Health Survey for England and the Oxford Healthy Life Survey. J Public Health Med 1999; 21: 255-270. PubMed

4 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. CrossRef | PubMed

5 Troosters T, Gosselink R, Decramer M. Six minute walking distance in healthy elderly subjects. Eur Respir J 1999; 14: 270-274. CrossRef | PubMed

a Faculty of Science and Engineering, Flinders University, SA 5042, Australia
 

Dolphin

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Letter from Bart Stouten, Ellen M Goudsmit & Neil Riley

Letter from Bart Stouten, Ellen M Goudsmit & Neil Riley

The Lancet, Early Online Publication, 17 May 2011

doi:10.1016/S0140-6736(11)60685-5

The PACE trial in chronic fatigue syndrome
Bart Stouten a, Ellen M Goudsmit b, Neil Riley c

The findings of the PACE trial1 seem impressive, but the discrepancy between the definitions of improvement in the protocol2 and paper requires an explanation. In the paper clinically useful differences were defined as 05 SD changes in fatigue or physical functioning compared with baseline. However, the criteria for improvement published in the trial protocol were much more demanding (table).2 Use of a cut-off score of 75 on the short-form 36 physical functioning subscale, as originally proposed, would halve the number of recovered patients.

Table http://www.thelancet.com/journals/l...l1&tableidtype=table_id&sectionType=lightBlue
Table image http://www.thelancet.com/journals/l...l1&tableidtype=table_id&sectionType=lightBlue
Definition of positive outcome/improvement in the trial protocol and the final publication

Moreover, consulting the normative data for the scale reveals that the mean score of 58 after both cognitive behaviour therapy and graded exercise improved a patient's physical functioning to the level of someone 40 years older than himself.3

Is this a case of outcome reporting bias?4

We declare that we have no conflicts of interest.

References

1 White PD, Goldsmith KA, Johnson AL, et alon 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; 377: 823-836. Summary | Full Text | PDF(309KB) | CrossRef | PubMed

2 White PD, Sharpe MC, Chalder T, et alon 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. BMC Neurol 2007; 7: 6. CrossRef | PubMed

3 Bowling A, Bond M, Jenkinson C, Lamping DL. Short form 36 (SF-36) health survey questionnaire: which normative data should be used? Comparisons between the norms provided by the Omnibus Survey in Britain, the Health Survey for England and the Oxford Healthy Life Survey. J Public Health Med 1999; 21: 255-270. PubMed

4 Smyth RMD, Kirkham JJ, Jacoby A, Altman DG, Gamble C, Williamson PR. Frequency and reasons for outcome reporting bias in clinical trials: interviews with trialists. BMJ 2011; 342: c7153. CrossRef | PubMed

a xxxxxxxxxxxx, xxxxxxxxx Utrecht, Netherlands
b School of Psychology, University of East London, London, UK
c xxxxxxxxxxxxxxxxxxx, Dorking, UK
 

Dolphin

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Tom Kindlon's letter

Tom Kindlon's letter

The Lancet, Early Online Publication, 17 May 2011

doi:10.1016/S0140-6736(11)60684-3

The PACE trial in chronic fatigue syndrome

Tom Kindlon a

Peter White and colleagues1 claim that, if cognitive behaviour therapy and graded exercise therapy are delivered as described, they are safe for chronic fatigue syndrome (CFS); the CONSORT statement on harms reporting recommends against such claims.2

If few participants are compliant with the intervention, harms-related data might not be reliable. Both cognitive behaviour therapy and graded exercise therapy are designed to increase activity; however, actometers were not used, so one cannot be sure how many patients were actually more active.1 Analysis of three trials of cognitive behaviour therapy found that activity levels before and after therapy were similar, despite improvements being reported on fatigue and other subjective measures.3 This finding suggests that patients might simply substitute the activity component of cognitive behaviour therapy for other activities;4 if this situation occurred in White and colleagues' study, we would not have information on the effects of actually increasing activity levels.

On the only objective test, the 6-min walking distance, the cognitive behaviour therapy group only improved by 21 m, suggesting that total daily activity might not have increased.1 The average increase for graded exercise therapy of only 67 m leaves open the possibility that many on that intervention did not achieve or maintain increased exercise or activity levels.

If, as seems likely, real-world graded exercise therapy practitioners expect higher yearly 6-min walking distance targets than a 379 m crawl (or higher weekly increases than 129 m), more adverse reactions could occur.

Given many patients' reports of adverse reactions from such interventions, the biological reasons why they might be problematic (eg, abnormalities in muscle and immunological response to exercise), and the fact that adverse reactions are often only noted outside of trials, the assumption that cognitive behaviour therapy and graded exercise therapy are safe is premature.2, 4, 5


I work in a voluntary capacity for the Irish ME/CFS Association.

References

1 White PD, Goldsmith KA, Johnson AL, et alon 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; 377: 611-690. Full Text | PDF(70KB) | CrossRef | PubMed

2 Ioannidis JP, Evans SJ, Gtzsche PC, et alfor the CONSORT Group. Better reporting of harms in randomized trials: an extension of the CONSORT statement. Ann Intern Med 2004; 141: 781-788. PubMed

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: 1281-1287. CrossRef | PubMed

4 Kindlon T. Harms of cognitive behaviour therapy designed to increase activity levels in chronic fatigue syndrome: questions remain. Psychother Psychosom 2011; 80: 110-111. CrossRef | PubMed

5 Twisk FN, 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: 284-299. PubMed

a Irish ME/CFS Association, PO Box 3075, Dublin 2, Ireland
 

Dolphin

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Mieko Shinohara's letter

Mieko Shinohara's letter

The Lancet, Early Online Publication, 17 May 2011

doi:10.1016/S0140-6736(11)60686-7

The PACE trial in chronic fatigue syndrome

Mieko Shinohara a

A very controversial paper was published on March 5, 2011, about treatments for chronic fatigue syndrome (CFS).1 I have suffered from this disease for more than 20 years and have been nearly bedridden for the past few years. I hope that the study will be beneficial for patients with CFS.

Surprisingly, patients who participated in the study were young, and their symptoms were mild to moderate. Furthermore, their disease duration was short, and they were still in the process of adjusting to the fact that they had an illness whose cause is not known. Probably, the participants learned coping skills through self-help strategies.2
Cognitive behaviour therapy and graded exercise therapy can be effective for many chronic diseases other than CFS. As this study showed, it is reasonable that cognitive behaviour therapy and graded exercise therapy are effective for CFS. However, whether these treatments will be effective for patients with severe CFS who need medical support remains unknown. I am concerned that this study might lead to further misunderstanding of this disease.

In Japan, much research on fatigue in general has been done, but more severely ill patients have been totally overlooked. We need more research where those patients are involved. We are sincerely hoping that the researchers will focus on the biological roots of CFS, so that eventually a cure can be found.

I declare that I have no conflicts of interest.

References

1 White PD, Goldsmith KA, Johnson ALon 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; 377: 823-836. Summary | Full Text | PDF(309KB) | CrossRef | PubMed

2 Carruthers BM, van de Sande MI. Myalgic encephalomyelitis/chronic fatigue syndrome: a clinical case definition and guidelines for medical practitioners. http://sacfs.asn.au/download/consensus_overview_me_cfs.pdf. (accessed May 6, 2011).

a Japan Chronic Fatigue Syndrome Association, Samei-biru 2B, 3-11-12 Takanodai, Nerima-ku, Tokyo 177-033, Japan
 

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Letter from Vlaeyen JWS, Karsdorp P, Gatzounis R, Ranson S & Schrooten Martien

Letter from Johan WS Vlaeyen, Petra Karsdorp, Rena Gatzounis, Saskia Ranson & Martien Schrooten

The Lancet, Early Online Publication, 17 May 2011

doi:10.1016/S0140-6736(11)60682-X

The PACE trial in chronic fatigue syndrome

Johan WS Vlaeyen a b, Petra Karsdorp b, Rena Gatzounis a, Saskia Ranson b, Martien Schrooten a b

Peter White and colleagues' sophisticated randomised PACE trial1 clearly shows that adaptive pacing is not more effective than specialist medical care in improving chronic fatigue outcomes. Although the results are in line with recent findings that activity pacing is not associated with disability in fibromyalgia,2 we raise several concerns about adaptive pacing therapy.

First, the basic assumptions that excessive task persistence in chronic fatigue increases symptoms and that regular pauses or activity alternation are needed are not supported empirically.3 The cognitive and motivational consequences of task interruption are largely unknown for fatigue and pain disorders.

Second, there is no clear definition of pacing as a treatment technique, probably because of the lack of an empirically tested mechanism of behavioural interruptions.

Third, activity pacing can involve at least three different approaches to task interruption. For example, symptom-contingent pacing uses fatigue or pain as signals for exertion, to avoid exacerbations. Time-contingent pacing encourages patients to interrupt when a preset time window has elapsed, irrespective of symptom change.4 Goal-contingent pacing guides patients in dividing higher-order goals into smaller, manageable pieces, with task interruption occurring after completion of lower-order goals, promoting a sense of control and mastery.5 Mixing of these different contingencies, as seems to occur in the PACE study, could create confusion in patients, reducing their unique effects.

Since the term pacing is widely used, but poorly defined, we would like to call for a better understanding and affective-motivational examination of the effects of task interruptions in the context of fatigue and pain.

We declare that we have no conflicts of interest.

References

1 White P, Goldsmith K, Johnson A, 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 377: 61190.

2 Karsdorp PA, Vlaeyen JW. Active avoidance but not activity pacing is associated with disability in fibromyalgia. Pain 2009; 147: 29-35. CrossRef | PubMed

3 Gill JR, Brown CA. A structured review of the evidence for pacing as a chronic pain
intervention. Eur J Pain 2009; 13: 214-216. CrossRef | PubMed

4 Fordyce WE. Behavioral methods for chronic pain and illness. St Louis: Mosby, 1976.

5 Nielson WR, Jensen MP, Hill ML. An activity pacing scale for the chronic pain coping inventory: development in a sample of patients with fibromyalgia syndrome. Pain 2001; 89: 111-115. CrossRef | PubMed

a Research Group Health Psychology, University of Leuven, 3000 Leuven, Belgium

b Department of Clinical Psychological Science, Maastricht University, Maastricht, Netherlands
 

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The PACE trial in chronic fatigue syndrome Authors' reply

The PACE trial in chronic fatigue syndrome Authors' reply

The Lancet, Early Online Publication, 17 May 2011

doi:10.1016/S0140-6736(11)60651-X

The PACE trial in chronic fatigue syndrome Authors' reply

PD White a, KA Goldsmith b, AL Johnson c d, R Walwyn b, HL Baber a, T Chalder e, M Sharpe f, on behalf of the coauthors

The PACE trial for patients with chronic fatigue syndrome (CFS) found that supplementation of specialist medical care with either cognitive behaviour therapy or graded exercise therapy was more effective in reducing fatigue and physical disability than was supplementation of specialist medical care with adaptive pacing therapy or specialist medical care alone. We chose patient-rated measures of fatigue and physical function as primary outcomes because this is how the disorder is defined.

The commonest concern of correspondents was our conclusion that these differences indicated moderate clinical usefulness. We based this conclusion on standard recommendations. First, we predefined a clinically useful difference between treatment group means for both primary outcomes, using the conventional criterion of 05 SD of baseline values;1 seven of eight comparisons between either cognitive behaviour therapy or graded exercise therapy and either adaptive pacing therapy or specialist medical care exceeded this difference. Second, we determined the proportion of participants who had improved by a predefined clinically useful amount by both primary outcomes at 1-year follow-up: 59% and 61% after cognitive behaviour therapy and graded exercise therapy versus 42% and 45% after adaptive pacing therapy and specialist medical care, respectively. Third, we calculated the proportions within the general population normal ranges for both primary outcomes at 1 year: 30% and 28% after cognitive behaviour therapy and graded exercise therapy versus 16% and 15% after adaptive pacing therapy and specialist medical care, respectively. Fourth, we interpreted the overall pattern of treatment comparisons across all outcomes,2 including the proportions of participants who rated themselves as very much or much better in their overall health: 41% after both cognitive behaviour therapy and graded exercise therapy versus 31% after adaptive pacing therapy and 25% after specialist medical care.

We determined the normal range by use of the conventional mean plus or minus 1 SD from what we regarded as the most relevant general population data. For physical function, this was a demographically representative sample (in our paper we stated that this was a UK working-age population, whereas more accurately this should have been an English adult population).3 For fatigue, this was a population sample of patients registered with a general practitioner in the southeast of England, who had consulted for a health problem at some time in the year after completion of the fatigue measure (ie, they were not consulting at the time). It is important to clarify that our paper did not report on recovery; we will address this in a future publication.

Changes to the original published protocol were made to improve either recruitment or interpretability, such as changing the proposed composite primary outcomes to single continuous scores. The analysis was guided by a Statistical Analysis Strategy (which we intend to publish), which was completed before analysis of outcome data, and which was much more detailed than the plan in the protocol; this is now conventional in the conduct of clinical trials. The eight secondary outcomes presented in our paper were selected for clinical relevance. All these decisions and plans were approved by the Trial Steering Committee, were fully reported in our paper, and were made before examining outcome data to avoid outcome reporting bias.

The safety of patients was a very important aspect of our trial and was measured in five distinct ways, using definitions and reporting standards of the European Union Clinical Trials Directive for medicinal products.4 Before the trial, patient organisations were most concerned about graded exercise therapy, which the trial found to be as safe as the other treatments, even though it increased physical activity (walking) more than the other treatments. The way treatments are delivered in a trial does not necessarily generalise to clinical practice, which is why we emphasised the importance of treatment delivery by appropriately qualified clinicians, who are properly trained and supervised.

PACE trial participants represented typical secondary-care CFS patients: young to middle-aged, significantly disabled, and ill for a mean of 27 years. The commonest reason for ineligibility of those screened in clinics was not having CFS, and the commonest stated reason for declining research assessment or randomisation was a clear preference for a specific PACE trial treatment. The findings do not generalise to the most disabled patients, as we only included those able to attend hospital regularly.

There are several descriptions of pacing, which is why we standardised it as adaptive pacing therapy. The manuals for this and the other treatments are available on the trial website. 84% of participants in adaptive pacing therapy regarded adaptive pacing therapy as logical before treatment, and 85% were satisfied with it after treatment, which suggests that they were not confused by it.

In conclusion, however we compared the results and however we defined CFS and myalgic encephalomyelitis, we found that cognitive behaviour therapy and graded exercise therapy provided a significant and clinically useful advantage of moderate size over adaptive pacing therapy and specialist medical care, but were no less safe. We suggest that the issue is not whether these treatments work and are safe, but how to make them available to those who might benefit from them.

We declare that we have no conflicts of interest other than those described in the original paper.

References

1 Guyatt GH, Osaba D, Wu AW, et al. Methods to explain the clinical significance of health status measures. Mayo Clinic Proc 2002; 77: 371-383. PubMed

2 Bowling A, Bond M, Jenkinson C, Lamping DL. Short form 36 (SF-36) health survey questionnaire: which normative data should be used? Comparisons between the norms provided by the Omnibus Survey in Britain, the Health Survey for England and the Oxford Healthy Life Survey. J Public Health Med 1999; 21: 255-270. PubMed

3 Dworkin RH, Turk DC, McDermott MP, et al. Interpreting the clinical importance of group differences in chronic pain clinical trials: IMMPACT recommendations. Pain 2009; 146: 238-244. CrossRef | PubMed

4 White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn Ron 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. BMC Neurol 2007; 7: 6. CrossRef | PubMed

a Barts and the London School of Medicine, Queen Mary University London, London EC1A 7BE, UK

b Mental Health and Neuroscience Clinical Trials Unit, Institute of Psychiatry, King's College London, London, UK

c Medical Research Council Biostatistics Unit, Institute of Public Health, University of Cambridge, Cambridge, UK

d Medical Research Council Clinical Trials Unit, London, UK

e Academic Department of Psychological Medicine, King's College London, London, UK

f Psychological Medicine Research, School of Molecular and Clinical Medicine, University of Edinburgh, Edinburgh, UK
 

Sean

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We chose patient-rated measures of fatigue and physical function as primary outcomes because this is how the disorder is defined.
STRAWMAN

It makes no difference what disorder or therapeutic model they are testing, they still have to use objective measures to find if the therapy produced real world changes, which is the whole aim of the exercise. Shifting scores on self report measures by very modest amounts, with no objective confirmation, is nothing more than games with words.

No substantial and sustained objective changes simply means that the therapy is ineffective. There is no way around that. Their excuse above, as with their excuse for failing to collect actometer outcome data, is just nonsense. If there are no (or only inadequate) objective measures used then it is not science.

Their persistent unwillingness to properly use (relevant) objective measures is a serious methodological and ethical problem.
 
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The reply seems merely to be a rehash of the paper and does not really address the specific concerns. If there were changes to the protocol based on 'Statistical Analysis Strategy', they should have mentioned this in the original paper.

We determined the normal range by use of the conventional mean plus or minus 1 SD from what we regarded as the most relevant general population data. For physical function, this was a demographically representative sample (in our paper we stated that this was a UK working-age population, whereas more accurately this should have been an English adult population)
This is invalid for the SF-36 PF score as the CFS sample systematically excluded people with other chronic diseases. The true mean minus 1 SD value should be that given by the figures in the letter by Andrew Kewley: 927 - 131 = 79.6. This is the true 'normal' figure according to the cited data.
 
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First, thanks to Dolphin for compiling this, and to all the successful letter writers who made important points and made them well.

The reply seems merely to be a rehash of the paper and does not really address the specific concerns. If there were changes to the protocol based on 'Statistical Analysis Strategy', they should have mentioned this in the original paper.
Agreed. Will be very interesting to see the Statistical Analysis Strategy, esp if it explain the rationale for changes from protocol. But nb they did say this in the paper:
The statistical analysis plan was finalised, including changes
to the original protocol, and was approved by the trial
steering committee and the data monitoring and ethics
committee before outcome data were examined
authors reply: We determined the normal range by use of the conventional mean plus or minus 1 SD from what we regarded as the most relevant general population data. For physical function, this was a demographically representative sample (in our paper we stated that this was a UK working-age population, whereas more accurately this should have been an English adult population)
So, they've now admitted they used the all-adult population instead of the working-age population which was broadly aged-matched to their cohort - without mentioning this drops with mean-1SD by 10-15 points. As snow leopard points out, they should be using healthy working age adults as the reference group.

They have also increased their claim for the study:
In conclusion, however we compared the results and however we defined CFS and myalgic encephalomyelitis, we found that cognitive behaviour therapy and graded exercise therapy provided a significant and clinically useful advantage of moderate size over adaptive pacing therapy and specialist medical care
In the original paper they somewhat sneakily said:
We suggest that these findings show that either CBT or GET, when
added to SMC
, is an effective treatment for chronic fatigue syndrome, and that the size of this effect is moderate
The claim of CBT/GET+SMC was defensible (though meaningless since there was then no control/comparison group), the claim of moderate effectiveness vs SMC in their letter is not. As I endlessly point out, they needed to treat 7-8 patients with CBT/GET for just one to improve modestly and this does not equate to a moderate effect. Will post more fully on effect size using Cohen's d, but this won't happen for a while.
We chose patient-rated measures of fatigue and physical function as primary outcomes because this is how the disorder is defined
I have to admit that this is a point well made! It sounds so convincing, even though it neglects the crucial issue of whether or not these self-rated improvements equate to real world changes - as Sean noted.

ETA: The authors point out they didn't report on recovery, but didn't explain why they chose to omit recovery status from a paper that assessed the effectiveness of therapies. It's bonkers.
 

Esther12

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Good point about them dropping reference to SMC oceanblue. Sadly, not a surprise. Has anyone had access to SMC? I've never had it offered to me.

Thanks to all those who managed to get their letters through - great work.

I thought their reply was appallingly weak... but the Lancet editorial is entirely condemning of patients' concerns, and supportive of White et al. There seems to be no concern about how their results were mis-sold to the media, or how this might effect patients.
 
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It is also sad that Mieko Shinohara's point was not addressed at all. It seems they weren't much concerned with the specific details in the letters, but merely saving face.
 

Dolphin

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From Tom Kindlon's letter:
If few participants are compliant with the intervention, harms-related data might not be reliable. Both cognitive behaviour therapy and graded exercise therapy are designed to increase activity; however, actometers were not used, so one cannot be sure how many patients were actually more active.1
Authors' reply:
The safety of patients was a very important aspect of our trial and was measured in five distinct ways, using definitions and reporting standards of the European Union Clinical Trials Directive for medicinal products.4
I'm not familiar with this directive. However any directive on medicinal products would presumably require manufacturers to define what dosages were used, something they didn't do with regard to dosages of activity/increases in the PACE Trial.
 
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The eight secondary outcomes presented in our paper were selected for clinical relevance. All these decisions and plans were approved by the Trial Steering Committee, were fully reported in our paper, and were made before examining outcome data to avoid outcome reporting bias.
Not quite. The headline grabbing yet nonsesical definition of normal which attracted so much attention in the letters, was dreamt up after they'd got their hands on the data:
A secondary post-hoc analysis compared the
proportions of participants who had improved between
baseline and 52 weeks by 2 or more points of the Chalder
fatigue questionnaire, 8 or more points of the short
form-36, and improved on both
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.
The 'improvers' outcome was used to support their claim of moderate effectiveness for the therapy, as was the 'within the normal range', while the 'within the normal range' data generated winning though misleading headlines.
 

Bob

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In conclusion, however we compared the results and however we defined CFS and myalgic encephalomyelitis, we found that cognitive behaviour therapy and graded exercise therapy provided a significant and clinically useful advantage of moderate size over adaptive pacing therapy and specialist medical care, but were no less safe. We suggest that the issue is not whether these treatments work and are safe, but how to make them available to those who might benefit from them.
As oceanblue says, this is an inaccurate statement. The changes recorded for SMC were far higher than the additional changes that were recorded for CBT and GET. It is not possible to know what changes CBT and GET were solely responsible for because of the methodology of the study.

The additional changes recorded for both CBT and GET were minimal (not 'moderate' in my opinion), and were only just above the threshold of clinical significance in 3 cases, for 3 of the 4 measurements in the primary outcomes, and did not reach clinical significance in one case.

Also, we don't know who might benefit from the 'treatments' because they used unofficial diagnostic criteria for the selection of patients such that any results cannot be used for the UK's CFS/ME patient population, as diagnosed using NICE guidelines.
 

Sean

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Oops, forgot to say congrats to those who got published.


Also 8/44 letters is not a bad yield.

I think we need to acknowledge that, whatever their serious failings might be, The Lancet did publish a good number of patient letters, and the ones they chose were a reasonable selection.