Comments(14)
Would it not be preferable if objective outcome measures were used?Tom Kindlon (23 May 2007) Irish ME/CFS Support Group I find it strange that, particularly in such a costly trial (over UK£3m), only subjective outcome measures are being used. The participants are assessed using actigraphy watches at the baseline assessment stage. Why are not these being used either during and particularly at the end of the trial? This is important given previous studies in the area. One study (on a single patient)[1] found "using a 26-session graded activity intervention involved gradual increases in physical activity" that "from baseline to treatment termination, the patient’s self-reported increase in walk time from 0 to 155 min a week contrasted with a surprising 10.6% decrease in mean weekly step counts." Another study [2], investigating CBT this time, found that (of 278 eligible) "241 patients had complete data (83 CBT, 80 support groups, 78 natural course) at 8 months. At 14 months CBT was significantly more effective than both control conditions for fatigue severity (CBT vs support groups 5.8 [2.2-9.4]; CBT vs natural course 5.6 [2.1-9.0]) and for functional impairment (CBT vs support groups 263 [38-488]; CBT vs natural course 222 [3-441]). Support groups were not more effective for CFS patients than the natural course. Among the CBT group, clinically significant improvement was seen in fatigue severity for 20 of 58 (35%), in Karnofsky performance status for 28 of 57 (49%), and self-rated improvement for 29 of 58 (50%)." Yet if one examines the actometer data from this study from the group given CBT, the increases in activity were minimal[3]. For instance, the baseline average was 67.9, which increased to 68.8 after treatment and to 72.2 at follow-up. About 4 points. Not unlike the medical care controls, who went from 64.9 to 68.7 in the same period. [3] One of the aims of CBT (for CFS) has been said to be "increased confidence in exercise and physical activity"[4] Thus it may be the case that when asked questions about one's ability to do things, such as in the physical functioning subscale of SF-36 (one of the two primary outcome measures), the patients might say that they are "Limited A Little" or "Not Limited At All" but may be just as limited as patients in other arms of study who say "limited a lot". Ideally more than one more objective measure would be used. White himself has found immunological changes after both exercise and activity in Chronic Fatigue Syndrome [5]. It would have been interesting to see whether any of these treatments had an effect on such cytokines. 1. Friedberg, F. Does graded activity increase activity? A case study of chronic fatigue syndrome. Journal of Behavior Therapy and Experimental Psychiatry, 2002, 33, 3-4, 203-215 2. Prins JB, Bleijenberg G, Bazelmans E, et al. Cognitive behaviour therapy for chronic fatigue syndrome: a multicentre randomised controlled trial. Lancet 2001; 357: 841-47. 3. Van Essen, M and de Winter, LJM. Cognitieve gedragstherapie by het vermoeidheidssyndroom (cognitive behaviour therapy for chronic fatigue syndrome). Report from the College voor Zorgverzekeringen. Amstelveen: Holland. June 27th, 2002. Bijlage B. Table 2. 4. O'Dowd, H., Gladwell, P., Rogers, CA., Hollinghurst, S and Gregory, A. Cognitive behavioural therapy in chronic fatigue syndrome: a randomised controlled trial of an outpatient group programme. Health Technology Assessment, 2006, 10, 37, 1-140. 5. White, PD., Nye, KE., Pinching, AJ., Yap, TM., Power, N., Vleck, V., Bentley, DJ., Thomas, JM., Buckland, M and Parkin, JM. Immunological changes after both exercise and activity in chronic fatigue syndrome: a pilot study. Journal of Chronic Fatigue Syndrome, 2004, 12, 2, 51-66. Competing interests No competing interests Another example as to why objective measures would be usefulTom Kindlon
(30 August 2007) Irish ME/CFS Support Group Another example of why objective measurements are important in studies involving CBT was shown in a recently published study by Knoop et al [1]. Their results state that "the level of self-reported cognitive impairment decreased significantly more after CBT than in the control conditions. Neuropsychological test performance did not improve." [1] Knoop H, Prins JB, Stulemeijer M, van der Meer JW, Bleijenberg G: The effect of cognitive behaviour therapy for chronic fatigue syndrome on self-reported cognitive impairments and neuropsychological test performance. Journal of Neurology and Neurosurgery Psychiatry. 2007 Apr;78(4):434-6. Competing interests No Competing Interests CFS intervention studies - lessons can be learned from a previous reviewTom Kindlon
(30 August 2007) Irish ME/CFS Support Group I have just been reminded that many of the points I have been made, such as suggesting the use of the actometer as an outcome measure, were covered in the Whiting et al review (2001) [1]. The review recommended the use of more objective outcome measures e.g. "Outcomes such as "improvement," in which participants were asked to rate themselves as better or worse than they were before the intervention began, were frequently reported. However, the person may feel better able to cope with daily activities because they have reduced their expectations of what they should achieve, rather than because they have made any recovery as a result of the intervention. A more objective measure of the effect of any intervention would be whether participants have increased their working hours, returned to work or school, or increased their physical activities." This review also recommended long-term follow-up: "The relapsing nature of CFS suggests that follow-up should continue for at least an additional 6 to 12 months after the intervention period has ended, to confirm that any improvement observed was due to the intervention itself and not just to a naturally occurring fluctuation in the course of the illness." It is slightly disappointing that the follow-up period in this study is scheduled at 52 weeks, only 16 weeks after the session at 36 weeks. It is particularly disappointing that this current trial didn't learn from the Whiting et al review [1] as both White and Sharpe have shown awareness of the review, having made reference to it in articles [2-5]. Perhaps it is not too late to collect data from even some subjects, using the actometers? [1] Penny Whiting, Anne-Marie Bagnall, Amanda J. Sowden, John E. Cornell, Cynthia D. Mulrow, Gilbert Ramírez: Interventions for the Treatment and Management of Chronic Fatigue Syndrome - A Systematic Review JAMA. 2001;286:1360-1368 http://jama.ama-assn.org/cgi/content/full/286/11/1360 [2] Peter White: Commentary. Adv. Psychiatr. Treat. 2002;8:363-365. (September 2002) http://apt.rcpsych.org/cgi/content/full/8/5/363 [3] Peter White: Chronic unexplained fatigue. Postgrad. Med. J. 2002;78:445-446. (August 2002) http://pmj.bmj.com/cgi/content/full/78/922/445
[4] Peter White: What causes chronic fatigue syndrome? BMJ 2004;329:928-929. http://www.bmj.com/cgi/content/full/329/7472/928 [5] Michael Sharpe: The symptom of generalised fatigue. PN 2006;6:72-77. http://pn.bmj.com/cgi/content/full/6/2/72 Competing interests No competing interests If CBT for CFS is "to help patients improve activity levels and quality of life", would not actometers be useful for measuring outcomes?Tom Kindlon (13 November 2007) Irish ME/CFS Support Group Just following up on a previous point: I have just read an oft-quoted paper on CBT for CFS[1], which was co-written by one of the co-authors and principal investigators in the current study, Prof Chalder. [CBT was provided, to the best of my knowledge, in one of the places where CBT will be offered in the PACE Trial]. The current paper says "Two independent systematic reviews have found that rehabilitative cognitive behaviour therapy (CBT) and GET were the most promising treatments for CFS/ME in secondary care". The two reviews reference this paper[1]. The paper[1] states that "cognitive behavior therapy was to help patients improve activity levels and quality of life". Unfortunately there is no mention of pedometers or actometers being used. So it seems disappointing that, according to the design presented, the researchers in the current trial (which many are hoping might be the definitive paper on the subject) will use actometers before the patients start the intervention but will not assess whether the treatment improves activity levels using the sort of measurements actometers can provide. [1] Deale A, Husain K, Chalder T, Wessely S. Long term outcome of cognitive behavior therapy versus relaxation therapy for chronic fatigue syndrome: a 5-year follow-up study. Am J Psychiatry 2001;158: 2038-42. Competing interests No competing interests Problems in the PACE TrialAngela Kennedy (13 November 2007) Individual In October 2004, a critique of the PACE trial was published on the One Click website. I feel it is important to read the above article in the context of the main relevant problems identified at the time, and which have not yet, to the best of my knowledge, been satisfactorily addressed: 1. The Confused Use of Criteria and Lack of Effective Identification of Sufferers of ME/CFS ICD-10 G93.3: The MRC has stated - as has The PACE Trial Identifier (FOOTNOTE 1) - that the Oxford criteria will be used for recruitment and entry to the PACE trial. The Oxford criteria exclusion definition prevents a patient with an organic brain disease from entering into this trial. ME/CFS ICD-10 G93.3 is an organic brain disease as listed by the WHO and this classification is agreed by the UK Government. What is more, most ME/CFS sufferers will exhibit signs and symptoms of organic brain disease, and especially those seriously affected. By the logic of the Oxford Criteria, they should be excluded. This anomaly is one of the major flaws of the Oxford Criteria. It therefore presents a major methodological problem, which we note has not been addressed by the authors of the Oxford Criteria, or the PACE Trial even though they have been aware of this criticism for some time. An important point to be emphasised is that co-authors of the Oxford Criteria are also the individuals running and controlling the PACE Trial. Using the Canadian Protocols (FOOTNOTE 2) at the onset instead of Oxford would prevent this methodological problem. What would then happen is that people with Idiopathic Chronic Fatigue and other illnesses would be excluded, and ME/CFS sufferers included. This should be the aim of the research project, which has been awarded government funds on the basis that research should be about ME/CFS (a "serious research priority", according to the MRC), not Idiopathic Chronic Fatigue. We note that this methodological flaw has NOT been addressed, and, within the Pace Trial Identifier, the Canadian Criteria are conspicuous by their absence in the literature review. Those conducting the PACE Trials have constantly repeated that the Oxford Criteria will be used for Recruitment and Entry to the trial. If patients with ME/CFS have already been excluded by this process, using the Fukuda and London Criteria later in the trial will be a superfluous exercise. In fact, the proposed use of two bolt-on criteria (Fukuda and London) is not discussed in the PACE Trial Identifier (see the PACE Report), and therefore just how bolt-on criteria are to be used has not been elucidated on. These appear to have been added on as an afterthought in response to criticism about the Oxford Criteria, to suppress those objections, without considering the discrepancies and methodological problems the use of three criteria would cause. This presents a major methodological discrepancy, particularly as the PACE Trial authors have ignored the Canadian Criteria. The Oxford criteria are now superseded, are not in use by international consensus, have no predictive value and are out of date. Why are they being used as the primary criteria in this trial when more up-to-date criteria have been produced? From the evidence, it appears that they are being used to increase attendance for the trial, and will include sufferers of idiopathic chronic fatigue (classified by the WHO as ICD-10 F48, a psychiatric disorder), depression, Fibromyalgia (Classified by the WHO as a Soft Tissue Disorder), 'burnout' and indeed ANY fatigue state, none of which are ME/CFS. This presents a major methodological problem because the trial is supposed to be for management of the neurological illness ME/CFS ICD-10 G93.3 only. In these circumstances, that fact that the results of this trial of such a heterogeneous sample will be generalised to ME/CFS ICD-G93.3 sufferers, will present serious risk to the health of future sufferers of ME/CFS G93.3. The use of the "London Criteria" (authors still yet to be established) is particularly problematic because these criteria have never been used in any published study, never been officially accepted into common usage, nor have they ever been validated or operationalised, and have not been published in any reputable peer reviewed Journal. (FOOTNOTE 3) Indeed, it is unheard of in modern research methodology for such criteria to be used in a clinical trial. In the PACE Trial Identifier, there is the following statement: "3.17 Are there any planned subgroup analyses? Not beyond the inter-centre comparisons of the two primary outcomes." This clearly demonstrates that the key issues on sub-grouping, and the problems of the Oxford Criteria in failing to differentiate ME/CFS ICD-10 G93.3, a neurological disease, from Fatigue syndromes that may have a psychological cause, have been ignored by the PACE Trial authors, despite the continued highlighting of this theoretical and methodological problem to them. It is therefore also astounding, bearing in mind that there is no intended stratification of the PACE patient sample, therefore no account has been made in PACE for the need for sub grouping of ME/CFS ICD-10 G93.3 sufferers, separately from Oxford Defined CFS (Two entirely different illness groups), as discussed by Hooper and Montague et al (FOOTNOTE 4), that the PACE Trial intends to use, not one, but three separate criteria. This will have the effect of negating the necessary consideration of subgroups, while at the same time applying more than one criteria superfluously to the same group of patients. 2. Problems of Access for Seriously Affected ME/CFS sufferers: It is also highly likely that those seriously affected will not be recruited as they cannot travel to the Centres. The FINE trial is a different project to PACE, and cannot be used to answer this criticism. The problems of those Seriously Affected by ME/CFS have been seriously neglected, as acknowledged in the Chief Medical Officer's Report. These are the very group that should be included in any trials on ME/CFS. The fact that NO provision has been made within the PACE Trial for studying them, while including those NOT suffering from ME/CFS ICD-10 G93.3, will mean that the results of the PACE Trial will be highly confounded. This present major methodological, theoretical and ethical problems, especially as the health of such sufferers are likely to be at further risk from incorrect generalisations of any confounded results as described above. 3. The Harmful Effects of CBT/GET Not Considered Adequately: Contrary to the claims made by the PACE Trial authors (FOOTNOTE 5) there is substantive evidence demonstrating that Graded Exercise Therapy (GET) adversely affects sufferers. This is discussed within the Canadian ME/CFS Case Definition and Treatment Protocols, for example. We note that such evidence has not formed part of the literature review in the PACE Trial Identifier. This therefore poses a profound ethical problem: The designers of the PACE trial Identifier intend to research a controversial 'treatment' on ME/CFS sufferers, even though this treatment may damage the health of those who receive it. The PACE Trial authors should be aware of these problems, but appear to be ignorant of or ignoring them. Cognitive Behavioural Therapy (CBT) has also been shown to harm ME/CFS sufferers. (FOOTNOTE 6) It should be noted that Cognitive Behavioural Therapy itself requires substantial mental and physical effort on the part of ME/CFS sufferers, and therefore can cause post-exertional malaise. We note that the evidence demonstrating this was not explicitly addressed in the PACE Trial Identifier. This therefore poses the same ethical problems as those of Graded Exercise Therapy. Neither CBT nor GET treatments have proved 'popular' - a claim made by White (FOOTNOTE 5) - on the contrary they have been shown to be DAMAGING in many instances. 4. Theoretical Confusion about the Strategy of 'Pacing': APT is merely a term coined by the PACE Trial proponents, to describe the supervision by a ' therapist' of (and logically, an interference in) an unquantifiable, individual self-managed strategy for coping with the severe physical limitations caused by ME/CFS. In fact, in the Pace Trial Identifier, the Acronym APT is used, but whether this indicates "Active Pacing Therapy" or "Adaptive Pacing Therapy" is not clarified, as no explanation as to the acronym is given. The fact that a 'therapist' will "input" into a self-managed strategy already suggests a major methodological problem to be addressed. The contents of the PACE Trial Identifier suggest this has not been considered. We would point out that true 'Pacing' does not include the use of targets and goals whereas 'APT' appears to do so, therefore this cannot be a true trial of 'Pacing'. In fact, 'PACING' is an autonomous practice by patients themselves, accompanied with advice from others such as ME specialists/Occupational Therapists about what might cause exertion, and ways in which energy can be conserved. This approach to managing one's illness is fundamentally, not much different from self-management approaches to other neurological illnesses, such as MS, for example. However, the term appears to have been inappropriately reconstructed by various therapists, so that removing the important factor of patient autonomy has become a key notion of such ideas as 'APT' (the PACE concept). Even recent articles claiming to be about PACING have actually been about Graded Activity and Cognitive Behavioural Therapy, imposed by therapists in the context of a 'therapeutic relationship'. Even where levels of activity are claimed to be negotiated, they nevertheless remove the choice for patients of autonomous flexibility in day-to-day activity self- management, as patients 'fail' to meet their 'targets'. In the context of an illness in which symptoms are often unpredictable, and patients' above all need maximum, day to day flexibility to manage symptoms, the attitudes of various 'therapists' towards Pacing have appeared naive at best, and in some cases, negligently so. Pacing, as used successfully by many in the ME/CFS community, is simply coping with one's physical limitations and preventing a cycle of relapse. If research needs to be undertaken on 'Pacing', it should be studied as an autonomous patient self-management strategy, (one project that could be undertaken, for example, is a qualitative study about how this is undertaken by patients). There are serious problems with establishing statistics on 'improvement' in functional ability which, in an illness where functional ability can change day-to-day, and is therefore unpredictable for many, is often transient and difficult or impossible to measure by 'therapists' (whether psychiatrists, physiotherapists, or cognitively behavioural therapists). This self-determination is often affected by unquantifiable factors. A qualitative study would set about asking patients themselves what they understand about pacing oneself, and how they 'pace'. If allowed to continue, the findings of PACE will be fundamentally flawed because they have failed, at the onset of the project, to address the key issue of patient self-managed activity within one's own limits, as opposed to externally imposed targets by therapists. They are effectively researching the wrong type of 'Pacing'. 5. The Problematic Ideological Standpoint of the PACE Trial Authors: What do the psychiatrists working on the PACE trial believe about ME? Do they subscribe to the WHO classification that ME/CFS is a neurological brain disease, or do they believe it is a 'somatization' disorder? A recent article by Winfried Rief and Michael Sharpe (FOOTNOTE 7) describes "Chronic Fatigue Syndrome" as a 'medically unexplained' and 'functional syndrome, along with Fibromyalgia. They describe both as somatoform disorders. This forms the crux of the problem: those psychiatrists, at least, conducting the PACE Trial, do NOT appear to subscribe to the WHO neurological classification of ME, but believe 'CFS' (which, under the WHO ICD-10 rubric, is merely another description for ME) is a 'somatization' disorder. For this reason, they also continue to (incorrectly) use the term Chronic Fatigue interchangeably with Chronic Fatigue Syndrome. We note that this legitimate criticism has not been addressed by the PACE Trial authors, and we have no assurances that those conducting the PACE Trial subscribe to the WHO neurological classification of ME/CFS either. This is particularly noteworthy as certain of these key psychiatrists are members of the Institute of Psychiatry at King's College, who were responsible for dissemination of misinformation about the ICD-10 classification of ME/CFS. (FOOTNOTE 8) That the frequently expressed belief in 'somatization disorder' and other mental disorders has been applied to ME/CFS by the psychiatrists involved in the PACE Trial, there is indeed a very clear assumption of an "original cause of illness", contrary to White et al's claims in their letter to the Independent. (FOOTNOTE 9). We would also bring to attention the large amount of evidence documenting the much criticised views of the psychiatrists involved in the PACE Trial about ME/CFS sufferers and the disease, exemplified by the comment quoted in the National newspaper The Independent (FOOTNOTE 10) and made by one of these psychiatrists: "I will argue that ME is simply a belief, the belief that one has an illness called ME". (FOOTNOTE 11) 6. Involvement in Delivery of CBT/GET by PACE Trial Directors: The PACE Trial Identifier, written by the psychiatrists and submitted to the MRC clearly shows that the PACE Trial is being run by the psychiatrists. We refer to clauses 4.1, 4.2, 4.4 and 4.6. As will also be seen within the PACE Trial Identifier, The psychiatrists involved in the PACE Trial are employed to provide these therapies (CBT/GET). These facts make the denial by Peter White in his Co-Cure post all the more remarkable, and poses yet another ethical problem. 7. The lack of Definition of "Standard Medical Care": In the PACE Trial Identifier the authors state that they will be comparing their interventions against that of "Standard Medical Care". Yet they make no indication of what such 'standard medical care' might entail. In addition, as 'standard medical care' has not actually been 'standardized', there is actually no 'standard medical care' for ME/CFS that can be measured against CBT/GET/APT. FOOTNOTES 1. This is available within: Bryant, J. The PACE Report, 2004. Available on The One Click Group Website: http://www.theoneclickgroup.co.uk 2. Carruthers, B. et al "Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols" Journal of Chronic Fatigue Syndrome, Vol. 11(1) 2003, pp 7 - 115. 3. See "The London Criteria and the PACE Trial" Archive number 182, The One Click Group Website. 4. Hooper, M, et al "Concepts of Accountability", 2001. Available on The One Click Website (ME/CFS Documents) 5. White, P. "The PACE and FINE trials: correcting some misunderstandings" 15 May 2004, Co-cure Message Board, http://listserv.nodak.edu/scripts/wa.exe?A2=ind0405C&L=co-cure&P=R579 6 Van Hoof, E. "Cognitive Behavioural Therapy as Cure-All for CFS" Journal: Journal of Chronic Fatigue Syndrome, Vol. 11(4) 2003, pp. 43-47 7. "Somatoform disorders-new approaches to classification, conceptualization, and treatment" Journal of Psychosomatic Research, Volume 56, Issue 4, April 2004, Pages 387-390. 8. "WHO Geneva Headquarters Classification Information, ME-CFS", 14th September, 2004. Available on The One Click Group Website 9. White, P et al , letter to the Independent Newspaper, 15th May, 2004. http://argument.independent.co.uk/letters/story.jsp?story=521407 10. Burne, J. 'Why won't they believe he's ill?' Independent Newspaper, 10 May, 2004. http://news.independent.co.uk/uk/health_medical/story.jsp?story=519815 11. Wessely , S. "Microbes, Mental Illness, the Media and ME: the Construction of Disease" Eliot Slater Memorial Lecture, 12 May 1994. Available with comment by Margaret Williams: http://www.meactionuk.org.uk/wessely_speech_120594.htm *See also Hooper, M. et al "The Mental Health Movement: Persecution of Patients?" Available on the One Click Group Website. Competing interests Parent of young woman diagnosed with ME/CFS. Social Sciences researcher. Previously Director of the One Click Group. Response to comments on “Protocol for the PACE trial”Peter White
(28 July 2008) Barts and the London Medical School, London, UK PD White, MC Sharpe, T Chalder, JC DeCesare, R Walwyn, for the PACE trial management group The following is a response to comments by Tom Kindlon (Irish ME/CFS Support Group) and Angela Kennedy on the protocol for the PACE trial. We respond to the comments in the order they were made. Objective outcome measures We have used several objective outcome measures; the six minute walking test [1], a test of physical fitness [2], as well as occupational and health economic outcomes [3]. Although we originally planned to use actigraphy as an outcome measure, as well as a baseline measure, 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. We will however test baseline actigraphy as a moderator of outcome. No biological measures were sufficiently well established to justify their use as outcomes in the trial. Long-term follow up We always planned to do a long-term follow-up (see protocol), and have now received research ethics committee approval to follow up participants two and a half years after randomisation (a year and a half after the end of the intervention). Patients with myalgic encephalomyelitis (ME) and use of the Oxford criteria ME is not an exclusion for the trial. In fact it is one of the stratifying criteria for treatment allocation. The Oxford criteria do exclude patients with “proven organic brain disease”, by which is meant such conditions as delirium and dementia [4]. The Oxford criteria have the added advantage over other criteria of requiring fatigue to be the “principal symptom” [4], and they do not require the four additional symptoms required for the Centers for Disease Control (CDC) criteria for chronic fatigue syndrome (CFS) [5]. This number of additional symptoms has been shown to be an arbitrary threshold for defining CFS [6]. Four additional symptoms do not provide a clear-cut delineation between CFS and other conditions. We did consider using the Canadian criteria for ME, but these are clinical not research criteria and their complicated and poorly defined nature would not have provided the reliability necessary for a multi-centre trial [7]. The London criteria for ME were chosen instead [8]. The London criteria were based on the original description of ME, given by Melvin Ramsay who, along with Acheson, provided the first detailed description of both epidemic and endemic ME [9, 10]. The criteria crucially include the characteristic features of ME described by Ramsay, such as “exercise-induced fatigue precipitated by trivially small exertion (physical or mental) relative to the patient’s previous exercise intolerance”, “impairment of short-term memory and loss of powers of concentration”, and “fluctuation of symptoms” [8]. These criteria are compatible with the ICD-10 description of ME, coded G93.3 [11]. Stratifying allocation by both the London criteria for ME [8] and the CDC criteria for CFS [5], will allow a separate examination of efficacy and adverse outcomes in patients who meet each of these criteria. Patients with severe disability The trial was not designed to include very severely disabled patients, but does include patients with significant disability so long as they can attend hospital for outpatient treatment. The protocol allows for treatment sessions to be given by telephone if the participant is too unwell to attend. The FINE trial, in contrast, delivers treatment in the patients’ homes and will therefore test how efficacious an active rehabilitation approach is in that setting (www.fine-trial.net). We agree that there may be a need for further clinical trials in patients with very severe disability, but the PACE trial was never intended to recruit these particular patients. Graded exercise and cognitive behaviour therapies The NICE guidelines on the management of CFS/ME recommend both graded exercise therapy (GET) and cognitive behaviour therapy (CBT) for mild to moderately affected patients with CFS/ME because “these are the interventions for which there is the clearest research evidence of benefit.” [12] Surveys of the membership of patient charities who report “harm” [13, 14] are likely to reflect lack of therapist input (e.g. being encouraged to join a gym) or inappropriate therapy from a therapist not adequately trained to deliver these treatments [15]. We have worked with the patient charity Action for M.E. to ensure we carefully measure and analyse adverse effects and reactions to all interventions. These are all assessed soon after they occur by senior clinicians experienced in CFS/ME, as well as being checked by other senior clinicians who are independent of all trial personnel, and who are masked to treatment allocation. Adaptive Pacing Therapy (APT) This therapy is being delivered by qualified occupational therapists, and is based on the ‘envelope theory’ of this illness [16]. APT is an energy management approach, which establishes a stable baseline of activity using a daily diary, with advice to plan and pace activity in order to avoid exacerbations. Strategies include developing awareness of early warning of exacerbations, limiting demands, regular planned rest and relaxation, and alternating of different sorts of activities. The aim is to achieve optimal adaptation to the illness and patient autonomy is encouraged. No targets or goals are set by a therapist and the guiding principle is optimal adaptation to the illness. The manuals were developed in conjunction with and fully approved by the patient charities Action for M.E. and Westcare (before they merged). The treatment was then piloted with patients and therapists before the trial, to ensure that it was as optimal a form of pacing therapy as possible. The addition of a therapist, rather than relying on self-help alone, was based on previous clinical practice found to be helpful [17], and provided the advantage of controlling for the non-specific therapeutic effects of seeing a therapist in other arms of the trial [18]. Beliefs and expectations of treatment and who is running the trial The trial has been designed and is being managed by many different healthcare and research professionals, including doctors, therapists, health economists, statisticians and a representative of a patient charity. The Trial Management Group includes five physicians and four psychiatrists. To measure any bias consequent upon individual expectations, all staff involved in the PACE trial recorded their expectations as to which intervention would be most efficacious before their participation, and we will publish these data after the end of the trial. Involvement of the principal investigators in providing CBT and GET in the trial and financial payments None of the three principal investigators (PIs) deliver either CBT or GET within the PACE trial or are employed to do so. No PI or local centre leader receives any personal financial reward for recruiting participants into the PACE trial. Standardised Specialist Medical Care This intervention has been defined and standardised with its own manual. Conclusion The PACE trial is designed to answer important questions regarding efficacy, adverse effects, and cost-effectiveness of four interventions currently being used across the world for patients with CFS/ME. It is due to finish recruitment by the end of this year. Patients, carers, healthcare professionals and commissioners need to know the answers to these questions, and we hope that this trial, the largest ever conducted for this illness, will provide these. 1. 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. 2. Petrella RJ, Koval JJ, Cunningham DA, Paterson DH: A self-paced step test to predict aerobic fitness in older adults in the primary care clinic. J Am Geriatr Soc 2001; 49:632-8. 3. Beecham J K, Knapp MRJ: Costing mental health interventions. In: Thornicroft G, Measuring Mental Health Needs. London, Gaskell, 2001. 4. Sharpe MC, Archard LC, Banatvala JE, et al: A report - chronic fatigue syndrome. J R Soc Med 1991; 84:118 121. 5. Reeves WC, Lloyd A, Vernon SD, et al: Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution. BMC Health Serv Res 2003, 3:25 http://www.biomedcentral.com/1472-6963/3/25 6. Sullivan PF, Pedersen NL, Jacks A, Evengard B: Chronic fatigue in a population sample: definitions and heterogeneity. Psychol Med 2005; 35:1337-1348. 7. Carruthers B, Jain AK, De Meirleir KL, et al: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols. J CFS 2003; 11:7-115. 8. The London criteria, quoted in: The National Task Force. Report on Chronic Fatigue Syndrome (CFS), Post Viral Fatigue Syndrome (PVFS) and Myalgic Encephalomyelitis (ME). Bristol; Westcare, 1994. 9. Ramsay AM: Postviral fatigue syndrome: The saga of Royal Free disease. Gower Medical Pub, London, 1986. 10. Acheson ED: The clinical syndrome variously called benign myalgic encephalomyelitis, Iceland disease and epidemic neuromyasthenia. Am J Med 1959; 26:569-95. 11. World Health Organisation: Tenth Revision of the International Classification of Diseases. World Health Organisation, Geneva, 1990. 12. National Institute for Health and Clinical Excellence: Chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy): diagnosis and management. London, NICE, Clinical Guideline CG53, 2007. http://guidance.nice.org.uk/CG53 13. Action for M.E.: Severely neglected ME in the UK. London: Action for M.E., 2001. http://www.afme.org.uk/res/img/resources/Severely%20Neglected.pdf 14. Action for M.E.: M.E. 2008: What progress? Initial findings of a national survey of over 2,760 people with M.E. focusing on their health and welfare. Bristol; Action for M.E., 2008. http://www.afme.org.uk/res/img/resources/Survey%20Summary%20Report%202008.pdf 15. Action for M.E.: Membership Survey 'your experiences' questionnaire. Wells: Action for M.E., 2003. 16. Pesek JR, Jason LA, Taylor RR: An empirical investigation of the envelope theory. J Hum Behav Soc Env 2000; 3:59-77. 17. Cox DL: Management of CFS: development and evaluation of a service. Internat J Ther Rehab 1998; 5:205-9. 18. Frank JD, Frank JB: Persuasion and healing: A comparative study of psychotherapy. JHU Press, 1991. Competing interests These are reported in our original paper. Misinformation in comments on the PACE trialEllen Goudsmit
(29 August 2008) UEL As one of the co-authors of the London criteria used in the PACE trial, I wish to correct inaccurate information posted by Mrs. Kennedy. She claims that "The use of the "London Criteria" (authors still yet to be established) is particularly problematic because these criteria have never been used in any published study, never been officially accepted into common usage, nor have they ever been validated or operationalised, and have not been published in any reputable peer reviewed Journal. (FOOTNOTE 3) Indeed, it is unheard of in modern research methodology for such criteria to be used in a clinical trial." These claims have been aired before and formed part of an orchestrated attack against the PACE trial several years ago. Then, as now, the agenda was to argue that the London criteria were flawed and so the PACE trial was flawed also. The following are the unconvenient truths. The authors of the London criteria are known to those who needed to know. The names were not listed on copies as the criteria were formulated solely for use in studies funded by the charity AFME. They were, essentially, AFME's criteria for ME. They still are. Incidentally, the authors also provided those in receipt of funding a questionnaire which could be used to 'operationalise' the criteria. That was noteworthy as I can think of no criteria for CFS or ME which were available at that time which provided clear guidance re operationalisation. As far as I know, some of the studies which used the criteria were published in peer reviewed journals (e.g. by Costa et al, Perrin, McCue and others). However, I admit that the criteria were not validated. None of the criteria were. Indeed, at time of writing, there are still no validated criteria for either CFS or ME. We have no data on specificity and sensitivity. If one defines validity in terms of use, then the most validated criteria are the Oxford and CDC criteria 1994. And these are the ones which were chosen for the PACE trial. I will not waste space by citing references as they are well known to Ms. Kennedy and those interested in ME. Perrin and McCue both refer to the London criteria by name, Costa et al do not, but AFME can confirm their use in the studies named, as can all the researchers. I also have the contract signed by Dr. Costa showing that they were to be used in the study which was published in the QJM 1995. That paper refers only to criteria from AFME (then called ME Action), probably because we had not started to refer to them as the 'London' criteria. Later, confusion arose because of a note that the AFME criteria were based on those formulated by Dr. Weir. I did not see the proofs and was therefore not able to correct the error before publication. As Professor White confirms, the London criteria are based on Ramsay's clinical definition of ME. Those familiar with the work of Dr. Ramsay will have noted the resemblance. As the London criteria were designed purely for 'in-house' use by AFME, they were not submitted for publication in a peer reviewed journal. (Many researchers have selected their patients with CFS using criteria which were also never published in a peer reviewed journal). As for the Canadian criteria, they were published in a journal edited by one of the co-authors. Peer reviewed? Yes. Rigorously? We shall never know. The London criteria worked so well in practice that other researchers asked AFME for permission to use them in their own studies. They saw no reason to refuse such requests. I'm not sure how helpful it is to challenge studies by providing people with erroneous and misleading information. I personally prefer to focus on more obvious problems, such as the use of the bimodal scoring method when assessing patients for fatigue using the Chalder Fatigue Scale. This has a low ceiling, so patients with maximal scores at baseline will not be able to record an exacerbation after treatment. Now that's what I call a flaw! Competing interests I co-authored the London criteria and was part of the team at AFME which decided on the funding of research. I therefore know which studies used the criteria and where studies were published. Some problems with the 'London Criteria'Angela Kennedy
(01 October 2008) Social Sciences Lecturer and Researcher With regard to Doctor Goudsmit's assertions regarding the 'London Criteria', it is important to set out what is known about these 'criteria' themselves for the purpose of clarifying their problematic inclusion in the PACE Trial: The “London” criteria have never been published in a peer reviewed publication. They were mentioned in the National Task Force Report as being one of nine different “PROPOSED” definitions and descriptions (see page 88, Appendix B, REPORT from THE NATIONAL TASK FORCE ON CFS/PVFS/ME: 13th September 1994: Westcare, Bristol (now apparently part of the charity AfME). Whatever flaws I or other may argue that the following criteria may have, nevertheless they have all been peer reviewed and published: 1988 Holmes et al criteria were published in Annals of Internal Medicine:1988:108:387-389; the 1991 Oxford criteria were published in the Journal of the Royal Society of Medicine:1991:84:118-121 and the 1994 CDC criteria were published in Annals of Internal Medicine: 1994:121:953-959. The London criteria have also not been consistently defined -- there are at least two different (online) VERSIONS of them and a definitive version has not been identified. The authors of the London criteria are unknown (various differing claims have been made by about the authorship.) They have NOT been referenced or stated as being used in the following studies, contrary to claims made in the past by Doctor Goudsmit: 1 "Brainstem perfusion is impaired in chronic fatigue syndrome". DC Costa, C Tannock and J Brostoff. Quarterly Journal of Medicine December 1995:88:767-773 2. "Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome" Lorna Paul et al. European Journal of Neurology 1999:6:63-69. The case definition used in this study was the CDC Fukuda 1994: the authors state, “The patients were all ambulatory, and fulfilled established criteria for chronic fatigue syndrome (Fukuda et al, 1994)”. 3. "The effect of exercise on gait and balance in patients with chronic fatigue syndrome" Lorna M. Paul, Leslie Wood, William Maclaren Gait and Posture 14 (2001) 19–27. Eleven subjects with CFS and 11 control subjects participated in the study. All patients fulfilled the CDC criteria for CFS. Also, one of my own criticisms of the “London Criteria” (or at least, of the two versions I have seen online) is that they were clearly not strict enough linguistically, and therefore can be open to multiple interpretations, therefore are subject to serious problems of validity and reliability when it comes to establishing a suitably defined 'ME' or 'CFS' research population i.e. the 'London Criteria' are subject to the same instabilities as Oxford and CDC criteria as mentioned in my first post. The inclusion of the "London Criteria" as superfluous, bolt-on criteria for selection after patients with neurological signs are likely excluded from the PACE trial, has rather opened a 'can of worms' in relation to the large number of other methodological and theoretical problems in this MRC-funded study. There are various discrepancies which were identified at the publication of the PACE Trial identifier, and the worries expressed about these problems have not been assuaged.Certainly there will be scope for a detailed critical evaluation of this study after its publication, but in the meantime I am happy to refer interested readers to other resources that set out some of the problems in more detail, if they wish to approach me by email. There is a large amount of complex evidence around the status of the London Criteria supporting the concerns I expressed in my post above, I suspect rather too large for this particular medium. This is also the case regarding the problematic rejection of the Canadian Criteria in the PACE Trial, and other identified problems. Competing interests Critic of the Psychiatric Paradigm of 'ME/CFS'. Mother of and advocate for severely disabled young woman who was diagnosed with 'CFS/ME'. One of many advocates for the 'ME/CFS and Lyme communities. Further information on existing data on management strategies for CFSTom Kindlon
(01 October 2008) Irish ME/CFS Association - for Information, Support & Research As well as giving the protocol for the PACE Trial, this paper also gives information and data from some previous studies in the area. Depending on which pieces of data are presented for any treatment in medicine, a treatment can often look more or less useful or effective. Readers of this paper may be interested to know about a recent meta-analysis of the efficacy of CBT for CFS[1]. The studies involved a total of 1371 patients. This involved calculating the size of an effect measure, the Cohen's d value. They calculated d using the following method: "Separate mean effect sizes were calculated for each category of outcome variable (e.g., fatigue self- rating) and for each type of outcome variable (mental, physical, and mixed mental and physical). Studies generally included multiple outcome measures. For all analyses except those that compared different categories or types of outcome variables, we used the mean effect size of all the relevant outcome variables of the study." d was calculated to be 0.48. For anyone unfamiliar with Cohen's d values, they are not bounded by 1; also, the higher the score, the bigger the "effect size" i.e. the more "effective" a treatment was found to be. Cohen's d values are considered to be a small effect size at 0.2, a moderate effect size at 0.5, and a large effect size at 0.8[2]. CBT had a more general definition in this paper and included some papers on GET. For example, the current paper gives some information on a study by Fulcher and White[3]. Malouff et al[1] calculated the d value for this study as 0.46 (95% CI: 0.03-0.95). [1] Malouff, J. M., et al., Efficacy of cognitive behavioral therapy for chronic fatigue syndrome: A meta-analysis. Clinical Psychology Review (2007), doi:10.1016/j.cpr.2007.10.004 [2] Cohen J: Statistical power analysis for the behavioural sciences. Edited by: 2. New Jersey: Lawrence Erlbaum; 1988. [3] Fulcher KY, White PD: Randomised controlled trial of graded exercise in patients with the chronic fatigue syndrome. BMJ 1997, 314:1647-1652. Competing interests No competing interests The dropping of actometers as an outcome measure and other points relating to the outcome measures being usedTom Kindlon
(22 October 2008) Irish ME/CFS Association - for Information, Support & Research In their reply to my comments, Peter White and colleagues say they are using [i]"several objective outcome measures"[/i] [1]. If they think these tests are useful as objective outcome measures, why is at least one of them not being used as a primary outcome measure rather than the current situation where there are only two subjective outcome measures being used. I have already made some points on the outcome measures but another one is that the bimodal Chalder Fatigue Scale hardly seems a very good outcome measure for a "CFS/ME" trial where there is likely going to be so many maximum or near maximum scoring initially[2] Also, there are so many (14) secondary outcome measures in this study, along with so many (18) predictor variables, that it seems unlikely all the different methods of looking at the secondary outcome measures can be explored in the final published paper, given authors are encouraged not to make papers too long (especially journals that have paper editions). The protocol itself is 20 pages long when all the different aspects of it are listed! At least some of the information will need to be re-iterated in the final paper. It is of course important to take the burden on participants into account when deciding what outcome measures to use. However I find the following point very strange: [i]"Although we originally planned to use actigraphy as an outcome measure, as well as a baseline measure, 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."[/i] Firstly they clearly don't find it that great a burden that they drop it altogether as it is being used on patients before the start. If they feel it was that big of a burden, it should probably have been dropped altogether. Of course, other studies in the area have used measuring over a similar or longer period. For example, Bazelmans [3] used an actometer over 14 days, Black [4] used actigraphy over 14 days, Sisto[5] used actigraphy over 7 days, Vercoulen[6] used an actometer over 12 days and Van der Werf [7] used an actometer for 12 days. Also if one wants to reduce the burden on patients, why not take out one or both of the exercise tests instead. As the clinicians in the study would know, post-exertional symptoms are part of the condition. For example, Nijs[8] performed a gentle walking exercise on patients where they walked on average 558m(+/-340) (range: 120-1620) at a speed of 0.9m/s (+/-0.2) (range: 0.6-1.1). This resulted in a statistically significant (p<0.05) worsening of scores in the following areas when comparing pre-exercise, post-exercise and 24 hour post-exercise scores using ANOVA: VAS fatigue, VAS musculoskeletal pain, VAS sore throat, SF-36 bodily pain and SF-36 general health percention. 14 out of 24 subjects experienced a clinically meaningful change (worsening) in bodily pain (i.e. a minimum change of the SF-36 bodily pain subscale score of at least 10). Those results are similar to another study[9] which involved the acute effects of 10 discontinuous 3-minute exercise bouts on a treadmill in 10 CFS patients. In between exercise bouts, there was a 3-minute recovery period between exercise bouts. The participants walked at a comfortable walking pace self-selected by the subjects. On average, the subjects walked at a speed of 0.71+/-0.20 m/s. Some patients reported experiencing headaches, leg pain, fatigue or sore throats. In another study, Lapp [10] (not to be confused with Clapp[9]) reported on the effects of 31 patients to his practice who were asked to monitor their symptoms three weeks before to 12 days after a maximal exercise test. 74% of the patients experienced worsening fatigue and 26% stayed the same. None improved. The average relapse lasted 8.82 days although 22% were still in relapse when the study ended at 12 days. There were similar changes with exercise in lymph pain, depression, abdominal pain, sleep quality, joing and muscle pain and sore throat. These are just a small selection of the studies which show patients experience an exacerbation of their symptoms following exercise testing. So these are the sorts of symptoms the patients may expect following the exercise. This reminds me that there seems to be a lot of concentration on measuring fatigue in this study - there are many other symptoms that are part of "CFS/ME". If they had used actometers instead of, say, doing one of the exercise tests, the response to the exercise could have been followed to see how long and how severe an effect the exercise had on the patient. Or they could have dropped both the exercise tests altogether. As well as "subjective" findings following exercise testing, there have also been objective findings. Arnold et al[11] found excessive intracellular acidoss of skeletal muscles with exercise. Jammes[12] found an increase of damaging oxidative stress following exercise testing. So patients could not just endure temporary sysptom but possibly also longer-term harm from exercise testing. There are numerous other exercise abnormalities. As the clinicians involved in the study probably hear from patients, one of the frustrating things about ME or CFS is that people don't realise the payback that they can have from doing things. This would have been an opportunity to investigate this as part of the study. But now the effort patients will put in and the payback they will feel in some ways is being wasted as the effects won't be measured. Anyway, to repeat again, given the authors familarity with the literature, I find it strange that they would decide using an actometer would be worse than putting patients through two exercise tests. I also find it surprising that in a study part-funded by the Department of Work and Pensions (DWP) that the objective outcome measures (not involving questionnaires) are all once-off exercise tests. It has been established that patients need to be able to do things on several days during a week before they can be passed fit for work. I have mentioned using actometers following exercise tests after an exercise test above; of course, actometers wouldn't have to be used at that time but also during a "normal week". Proponents of pacing methods including APT would say that there is a "ceiling of activity" that patients can't go above without experiencing a worsening of symptoms. Black[13] has found evidence of this. Proponents of CBT or GET for "CFS/ME" would suggest that patients can gradually just increase how much activity they can do. Actometers would also have tested the hypothesis. As it stands, the study will not give us information on this as just because patients answer questionnaires saying they're improved (which could simply be because they think they're better) or improve their exercise results (which might simply be because they're willing to push themselves more) doesn't prove that they don't have an activity ceiling above which they experience disabling symptoms (esp. when, as in this study, there is no follow-up period following the exercise testing). [b]This is the real "heart" of the issue but given the current design, the question won't be answered.[/b] [1] 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" http://www.biomedcentral.com/1471-2377/7/6/comments#306608 [2] Goudsmit EM, Stouten B, Howes S: Fatigue in Myalgic Encephalomyelitis. Bulletin of the IACFS/ME - Volume 16, Issue 3. http://tinyurl.com/3zcgw8 i.e. http://www.iacfsme.org/BULLETINFALL2008/Fall08GoudsmitFatigueinMyalgicEnceph/tabid/292/Default.aspx [3] Bazelmans E, Bleijenberg G, van der Meer JWM, Folgering H. Is physical deconditioning a perpetuating factor in chronic fatigue syndrome? A controlled study on maximal exercise performance and relations with fatigue, impairment and physical activity. Psychol Med 2001; 31: 107–14. [4] Black CD, O’Connor PJ, McCully KK. Increased daily physical activity and fatigue symptoms in chronic fatigue syndrome. Dyn Med 2005; 4: 3. [5] Sisto SA, Tapp WN, LaManca JJ et al. Physical activity before and after exercise in women with chronic fatigue syndrome. Q J Med 1998; 91:465–73. [6] Vercoulen JHMM, Bazelmans E, Swanink CMA et al. Physical activity in chronic fatigue syndrome assessment and its role in fatigue. J Psych Res 1997; 31: 661–73. [7] Van der Werf SP, Prins JB, Vercoulen JHM, van der Meer JWM, Bleijenberg G. Identifying physical activity patterns in chronic fatigue syndrome using actigraphic assessment. J Psychosom Res 2000; 49: 373–79. [8] Nijs J, Almond F, De Becker P, Truijen S, Paul L. Can exercise limits prevent post-exertional malaise in chronic fatigue syndrome? An uncontrolled clinical trial. Clin Rehabil. 2008 May;22(5):426-35. [9] Clapp LL, Richardson MT, Smith JF, Wang M, Clapp AJ, Pieroni RE. Acute effects of thirty minutes of light-intensity, intermittent exercise on patients with chronic fatigue syndrome. Phys Ther 1999; 79: 749-56. [10] Lapp, C (1997). Exercise limits in chronic fatigue syndrome. Am J Med, 103: 83-84. [11] DL Arnold et al. Excessive intracellular acidosis of skeletal muscles on exercise in the post viral exhaustion / fatigue syndrome: a 31P-NMR Study. Proceedings of third Annual Meeting of the Society for Magnetic Resonance in Medicine, New York, 1984, 12-13. [12] Jammes Y, Steinberg JG, Mambrini O, Bregeon F, Delliaux S: Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise. Journal: J Intern Med., 2005 Mar;257(3):299-310. [13] Black CD, McCully KK: Time course of exercise induced alterations in daily activity in chronic fatigue syndrome. Dyn Med. 2005 Oct 28;4:10. Competing interests No competing interests Does housework count as exercise for somebody in the GET leg of the trial?Tom Kindlon
(06 March 2009) Irish ME/CFS Association - for Information, Support & Research I wonder could the authors answer a question which is relevant to the real world application of Graded Exercise Therapy (GET). Competing interests No competing interests Further evidence showing why objective measures are preferable in CFS trials particularly where cognitions could be changed following the interventionTom Kindlon
(06 March 2009) Irish ME/CFS Association - for Information, Support & Research Since writing my previous posts, further data on the subject has come to my attention. Competing interests No Competing Interests Problematic definition of 'fibromyalgia'Dan Horovitz (06 March 2009) Individual I would like to draw the authors attention to their use of the term 'fibromyalgia' in the protocol, as I believe it has been used in a way that has the potential to misinform some readers. Competing interests No competing interests Discrepancies between momentary fatigue and recalled fatigue can existTom Kindlon
(01 July 2009) Irish ME/CFS Association - for Information, Support & Research One of the primary outcome measures in this study is the bimodal Chalder Fatigue Scale [1] (possible individual scores 0 and 1, total scores can range from 0-11). One of the secondary outcome measures is the Chalder Fatigue Scale[1] using a different method of scoring (possible individual scores: 0-3, total scores can range from 0-33). This asks questions about the last month: "For the next few questions, we would like to know whether or not you have had any problems with feeling tired, weak, or lacking in energy in the last month". Competing interests No competing interests Have something to say? Post a comment on this article! |
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