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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

Peter D White*, Michael C Sharpe, Trudie Chalder, Julia C DeCesare, Rebecca Walwyn and the PACE trial group

BMC Neurology 2007, 7:6  doi:10.1186/1471-2377-7-6

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CONSORT statement recommends sufficient details to allow replication (for nonpharmacologic treatments, the publishing of manuals is recommended)

Tom Kindlon   (2010-07-09 16:55)  Irish ME/CFS Association - for Information, Support & Research email

The publishing of this trial protocol [1] is to be welcomed – it is something that the CONSORT statement on Randomized Control Trials (RCTs) recommends[2].

Item 5 of the checklist in the CONSORT guidelines [2] states the following information should be given: "The interventions for each group with sufficient details to allow replication, including how and when they were actually administered."

The explanation for this is given as [3]:
"Explanation—Authors should describe each intervention thoroughly, including control interventions. The description should allow a clinician wanting to use the intervention to know exactly how to administer the intervention that was evaluated in the trial.102 For a drug intervention, information would include the drug name, dose, method of administration (such as oral, intravenous), timing and duration of administration, conditions under which interventions are withheld, and titration regimen if applicable. If the control group is to receive “usual care” it is important to describe thoroughly what that constitutes. If the control group or intervention group is to receive a combination of interventions the authors should provide a thorough description of each intervention, an explanation of the order in which the combination of interventions are introduced or withdrawn, and the triggers for their introduction if applicable.

"Specific extensions of the CONSORT statement address the reporting of non-pharmacologic and herbal interventions and their particular reporting requirements (such as expertise, details of how the interventions were standardised).43 44 We recommend readers consult the statements for non-pharma-cologic and herbal interventions as appropriate."

The equivalent item in the Extension for Trials Assessing Nonpharmacologic Treatments is:

"Precise details of both the experimental treatment and comparator

4A Description of the different components of the interventions and, when applicable, descriptions of the procedure for tailoring the interventions to individual participants

4B Details of how the interventions were standardized

4C Details of how adherence of care providers with the protocol was assessed or enhanced"

Here is an extract from the explanation for part a[5]:
“It is important to provide a detailed description of nonpharmacologic treatments, which are usually complex interventions involving several components (75), each of which may influence the estimated treatment effect (27–32).”

[..]

“The description of any standardization methods is essential to allow adequate replication of the nonpharmacologic treatment. We recommend that authors allow interested readers to access the materials they used to standardize the interventions, either by including a Web appendix with their article or a link to a stable Web site. Such materials include written manuals, specific guidelines, and materials used to train care providers to uniformly deliver the intervention.”

[..]

“In a review of behavioral medicine interventions, insufficient intervention detail was a barrier to assessment of evidence and development of guidelines (80–82).”

[..]

“For rehabilitation, behavioral treatment, education, and psychotherapy, authors should report qualitative and quantitative data. Qualitative data describe the content of each session, how it is delivered (individual or group), whether the treatment is supervised, the content of the information exchanged with participants, and the instruments used to give information. Quantitative data describe the number of sessions, timing of each session, duration of each session, duration of each main component of each session, and overall duration of the intervention. It is also essential to report how the intervention was tailored to patients’ comorbid conditions, tolerance, and clinical course.”

Here is an extract from the explanation for part b which seems particularly relevant as treatment manuals are referred to in the protocol (but they have not been published):

“The description of any standardization methods is essential to allow adequate replication of the nonpharmacologic treatment. We recommend that authors allow interested readers to access the materials they used to standardize the interventions, either by including a Web appendix with their article or a link to a stable Web site. Such materials include written manuals, specific guidelines, and materials used to train care providers to uniformly deliver the intervention.”

The descriptions of Cognitive Behaviour Therapy (CBT) and Graded Exercise Therapy (GET) are 73 and 68 words respectively. These are not sufficient for replication. For example, what is the advice a therapist should give if a patient experiences an exacerbation of symptoms, which is common with this condition e.g. should they maintain their level of activity or exercise or reduce? And if they maintain their level of activity, how long should this continue for? Also what constitutes treatment adherence? In a previous comment, I pointed out a patient who is counting minutes spent doing housework as minutes for her exercise program.

This estimated cost for this trial is now 5m UK pounds of taxpayers' money[6]. It is important that it is reported as well as possible.

References:

[1] White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R; PACE trial group. Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurol. 2007 Mar 8;7:6.

[2] Schulz KF, Altman DG, Moher D; CONSORT Group. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMC Med. 2010 Mar 24;8:18. http://www.biomedcentral.com/1741-7015/8/18/

[3] Moher D, Hopewell S, Schulz KF, Montori V, Gøtzsche PC, Devereaux PJ, Elbourne D, Egger M, Altman DG. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ. 2010 Mar 23;340:c869. doi: 10.1136/bmj.c869 http://www.bmj.com/cgi/content/full/340/mar23_1/c869

[4] Boutron I, Moher D, Altman DG, Schulz K, Ravaud P, for the CONSORT group. Methods and Processes of the CONSORT Group: Example of an Extension for Trials Assessing Nonpharmacologic Treatments. Ann Intern Med. 2008:W60-W67. http://www.consort-statement.org/index.aspx?o=1416

[5] Boutron I, Moher D, Altman DG, Schulz K, Ravaud P, for the CONSORT group. Extending the CONSORT Statement to randomized trials of nonpharmacologic treatment: explanation and elaboration. Ann Intern Med. 2008:295-309. http://www.consort-statement.org/index.aspx?o=1415

[6] Psychiatry, Neuroscience and Clinical Psychology
University of Edinburgh submission. http://www.rae.ac.uk/submissions/ra5a.aspx?id=176&type=hei&subid=3181

Competing interests

No competing interests

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PACE Trial Strata Criteria

Peter Kemp   (2010-07-09 16:51)  Private email

For an overview of the pros and cons of Stratified Sampling see: http://en.wikipedia.org/wiki/Sampling_(statistics)

The PACE Trial Identifier indicated an intention to stratify participants by treatment centre. In the PACE Trail Protocol participants are stratified into those that meet Oxford, London or CDC criteria as well as those that have depression or not. These strata are divided between 4 treatment arms (APT, GET, CBT, Control group - Secondary Care).

Each strata is like a separate research project with a carefully defined and selected group of participants. One of the main advantages of using strata is that data should be matched to other strata; allowing accurate comparison. Unfortunately there are some disadvantages to this approach.

The reduced sample size in each strata/arm is susceptible to other problems due to the nature of the theories being tested. As has been pointed out prolonged inactivity can produce symptoms. Some of these might match symptoms required for different criteria. People at different stages of an illness may fit different criteria. There may be participants who are prone to somatization and others with missed diagnoses (Reeves lost 20% of participants with the latter - www.biomedcentral.com/1741-7015/3/19).

There is a risk that the three criteria strata include arbitrary elements. As Professor White remarks: (Peter D White. How common is chronic fatigue syndrome; how long is a piece of string? Population Health Metrics 2007, 5:6doi:10.1186/1478-7954-5-6)

“If the disease in question has no biological marker and is difficult to define clinically, the problem of working out the accurate prevalence becomes esoteric.”

And: “Since fatigue is one of the most common symptoms reported by patients in general, delineating a specific syndrome with fatigue as a central feature risks arbitrary decisions about ascertainment.”

This suggests that distinguishing CFS requires stringent criteria expertly applied; which makes the choice of the imprecise Oxford criteria for the PACE Trial seem rather odd. In the same paper White wrote:

“But perhaps the most important conclusion is that there were about twice as many people in Georgia who were unwell with fatigue, who did not meet the criteria for CFS. Our current criteria for diagnosing CFS are arbitrary [16], and we need to widen the net to capture all those people who become so chronically tired and unwell that they can't live their lives to their full potential. The jobbing physician does not close the door on those who don't meet criteria.”

This may be true but the PACE Trial is researching ME and CFS, as per the research title. One of the criticisms of some CFS research is the criteria used. This can impair comparison and meta-analysis. Some researchers have avoided this problem by using the CDC criteria, which though it might have some weaknesses does have provenance. There is a risk that much of the PACE Trial data will not be comparable with mainstream research or be generalisable to CFS.

Perhaps it could be argued that using fatigue as the entry criteria will increase generalisability because the research data will refer to a greater number of patients; i.e., any patient presenting with prolonged unexplained fatigue. The problem here would be if the fatigue had a variety of causes that do not respond in similar ways to the treatments being tested.

With the added complication of stratified sampling and the difficulty of recruiting participants for research, uninformative strata are not a good idea. Bechhofer and Paterson point out (2000. Principles of research design in the social sciences. Routledge), "Another problem in choosing strata is that you very quickly run out of enough people in your sample to fit into all the strata.". They also remark, "The general point, however, is to stratify with respect to factors that you think are related to the main object of the study."

In the PACE Trial it seems the treatments GET and CBT are intended to be rehabilitative and to address incapacity originating from perceptual and deconditioning problems. If this is correct then there are no symptoms other than fatigue related to the ‘main object of the study’ and they are therefore arbitrary.

If the PACE Trial strata identifies groups that respond differently to treatments, this might be useful information. This approach might for example, show that participants that have more symptoms are less suitable for GET and CBT than participants who are simply fatigued.

It might be that the three criteria used will separate participants into groups such as mainly fatigue; mainly neuro-cognitive symptoms; and CDC criteria CFS. If this were the case then stratifying participants by criteria could represent stratifying participants according to how they express neurotic disturbances through physical symptoms. This would be a novel use of the three criteria but one for which they were not designed.

Problems may arise when participants fit into more than one strata which might happen due to overlapping aspects of the criteria. Participants must fit the Oxford criteria to be in the Trial. Yet presumably 66% will also fit into one or both of the other criteria.

CFS research criteria were designed as stand-alone instruments intended to derive a whole research population. They were not designed to derive unique and rational segments from a different CFS criteria. Stratifying participants by criteria that are not adequately differentiated would be an inefficient use of the method.

To avoid this problem it might have made more sense to limit strata to two criteria only or design a specific instrument (which could be derived from the criteria) for the purposes of differentiating participants by symptoms to create unique strata. This might have been done in the data analysis, thus avoiding the complication and additional resources required for stratification.

Generalisation of the PACE Trial results could prove impossible if some participants have an ongoing biomedical illness - such as neurological or infectious disease that has fatigue as a feature. If these participants were mixed with others who have post viral fatigue, burnout, deconditioning, depression, phobia etc., then the strata criteria might combine various physical and psychological illnesses in an unpredictable way.

In such circumstances much of the data may not be generalisable because it would not be related to a specific disease or even to a well defined syndrome. Unless the results show well correlated non/efficacy for a substantial portion of participants with a certain treatment, speculation will remain about how and for whom a treatment works or fails.

Paul Meier, (Controlled Clinical Trials. Volume 1, Issue 4, May 1981), states:

“Stratification in the design of a clinical trial is often advanced as a method for greatly improving the precision of comparisons. It is argued here that stratification in design rarely achieves more than modest benefits in precision and that it exacts a heavy price in clumsiness and increased possibilities for error in the execution of a trial. Poststratification and covariance methods are important elements in analysis, but only limited stratification is justified in the design phase.”

Perhaps the stratification by criteria in the PACE Trial is a compromise to ensure that the investigators get to study participants who are simply fatigued and the other criteria were added to satisfy those who believe M.E. and CFS are biomedical illnesses not simply defined by fatigue. If outcomes can be substantially related to the criteria strata this could be valuable information.

However, if the three criteria strata produce results that vary significantly within the strata it might indicate a failure to group participants in a meaningful way and the strata may prove to have been a waste of resources. This is a possibility because the strata do not appear to be derived by criteria designed for the purpose nor related to the main object of the study.

Competing interests

None

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Reply to misleading information A Kennedy 1st October 2008

Ellen Goudsmit   (2010-06-21 17:16)  University of East London email

In her comment responding to an earlier contribution, Ms Kennedy repeated certain criticisms of the London Criteria for ME. As some of her statements suggested that I had been untruthful in my comment, I asked the editorial board to remove her response d.d. 1st October 2008 and when requested, sent them evidence to show that the London criteria had been used in research, that they were operationalised etc and that I had provided totally accurate information in my first comment. I also clarified that none of the criteria for CFS and ME had been 'validated' at the time of writing, ergo, Ms Kennedy seemed to require a higher standard for the LC than for other criteria.

Regretfully, the editors decided not to remove the disputed comment. This means that readers may be left with information which will essentially mislead them and could cast doubts on my professionalism and honesty.

I have therefore copied a response to criticisms made several years ago on a support site, written by a second author, a physician with many years' experience in relation to ME and CFS.

Charles Shepherd on the London Criteria (LC)

"To start with it’s worth noting that we wrote the LC at a time (1992/1993) when the term ME had almost been eradicated from the medical literature and researchers were being pressurised into only carrying out studies involving patients who met with one of the new CFS (or occasionally PVFS) research criteria (ie. 1991 Oxford; 1991 Behan et al for PVFS; 1990 Australian/Lloyd et al; or 1988 CDC/Holmes et al). But we still believed it was worth having a go at producing some criteria for pure ME which could be used for research purposes. The LC were also slightly modified and turned into clinical guidelines that were quite widely distributed at the time.

It’s also important to appreciate that we very much based the LC on Dr Melvin Ramsay’s clinical descriptions of ME. But just as Melvin Ramsay revised his description of ME (in 1988) from the type of very neurological presentations seen in the 1955 Royal Free outbreak (you don’t see ME patients presenting with cranial nerve palsies any more) we made some changes as well.

As far as research groups making use of the LC: the numbers are very low, partly because there’s been so little research carried out over the past ten years on pure ME. I see that some of the papers that have made use of the LC have already been pointed out here and on another list (these are no longer in existence, EMG) - if I have time I’ll do a comprehensive literature search to give a more complete list.

And as far as the PACE trial is concerned: as far as I know, none of us who produced the LC have been involved in any kind of lobbying for them to be used in PACE. The fact that they are going to be employed in the secondary analysis to select the ME patient group came as a complete surprise to me. But if you are going to start off by using Oxford to select a wide spectrum of chronic fatigue patients, and then see what happens to the ME sub-group, the use of the LC is obviously one way of doing it.

So the bottom line is that we did at least try to produce a research definition that would stimulate/maintain interest in looking at pure ME. I’m not claiming that the LC are perfect but I don’t understand why some people are being quite so unpleasant about what we did 10+ years ago when nobody else was willing to challenge the move towards all research being restricted to CFS."


NB. The LC have now been replaced with new criteria for ME and these HAVE been published in a peer reviewed publication. People wishing to know where to obtain a copy can google my name and CV, and this will lead them to the paper, and I believe, a link. I sincerely hope that they meet Ms. Kennedy's high linguistic standards.

EM Goudsmit PhD FBPsS

Competing interests

None declared

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PACE Trial Strata Criteria

Peter Kemp   (2010-05-12 10:04)  private email

PACE Trial Strata Criteria

The PACE Trial Identifier indicated an intention to stratify participants by treatment centre only. In the PACE Trail Protocol participants are stratified into those that meet Oxford, London or CDC criteria and these are also divided into those that have depression or not, creating 6 strata divided between four treatment arms (APT, GET, CBT, Secondary Care).

This reduced sample size in each strata/arm is susceptible to other problems due to the nature of the illnesses under study and the theories being tested. As the Wessely School have been at pains to point out over the years, fatigue and its resulting reduced activity can produce symptoms; some of which could match those required for different criteria. People at different stages of an illness may fit different strata. There may be participants who are prone to somatization and others with missed diagnoses (Reeves lost 20% of participants with the latter - http://www.biomedcentral.com/1741-7015/3/19).

There is a risk that the 3 proposed strata are arbitrary. As Professor White remarks: (Peter D White. How common is chronic fatigue syndrome; how long is a piece of string? Population Health Metrics 2007, 5:6doi:10.1186/1478-7954-5-6)

“If the disease in question has no biological marker and is difficult to define clinically, the problem of working out the accurate prevalence becomes esoteric.”

And: “Since fatigue is one of the most common symptoms reported by patients in general, delineating a specific syndrome with fatigue as a central feature risks arbitrary decisions about ascertainment.”

If CFS is “difficult to define clinically” and demands expertise why did the investigators choose the imprecise Oxford criteria for the PACE Trial? Perhaps there is a clue in the same paper mentioned above, where White wrote:

“But perhaps the most important conclusion is that there were about twice as many people in Georgia who were unwell with fatigue, who did not meet the criteria for CFS. Our current criteria for diagnosing CFS are arbitrary [16], and we need to widen the net to capture all those people who become so chronically tired and unwell that they can't live their lives to their full potential. The jobbing physician does not close the door on those who don't meet criteria.”

This may be true but the PACE Trial claims to be researching ME and CFS (as per the research title). One of the frequent criticisms of CFS research is the variety of criteria used. These shortcomings can make comparison and meta-analysis impossible and even leads to controversy over what illness the research was investigating. Many researchers have avoided this criticism by using the CDC criteria, which though it might have some weaknesses at least has some provenance and credibility.

The choice of the Oxford criteria undermines the comparability and generalisability of the research. I can only speculate as to why the London and CDC criteria were added in to the Protocol; but imagine the choice of the indiscriminate Oxford criteria in the first place contributed to this decision.

The additional two criteria may affect the generalisability of results because of the reduced strata size. Also, with more strata more volunteers are needed for the selection process to match numbers in each strata. With the well known difficulty of recruiting participants in research, uninformative or arbitrary strata are a bad idea.

Bechhofer and Paterson point out (2000. Principles of research design in the social sciences. Routledge), "Another problem in choosing strata is that you very quickly run out of enough people in your sample to fit into all the strata.", and, "The general point, however, is to stratify with respect to factors that you think are related to the main object of the study."

As the PACE Trial appears designed to investigate neurotic/phobic disorders, the criteria strata for physical symptoms are unrelated to the ‘main object of the study’ so are meaningless in this context.

The drawbacks of criteria strata in the PACE Trial could be irrelevant if all the participants actually have the same illness (and therefore all the strata produce correlated results); and this seems to be an assumption of the researchers: i.e., all the participants are experiencing somatization due to phobic/neurotic problems or deconditioning with varying degree and symptoms. If this were the case then stratifying participants by criteria could represent stratifying participants according to how strongly they express neurotic or phobic disturbances through physical symptoms. This may be novel but is hardly scientific as CFS research criteria were not designed for this purpose.

Generalisation could be impossible if some participants had an ongoing biomedical illness - such as neurological or autoimmune disease that has fatigue as a feature. If these patients were mixed with participants who have post viral fatigue, burnout, deconditioning, neurosis, phobia etc., then the stratifying criteria might combine various physical and psychological illnesses in an unpredictable manner.

In these circumstances generalisation would be impossible because the results would not be related to a specific disease or even a well defined syndrome. Unless the results show distinct non/efficacy for a large majority of participants with a certain treatment - it is likely to boil down to speculation about how and for whom a treatment works or fails. This is because of overlaps in the strata criteria and the apparent assumption that it is possible to divide somatization into meaningful groups using criteria not designed for this purpose.

Paul Meier, (Controlled Clinical Trials. Volume 1, Issue 4, May 1981), states:

“Stratification in the design of a clinical trial is often advanced as a method for greatly improving the precision of comparisons. It is argued here that stratification in design rarely achieves more than modest benefits in precision and that it exacts a heavy price in clumsiness and increased possibilities for error in the execution of a trial. Poststratification and covariance methods are important elements in analysis, but only limited stratification is justified in the design phase.”

Maybe the stratification by criteria in the PACE Trial is a compromise to ensure that White et al get to study participants who are simply fatigued and the other criteria were added as a sop to patients and doctors who believe M.E. and CFS are biomedical illnesses. If outcomes can be substantially related to the criteria strata this would be useful information. If the results are equivocal within the strata and cannot be related to other measures then they will at best raise more questions or at worst were a complete waste of time. These problems could have been avoided by simply using the CDC criteria at the outset.


Competing interests

None

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Risks of Participation in the PACE Trial

Peter Kemp   (2010-05-12 10:00)  Private email

The authors give mixed messages in the PACE Trial Protocol. On the one hand they claim:

“We will also carefully monitor all participants for any adverse effects of the treatments…”
(the results will) “provide evidence about the efficacy and adverse effects of the four treatments…”
“The individual treatment programmes used in PACE will minimise this risk by being mutually agreed between participant and therapist, carefully monitored and flexibly implemented…”

On the other hand they state:

“whereas the trial evidence suggests minimal or no risk with these treatments.”
“A risk assessment has been undertaken, and we have concluded that the therapies are of low risk to participants”

Why do the statements above appear to acknowledge risk whilst at the same time down-playing the issue?

From the documented theories and opinions of the investigators there appears to be an assumption that potential participants are somatizing or deconditioned and therefore not suffering from any physical disease that could result in injury from the trial treatments. As the therapies appear intended to address somatization to improve patient functioning it might seem counterproductive to exacerbate participant’s fearful state by telling them that participation involves risk.

However, adequate warning of foreseeable risks is requirement of research else participants cannot be said to have given Informed Consent. If foreseeable risks were ignored this would be in breach of the Declaration of Helsinki and other medical and research guidelines.

The CMO Working Group 2002, to which the authors refer states (http://tinyurl.com/56ek8d):

“All interventions need to be administered with thought and care and in accordance with revised Department of Health recommendations on informed consent…”

“Existing concerns from voluntary organisations and some clinicians include the view that patients have a primary disease process that is not responsive to or could progress with graded exercise, and that some individuals are already functioning at or very near maximum levels of activity...”

“Patient reports – Voluntary organisations, as well as the Sounding Board events, note that graded exercise therapy can be effective in some individuals, but substantial concerns exist regarding the potential for harm, particularly when such therapy is applied inflexibly or without mutual agreement with the patient. The non random survey of people who were severely affected found that out of 1214 who had tried graded exercise, 417 believed it was ‘helpful’, 187 reported ‘no change’, and 610 believed it had made their condition ‘worse’. Similar adverse comments were also reported in patient group survey results from less severely affected patients, and no other treatment – pharmacological or non-pharmacological - received such negative feedback in patient surveys.”

How were participants in the PACE Trial made aware of these risks?


Competing interests

None

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Post Exertional Malaise and Recovery from Exercise

Peter Kemp   (2010-05-12 09:55)  Private email

The Chief Medical Officer’s working group report states: “One of the most common and characteristic complaints of adults, particularly in the early stages of the illness, is of intolerance to both physical and mental exertion with delayed impact. So perhaps the key pointer to a diagnosis of CFS/ME is the way in which the symptoms behave after increased activity.”

All 3 of the strata criteria for the PACE Trial include fatigue and symptoms following activity and the CDC criteria specifies fatigue, ‘‘is not substantially alleviated by rest” and “post-exertional malaise lasting more than 24 hours”, the latter being one of the multi-choice factors. There appears to be no mention of the delayed affects of effort which mean that people with ME/CFS might still be experiencing worsening of symptoms hours later and often cannot repeat an exercise the following day.

The ME Association and The Young ME Sufferers Trust wrote (2008. http://tinyurl.com/yc63ome):

“When patients are made worse by GET (which is based on the flawed concept of deconditioning) this is not merely due to a problem with the way in which the therapy is delivered. Post-exertional malaise is a key diagnostic criterion for ME/CFS. Put simply, the illness worsens as a result of physical and mental effort. Advocating progressive exertion is to show a worrying lack of knowledge about the nature of the illness itself.”

The MEA’s view is supported by the research of Paul et al who tested delayed recovery from exercise in CFS. They concluded, “These findings support the clinical complaint of delayed recovery after exercise in patients with CFS.” (http://www.ncbi.nlm.nih.gov/pubmed/10209352)

Cort Johnson wrote about the Pacific Fatigue Lab findings when they had people with ME/CFS repeat an exercise test the following day (http://aboutmecfs.org/News/PRJan09Pacific.aspx):

“Their results are both profound and disturbing. About half of the ME/CFS patients they’ve tested do, in fact, ‘fail’ or significantly under perform in the first single exercise test – they cannot generate normal amounts of energy even when they’re ‘rested’. It’s the rest of the patients that are so intriguing, though. When you give these patients a second test a day later many of them will fail as well--and fail spectacularly.”

“The amount of impairment the Lab see’s can be astonishing - some patients suffer as much as a 50% drop in their ability to produce energy the next day. Ms. Stevens spoke of a twenty-something man whose next day exercise tests were worse that those of a normal 85 year old. In a hospital setting his cardiopulmonary exercise profile would suggest he had heart failure.”

Why is the PACE trial not studying the delayed effects of exertion which can be objectively measured and which seems to be quite specific to ME/CFS? This phenomenon might provide valuable insights into subgroups and the suitability of the therapies for particular patients according to how well they can recover from exercise.

Competing interests

No competing interests.

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New paper lists 3 CFS studies where there was no improvement in the actometer readings but an improvement was reported in subjective outcome measures

Tom Kindlon   (2010-05-12 09:53)  Irish ME/CFS Association - for Information, Support & Research email

I know it might perhaps have seemed to some who have read these posts that I might be concerned about something that was not important (when I was calling for actometers to be used if possible for at least some of the patients at the end of the trial). So I feel "vindicated" in a way by a review[1] that has just been published. It found that in the three Dutch CFS trials looked at, studies which all found improvements in fatigue[2-4], there was no statistically significant increase in physical activity levels as measured by actometers.

The review also found that "changes in physical activity were not related to changes in fatigue."

The authors of the review (who include people who were involved in all the studies) say that, in the three studies, "treatment was based on the manual of CBT for CFS described in detail by Bleijenberg et al. (2003)" [5]. This form of CBT is comparable to the form of CBT being assessed in the PACE Trial [6].

It is useful to point out that fatigue wasn't the only subjective outcome measure that was said to have improved (in these trials where there was no increase in physical activity).

In all of the three studies [2-4], improvements were reported in functional impairment (as measured by questionnaires). In two of the studies [2,3], improvements in physical functioning as measured by the SF-36 physical functioning subscale were reported (this questionnaire does was not used in the third study[4]). So the patients reported improvements in "physical functioning" (as measured by the SF-36 physical functioning subscale) but there was no improvement in physical activity as measured by the actometers. The SF-36 physical functioning subscale is one of the primary outcome measures in the PACE Trial[6].

This discrepancy between objective measures of activity and questionnaire is similar to data I have previously drawn attention to[7] in a study by Friedberg and Sohl[8].

References:

[1] 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 Jan 5:1 -7. [Epub ahead of print]

[2] Stulemeijer M, de Jong LW, Fiselier TJ, Hoogveld SW, Bleijenberg G (2005). Cognitive behaviour therapy for adolescents with chronic fatigue syndrome: randomised controlled trial. British Medical Journal 330. Published online : 7 December 2004. doi:10.1136/bmj.38301.587106.63.

[3] Knoop H, van der Meer JW, Bleijenberg G (2008). Guided self-instructions for people with chronic fatigue syndrome: randomised controlled trial. British Journal of Psychiatry 193, 340–341.

[4] Prins JB, Bleijenberg G, Bazelmans E, Elving LD, de Boo TM, Severens JL, van der Wilt GJ, Spinhoven P, van der Meer JW (2001). Cognitive behaviour therapy for chronic fatigue syndrome: a multicentre randomised controlled trial. Lancet 357, 841–847.

[5] Bleijenberg G, Prins JB, Bazelmans E (2003). Cognitive-behavioral therapies. In Handbook of Chronic Fatigue Syndrome (ed. L. A. Jason, P. A. Fennell and R. R. Taylor), pp. 493–526. Wiley: New York.

[6] White PD, Sharpe MC,Chalder T, DeCesare JC and Walwyn R for the PACE trial group. Protocol for the PACE trial: A randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurology 2007, 7:6

[7] Kindlon T. Further evidence showing why objective measures are preferable in CFS trials particularly where cognitions could be changed following the intervention http://www.biomedcentral.com/1471-2377/7/6/comments#333618

[8] Friedberg F, Sohl S. Cognitive-behavior therapy in chronic fatigue syndrome: is improvement related to increased physical activity? J Clin Psychol. 2009 Feb 11.

Competing interests

No competing interests

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Discrepancies between momentary fatigue and recalled fatigue can exist

Tom Kindlon   (2009-07-01 14:31)  Irish ME/CFS Association - for Information, Support & Research email

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".

But is it recalled fatigue, or the memory for fatigue, exactly equal to the fatigue people actually felt during a period?

Friedberg and Sohl have investigated this using electronic diaries[2]. Here is a description of what was involved:
"In order to obtain a representative diurnal sample of symptoms without undue subject burden (Stone & Shiffman, 2002), the palm pilots prompted subjects for 21 days, 6 times a day, every 2 hr plus or minus a randomly programmed 1-20 min interval (Stone & Shiffman, 1994). The first daily prompt occurred within 1 hr of the subject's wakening and the last daily prompt approximately 12 hr later. No prompt signals occurred during the subject's reported sleep time. After each prompt, a screen was displayed with a numerical rating scale (0-10) that was labeled "Fatigue Now." The end point anchors on the numerical scales were None (0) and Highest (10). Subjects were instructed to record intensity ratings on the numerical scale for their current levels of fatigue."

What they found was "average weekly recall of fatigue intensity was significantly higher than average momentary ratings" (8.5% higher on average). If one used a scale like the Chalder Fatigue Scale[1] which asked for a period of over the preceding month, one could speculate that the discrepancy would be even higher.

This suggests that self-report fatigue questionnaires may not be ideal for intervention studies particularly in expensive trials like this one where one might be willing to pay a bit extra for greater accuracy; just as it has been shown that self-report questionnaires may not correlate strongly with more objective measures of activity (such as actometers)[3,4] (of course, in this study, the reason actometers are not being used does not seem to be due to the cost of obtaining them or the need to train participants to use them, as baseline measurements from actometers are being used).

References:

[1] Chalder T, Berelowitz G, Hirsch S, Pawlikowska T, Wallace P, Wessely S, Wright D: Development of a fatigue scale. J Psychosom Res 1993, 37:147-153.

[2] Friedberg F, Sohl SJ. Memory for fatigue in chronic fatigue syndrome: the relation between weekly recall and momentary ratings. Int J Behav Med. 2008 Jan-Mar;15(1):29-33.

[3] Friedberg F, Sohl S. Cognitive-behavior therapy in chronic fatigue syndrome: is improvement related to increased physical activity? J Clin Psychol. 2009 Feb 11.

[4] Vercoulen JH, Bazelmans E, Swanink CM, Fennis JF, Galama JM, Jongen PJ, Hommes O, Van der Meer JW, Bleijenberg G. Physical activity in chronic fatigue syndrome: assessment and its role in fatigue. J Psychiatr Res. 1997 Nov-Dec;31(6):661-73.

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Further evidence showing why objective measures are preferable in CFS trials particularly where cognitions could be changed following the intervention

Tom Kindlon   (2009-03-06 21:15)  Irish ME/CFS Association - for Information, Support & Research email

Since writing my previous posts, further data on the subject has come to my attention.

Friedberg and Sohl [1] have just published the results of a study on an intervention involving Cognitive Behavior Therapy (CBT) which included encouraging patients for going for longer walks. It found that on the SF-36 Physical Functioning (PF) scale, patients improved from a pre-treatment mean (SD) of 49.44 (25.19) to 58.18 (26.48) post-treatment, equivalent to a Cohen's d value of 0.35. On the Fatigue Severity Scale (FSS), the improvement as measured by the cohen's d value was even great (0.78) from an initial pre-treatment mean (SD) of 5.93 (0.93) to a 5.20 (0.95) post-treatment.

However on actigraphy there was actually a numerical decrease from a pre-treatment mean (SD) of 224696.90 (158389.64) to 203916.67 (122585.92) post-treatment (cohen's d: -0.13). So just because patients report lower fatigue and better scores on the SF-36 PF scale, doesn't mean they're doing more, which is what GET and CBT based on GET claim to bring about. These results seem particularly pertinent for this study given the primary outcome measures are the SF-36 PF scale and a fatigue scale.

Further reading show that another study[2], published over a decade ago, showed the problem of using self-report data in CFS patients. The authors' rationale for the study was: "It is not clear whether subjective accounts of physical activity level adequately reflect the actual level of physical activity. Therefore the primary aims of the present study were to assess actual activity level in patients with CFS to validate claims of lower levels of physical activity and to validate the reported relationship between fatigue and activity level that was found on self-report questionnaires. In addition, we evaluated whether physical activity level adequately can be assessed by self-report measures. An Accelerometer was used as a reference for actual level of physical activity.". The authors reported on the correlations on 7 outcome measures in relation to the actometer readings: "none of the self-report questionnaires had strong correlations with the Actometer. Thus, self-report questionnaires are no perfect parallel tests for the Actometer."

Prof. White seems to be aware of the findings of this study as he has been co-authored at least two papers [3,4] which quoted the findings. One of the times this paper was referenced even shows the problem I'm highlighting e.g. "support for this explanation comes from investigations that have described discrepancies between subjectively reported impairments and objective measures of activity" [4].

The authors of the 1997 study[2] pointed out that "The subjective instruments do not measure actual behaviour. Responses on these instruments appear to be an expression of the patients' views about activity and may be biased by cognitions concerning illness and disability." This was re-iterated in another paper[5]: "In earlier studies of our research group, actual motor activity has been recorded with an ankle-worn motion-sensing device (actometer) in conjunction with self-report measures of physical activity. The data of these studies suggest that self-report measures of activity reflect the patients' view about their physical activity and may have been biased by cognitions concerning illness and disability."

A corollary of the last statement is that reports of improvement in self-report measures in interventions which change "cognitions concerning illness and disability" may not be reliable. "Improvements" in self-report measures may simply show that patients have changed their cognitions with regard to how they view their illness, disability, symptoms, etc rather than actually representing improvements in activity levels and functional capacity.

Thus, I would suggest that actometers should be used whenever possible in CFS trials where one is investigating whether an intervention has brought about increased activity.

It is also interesting to note that in the large Van der Werf (2000) study[5], which involved 277 CFS patients (and 47 healthy controls), the authors divided the patients up "pervasively passive" (representing 24% of the patients), "moderately active" and "pervasively active". They found that "levels of daily experienced fatigue and psychological distress were equal for the three types of activity patterns". So one can't necessarily tell how active a patient is from the fatigue levels they report.

Incidentally they also "there were no significant group, gender or interaction effects for the number of absolute large or relatively large day-to-day fluctuations (Table 2 and Table 3)." "The day-to-day fluctuation measures were based on somewhat arbitrary criteria (1 S.D. and 33% activity change). However, when we post hoc tested alternative criteria (50% or 66% activity change), again no significant group differences between controls and CFS patients emerged." Part of the rationale of many behavioural interventions in CFS patients is said to be to reduce "boom and bust" (sample reference,[6]). However, it may be the case that the frequency of this activity pattern in CFS has been exaggerated.

Tom Kindlon



[1] Friedberg F, Sohl S. Cognitive-behavior therapy in chronic fatigue syndrome: is improvement related to increased physical activity? J Clin Psychol. 2009 Feb 11.

[2] Vercoulen JH, Bazelmans E, Swanink CM, Fennis JF, Galama JM, Jongen PJ, Hommes O, Van der Meer JW, Bleijenberg G. Physical activity in chronic fatigue syndrome: assessment and its role in fatigue. J Psychiatr Res. 1997 Nov-Dec;31(6):661-73.

[3] Fulcher KY, White PD. Strength and physiological response to exercise in patients with chronic fatigue syndrome. J Neurol Neurosurg Psychiatry. 2000 September; 69(3): 302–307.

[4] Smith WR, White PD, Buchwald D. A case control study of premorbid and currently reported physical activity levels in chronic fatigue syndrome. BMC Psychiatry. 2006 Nov 13;6:53.

[5] van der Werf SP, Prins JB, Vercoulen JH, van der Meer JW, Bleijenberg G. Identifying physical activity patterns in chronic fatigue syndrome using actigraphic assessment. J Psychosom Res. 2000 Nov;49(5):373-9.

[6] Deary V, Chalder T: Chapter 11, "Conceptualisation in Chronic Fatigue Syndrome" in Formulation and Treatment in Clinical Health Psychology Edited by Ana V. Nikcevic, Andrzej R. Kuczmierczyk, Michael Bruch

Competing interests

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Problematic definition of 'fibromyalgia'

Dan Horovitz   (2009-03-06 21:08)  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.

The protocol states that trial participants will be assessed for the 'Presence or absence of fibromyalgia' using 'chronic widespread pain criteria only and not tender points', citing The American College of Rheumatology 1990 Criteria[1] to support this assessment. The American College, however, require the presence of tender points for a diagnosis of fibromyalgia to be made. Therefore, what is described as 'fibromyalgia' in the protocol is not fibromyalgia as described by The American College of Rheumatology, but the proximate citation of their diagnostic criteria may lead a reader to believe that it is.

The protocol also states that the 'Presence or absence of "fibromyalgia"' is considered to be a predictor of outcome, and again cites the American College report. It is noteworthy that this time, fibromyalgia appears in inverted commas, suggesting the authors are aware of the problem described above.

The use of the term 'fibromyalgia', in conjunction with the repeated proximate citation of the American College report, implies participants have been assessed for fibromyalgia using widely accepted criteria, when in fact, they have been assessed only for the presence of chronic widespread pain. I hope the authors will clarify this when the results of the trial are published.

[1] Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, al. : The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee.

Arthritis Rheum 1990,33:160-172.

www.biomedcentral.com/pubmed/2306288

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No competing interests

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Does housework count as exercise for somebody in the GET leg of the trial?

Tom Kindlon   (2009-03-06 21:04)  Irish ME/CFS Association - for Information, Support & Research email

I wonder could the authors answer a question which is relevant to the real world application of Graded Exercise Therapy (GET).

I have heard a participant in the Graded Exercise Therapy (GET) leg of the trial say that they are counting 10 minutes housework in lieu of a 10-minute walk. I think it would be very useful for the authors to clarify whether they think x minutes housework can be used in lieu of x minutes of walking or whether this is not in compliance with the protocol?

I think attention to detail in this matter is very important if one is to apply the findings in the real world. With a drug it is easy to check whether the dosage is the same as published trials. With Graded Exercise Therapy (GET), we need clarification from the authors about what is meant by exercise, so that the protocol can be applied as in the trial, so that people either don't get too low a "dose" or too high a "dose" at the wrong stage.

Competing interests

No competing interests

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The dropping of actometers as an outcome measure and other points relating to the outcome measures being used

Tom Kindlon   (2008-10-22 14:34)  Irish ME/CFS Association - for Information, Support & Research email

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

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Further information on existing data on management strategies for CFS

Tom Kindlon   (2008-10-01 17:18)  Irish ME/CFS Association - for Information, Support & Research email

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

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Some problems with the 'London Criteria'

Angela Kennedy   (2008-10-01 17:17)  Social Sciences Lecturer and Researcher email

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.

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Misinformation in comments on the PACE trial

Ellen Goudsmit   (2008-08-29 11:20)  UEL email

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.

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Response to comments on “Protocol for the PACE trial”

Peter White   (2008-07-28 12:24)  Barts and the London Medical School, London, UK email

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.

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Problems in the PACE Trial

Angela Kennedy   (2007-11-13 17:44)  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.

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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   (2007-11-13 17:24)  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

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CFS intervention studies - lessons can be learned from a previous review

Tom Kindlon   (2007-08-30 17:28)  Irish ME/CFS Support Group email

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

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Another example as to why objective measures would be useful

Tom Kindlon   (2007-08-30 08:05)  Irish ME/CFS Support Group email

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

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Would it not be preferable if objective outcome measures were used?

Tom Kindlon   (2007-05-23 17:00)  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

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