CFS - PACE trial objective data enable comparison with patients own objective data

Gwrthodwyd y cais gan Queen Mary University of London.

Kathryn Dickenson

Dear Queen Mary, University of London,

I am writing to request the release of the objective physiological and physical data, collected during the PACE trial, and at follow up. This data was collected according to the procedures detailed in the PACE trial manual and the trial protocol published in the BMC in 2007 and follow up papers.

It is appropriate to release this data since, the State, and taxpayers, ultimately fund clinical research for the benefit of patients, so it’s important patients are provided with accurate, reliable information on the effectiveness of any proclaimed treatments.

This is particularly imperative in cases such as the PACE trial, where the beliefs and claims made by the authors, their colleagues and the insurance industry appear to be at odds, with the patient experience of living with the disease, biomedical research findings, physiological findings and those of CFS clinicians based outside the mental health field.

There is no evidence that the disclosure of the trial’s objective raw data will prejudice to QMUL’s research programme, reputation, or funding streams. In the contrary, it could be claimed, that the non-release of the data, may look like an attempt to hide scientific findings from scrutinty and be harmful to the universities reputation.
I request this data so that myself and other independent researchers may determine the effect of PACE-style GET, CBT, APT and SMC on reducing physiological/physical dysfunction in patients with CFS.

I request, that the data is provided in a manner that enables me to distinguish between data from patients with CFS and those with mental health disorders, since these 3 patient cohorts were included in the PACE trial:
(i) Patients diagnosed with CFS and no mental health disorders
(ii) Patients diagnosed with psychiatric disorder
(iii) Patients diagnosed with depressive disorder

This separation of patient streams is necessary as the mixing of patients diagnosed with psychiatric and depressive disorders and “pure” CFS patients, may severely affect the results and compromise the conclusions. Other, authors have found that CFS and mental health disorders respond very differently and in opposite directions to exertion and exercise and in fact this difference may be used, in part, to distinguish between the disease CFS and mental health disorders [1]. In addition, the recent Centre for Disease Control multi-site clinical study, found severe physiological and biological abnormalities in patients with CF, yet these very ill patients had good mental and emotional health [2].

QMUL is aware that the objective raw data, may be anonymised to the extent that the risk of identification is remote. The release of some of the subjective PACE trial raw data and the raw data from PACE’s sister trial, the FINE trial has not led to the identification of any patient/s.

In contrast to the subjective observations favoured by the PACE authors, patients are documenting objective improvements in their health and the release of the objective data will enable them to compare their progress using other management techniques such as flexible pacing and pacing assisted by a heart rate monitor to the PACE trial findings.
Patients appear to be benefiting from findings of the Workwell Foundation [3], the International Consensus Criteria [4] and exercise physiological principles used for other categories of severely ill patients, such as those with congestive heart disease. These ideas are largely consistent with the ideas of the UK CFS doctors achieving positive outcomes such as Dr. Nigel Speight, Dr. Sarah Myhill, Dr. Peter Smith.

Ironically one of the PACE authors Peter White, published a paper on the successful use of a physiologically based exercise program in 1997 [5]. It is not clear why physiologically guided programs were dropped. Replacement of physiologically based programs, with uncontrolled programs where CFS patients are told to ignore their symptoms, and exercise despite worsening health appears to have been detrimental to CFS patients. Patients report worsening of health and unsustainable increases in activity that lead to a severe worsening of health, on these programs.

Many patients are now wearing continuous heart rate monitors and are identifying and quantifying severely abnormal heart rate drops and rises, in response to everyday activities. Many patients find that they need to REDUCE their activity levels, in the first instance to enable sustainable health improvements in the longer term.

The release of the objective data from the 5 million pound PACE trial will enable independent researchers and patients to compare their own findings and data with that measures during the trial.

In order to ease the burden of staff and not requiring them to do any calculations themselves once the relevant data is located and retrieved. I would like to request the data on the following selection of assessments, as detailed in the published protocol [6] and the PACE, GET manual version 7, MREC Version 2; 16/11/04 [7].

I seek the data for all 640 individual PACE Trial participants, for which the requested data exists, in a spreadsheet or equivalent file with separate columns for each variable/descriptor and the three clinical groups of patients as described above be provided separately.

MEASURE
Actometer results (BMC reference 18)
VO2 max (manual page 40)
TUAG (timed up and go. Chair-stand-walk 3 metres-turn- walk back -sit down (manual page 88)
Sit-stand test (count number in one minute – manual page 88))
2-minute walk (manual page 88)
6 minute walk objective measure of recovery (BMC reference 31)
Self-paced step. Test of fitness (BMC reference 43)
Exercise and activity scale (BMC reference 36)
For each physiological measure I require, The time, End heart rate and Borg measure. (Borg Scale of perceived physical exertion [BMC reference 44], is used to measure effort with exercise.)
I request, the information for each of the time periods, that the PACE authors specified they would collect, objective measurements of physical functioning, as follows:
Baseline (PACE manual)
After randomisation (BMC)
10 weeks
12 weeks (authors response to review)
Mid assessment (PACE manual)
24 weeks
Final assessment (PACE manual)
39 weeks
One year follow up
2.5 year follow up

I look forward to your response.

Yours faithfully,

Kathryn Dickenson

[1] Eleanor Stein Assessment and Treatment of Patients with ME/CFS: Clinical Guidelines for Psychiatrists.http://sacfs.asn.au/download/guidelines_...
[2] Multi-Site Clinical Assessment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (MCAM): Design and Implementation of a Prospective/Retrospective Rolling Cohort Study. Unger ER, Lin JS, Tian H, Natelson BH, Lange G, Vu D, Blate M, Klimas NG, Balbin EG, Bateman L, Allen A, Lapp CW, Springs W, Kogelnik AM, Phan CC, Danver J, Podell RN, Fitzpatrick T, Peterson DL, Gottschalk CG, Rajeevan MS; MCAM Study Group. Am J Epidemiol. 2017 Apr 15;185(8):617-626. doi: 10.1093/aje/kwx029.
[3] Conceptual model for physical therapist management of chronic fatigue syndrome/myalgic encephalomyelitis. Davenport TE1, Stevens SR, VanNess MJ, Snell CR, Little T. Phys Ther. 2010 Apr;90(4):602-14. doi: 10.2522/ptj.20090047. Epub 2010 Feb 25.
http://www.workwellfoundation.org/resear...

[4] Myalgic encephalomyelitis: International Consensus Criteria
Authors B. M. Carruthers, M. I. van de Sande, et al Journal of Internal Medicine
First published: 22 August 2011 DOI: 10.1111/j.1365-2796.2011.02428.x
http://www.investinme.org/Documents/Guid...

[5] Physiotherapy. Graded Exercise Therapy for Chronic Fatigue Syndrome
Dr Peter D White Vanessa AB Naish2 DOI: http://dx.doi.org/10.1016/S0031-9406(05)...
[6] GET manual version 7, MREC Version 2; 16/11/04 – pages 40- 88
[7] BMC Neurology Study protocol Open Access 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*1, Michael C Sharpe2, Trudie Chalder3, Julia C DeCesare4, Rebecca Walwyn5 and the PACE trial group. BMC Neurology2007 DOI: 10.1186/1471-2377-7-6 © White et al; licensee BioMed Central Ltd. 200 Received: 30 October 2006 Accepted: 08 March 2007 Published: 08 March 2007
[8] Author's response to reviews Title: 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 Authors: Peter D White, Michael C Sharpe, Trudie Chalder ) =Julia C DeCesare, Rebecca Walwyn Version: 2 Date: 24 January 2007 Author's response to reviews: see over
Outcome will be assessed at 12, 24, and 52 weeks after randomisation. Two primary outcomes of self rated fatigue and physical function will assess differential effects of each treatment on these measures. Secondary outcomes include …..objective measures of physical activity, fitness.
https://static-content.springer.com/open...

Yours faithfully,

Kathryn Dickenson

QM FOI Enquiries, Queen Mary University of London

We acknowledge receipt of your request and will respond as soon as we can.

Gadawodd Kathryn Dickenson anodiad ()

http://www.bmj.com/content/350/bmj.h227/...
BMJ 2015; 350 doi: https://doi.org/10.1136/bmj.h227 (Published 14 January 2015)

Cite this as: BMJ 2015;350:h227
Tom Kinlon

Tackling fears about exercise is important for ME treatment, analysis indicates. Objective measures found a lack of improvement for CBT & GET in the PACE Trial: subjective improvements may simply represent response biases or placebo effects in this non-blinded trial

This BMJ article and a flurry of articles in the lay media this week followed the publication in Lancet Psychiatry of an analysis of the mediators of change in the important PACE Trial, a chronic fatigue syndrome (CFS) trial which cost UK taxpayers £5 million[1,2]. What seems to have been lost in the coverage is that, although there were some modest improvements in the self-report measures, there was an almost complete absence of improvements in objectively measured outcomes for cognitive behavioural therapy (CBT) and graded exercise therapy (GET) compared to the control group (specialist medical care only (SMC)).

This is a non-blinded trial, where participants were told CBT and GET had previously been found to be effective in CFS and other conditions[3,4]: one way to look at the mediation results for subjective measures when there was a lack of objective improvements is that they may merely tell us how response biases and/or placebo effects are mediated[5].

The focus on subjective measures in some CFS studies was previously criticised in a systematic review published back in 2001 (long before the PACE Trial started)[6]. They suggested instead "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."

The model presented for cognitive behaviour therapy (CBT) in the PACE Trial manuals posits that the impairments and symptoms are reversible with the therapy[3,7]. However, the latest paper shows that fitness, as measured by a step test, didn't improve following CBT[2]. An earlier PACE Trial publication reported that the addition of CBT to SMC did not result in an improvement in 6-minute walking test scores compared to SMC alone[8].

The PACE Trial was part funded by the UK Department of Work and Pensions, a rare move for them, presumably done due to an expectation that the therapies would improve measures of employment and levels of benefit receipt. However, again CBT brought about no improvement using objective measures, such as days of employment lost, levels of disability benefits received and levels of receipt of insurance payments[9].

These results are in line with earlier studies of CBT. For example, an analysis of three randomized controlled trials of CBT interventions for CFS found no improvement in objectively measured activity, despite participants reporting a reduction in (self-reported) fatigue and (sometimes) functional impairments[10]. Similar results were found in another uncontrolled trial where changes in objectively measured activity did not predict fatigue levels, and objectively measured activity on completion remained low compared to population norms[11]. An uncontrolled study found improvements in self-reported physical functioning and fatigue were reported despite a numerical decrease in (objectively measured) activity[12]. In another study, the level of self-reported cognitive impairment in CFS patients decreased significantly after CBT, however, cognition had not improved when it was measured objectively using neuropsychological test performance[13].

It is unsurprising that 15 sessions of CBT (and the associated homework exercises and management program) might alter how participants respond to self-report questionnaires. A PACE Trial manual itself says "the essence of CBT is helping the participant to change their interpretation of symptoms": this could lead to altered or biased fatigue scores, one of the two primary outcome measures[14]. Also, one of the aims of CBT (for CFS) has been said to be "increased confidence in exercise and physical activity"[15]. The possible responses for the other primary outcome measure, the SF-36 physical functioning subscale, are "yes, limited a lot", "yes, limited a little" and "no, not limited at all" to questions on a range of physical activities. Such responses could be easily be artificially altered following a therapy like CBT for CFS.

The results were not that different with the GET cohort in the PACE Trial. Again the manuals predicted that the impairments and symptoms are reversible using the intervention[4,15]. The model said there was no reason participants should not be able to get back to full functioning. Deconditioning was posited to be an important maintaining factor. However, GET did not result in an improvement in fitness, as measured by the step test. GET did result in a small improvement on the six minute walking test to a final distance of 379 metres, or 35 metres more than the SMC-only group[7]. However, as Knoop and Wiborg commented in an accompanying editorial in Lancet Psychiatry: "an increase in distance walked during a test situation without an increased fitness suggests that patients walk more because of a change in cognitive processes (eg, daring to do more or an increased self-efficacy with respect to activity), not because of a change in physiological capacity”[16]. The result remained very poor given that normative data would suggest a group of similar age and gender should walk an average of 644 or so metres[17]. The distance walked remained comparable to people with many serious conditions[18-21], and considerably worse than the distance walked by healthy elderly adults[22,23], despite the PACE trial cohort having a mean age of only 40[8]. Also, to be allowed entry into CFS research studies such as the PACE Trial one can not have a range of chronic illnesses so with genuine recovery one would expect results comparable to healthy people[8].

As with CBT, measures relating to employment showed no improvement following GET in days of work missed, which remained very high, nor a reduction in levels of benefits (financial support from the state) or payments from insurance companies[9].

These results are in line with an audit of Belgian rehabilitation centres for CFS offering CBT and GET[24-26]. Some improvements in subjective measures were found, but there was no improvement in the results of the exercise test and hours in employment actually decreased.

Probably the main contribution of the PACE Trial has been to add to a growing body of evidence that while CBT and GET for CFS have resulted in some changes on subjective measures, they haven't lead to improvements on objective measures.

References:

1. Torjesen I. Tackling fears about exercise is important for ME treatment, analysis indicates. BMJ 2015;350:h227 http://www.bmj.com/content/350/bmj.h227

2. Chalder T, Goldsmith KA, White PD, Sharpe M, Pickles AR. Rehabilitative therapies for chronic fatigue syndrome: a secondary mediation analysis of the PACE trial. Lancet Psychiatry 14 Jan 2015, doi:10.1016/S2215-0366(14)00069-8.

3. Burgess M, Chalder T. Manual for Participants. Cognitive behaviour therapy for CFS/ME.http://www.pacetrial.org/docs/cbt-partic... (accessed: January 17, 2015)

4. Bavinton J, Darbishire L, White PD -on behalf of the PACE trial management group. Graded Exercise Therapy for CFS/ME. Information for Participants http://www.pacetrial.org/docs/get-partic... (accessed: January 17, 2015)

5. Wechsler ME, Kelley JM, Boyd IO, Dutile S, Marigowda G, Kirsch I, Israel E, Kaptchuk TJ. Active albuterol or placebo, sham acupuncture, or no intervention in asthma. N Engl J Med. 2011;365(2):119-26.

6. Whiting P, Bagnall AM, Sowden AJ, Cornell JE, Mulrow CD, Ramírez G. Interventions for the treatment and management of chronic fatigue syndrome: a systematic review. JAMA. 2001 Sep 19;286(11):1360-8.

7. Burgess M, Chalder T. PACE manual for therapists. Cognitive behaviour therapy for CFS/ME.http://www.pacetrial.org/docs/cbt-therap... (accessed: January 17, 2015)

8. White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, et al, for the PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet 2011;377:823-36.

9. McCrone P, Sharpe M, Chalder T, Knapp M, Johnson AL, Goldsmith KA, White PD. Adaptive pacing, cognitive behaviour therapy, graded exercise, and specialist medical care for chronic fatigue syndrome: a cost-effectiveness analysis. PLoS One. 2012;7(8):e40808. doi: 10.1371/journal.pone.0040808

10. 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 Aug;40(8):1281-7. doi: 10.1017/S0033291709992212. Epub 2010 Jan 5.

11. Heins MJ, Knoop H, Burk WJ, Bleijenberg G. The process of cognitive behaviour therapy for chronic fatigue syndrome: which changes in perpetuating cognitions and behaviour are related to a reduction in fatigue? J Psychosom Res. 2013 Sep;75(3):235-41. doi: 10.1016/j.jpsychores.2013.06.034. Epub 2013 Jul 19.

12. Friedberg F, Sohl S. Cognitive-behavior therapy in chronic fatigue syndrome: is improvement related to increased physical activity? J Clin Psychol. 2009 Apr;65(4):423-42. doi: 10.1002/jclp.20551.

13. 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.

14. Bavinton J, Darbishire L, White PD -on behalf of the PACE trial management group. Graded Exercise Therapy for CFS/ME (Therapist manual): http://www.pacetrial.org/docs/get-therap... (accessed: January 17, 2015)

15. O'Dowd H, Gladwell P, Rogers CA, Hollinghurst S, 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.

16. Knoop H, Wiborg JF. What makes a difference in chronic fatigue syndrome? Lancet Psychiatry 13 Jan 2015 DOI: http://dx.doi.org/10.1016/S2215-0366(14)...

17. Kindlon T. Reporting of Harms Associated with Graded Exercise Therapy and Cognitive Behavioural Therapy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Bulletin of the IACFS/ME. 2011;19(2):59-111http://iacfsme.org/BULLETINFALL2011/Fall......

18. Lipkin DP, Scriven AJ, Crake T, Poole-Wilson PA. Six minute walking test for assessing exercise capacity in chronic heart failure. Br Med J (Clin Res Ed) 1986. 292:653–655.
http://www.ncbi.nlm.nih.gov/pmc/articles......

19. Marin JM, Carrizo SJ, Gascon M, Sanchez A, Gallego B, Celli BR. Inspiratory Capacity, Dynamic Hyperinflation, Breathlessness, and Exercise Performance during the 6-Minute-Walk Test in Chronic Obstructive Pulmonary Disease. Am. J. Respir. Crit. Care Med. 2001 63(6):1395-1399.http://171.66.122.149/content/163/6/1395...

20. Goldman MD, Marrie RA, Cohen JA. Evaluation of the six-minute walk in multiple sclerosis subjects and healthy controls. Multiple Sclerosis 2008. 14(3):383-390.
http://pocketknowledge.tc.columbia.edu/h... six-minute walk test.pdf

21. Ross RM, Murthy JN, Wollak ID, Jackson AS. The six minute walk test accurately estimates mean peak oxygen uptake. BMC Pulm Med. 2010 May 26;10:31. PMID 20504351.http://www.biomedcentral.com/1471-2466/1...

22. Camarri B, Eastwood PR, Cecins NM, Thompson PJ, Jenkins S. Six minute walk distance in healthy subjects aged 55–75 years. Respir Med. 2006. 100:658-65
http://www.resmedjournal.com/article/S09...

23. Troosters T, Gosselink R, Decramer M. Six minute walking distance in healthy elderly subjects. Eur Respir J. 1999. 14:270-4. http://www.ersj.org.uk/content/14/2/270....

24. Rapport d'évaluation (2002-2004) portant sur l'exécution des conventions de rééducation entre le Comité de l'assurance soins de santé (institué auprès de l'Institut national d'assurance maladie invalidité) et les Centres de référence pour le Syndrome de fatigue chronique (SFC), Bruxelles, juillet 2006. (French language edition)

25. Evaluatierapport (2002-2004) met betrekking tot de uitvoering van de revalidatieovereenkomsten tussen het Comité van de verzekering voor geneeskundige verzorging (ingesteld bij het Rijksinstituut voor Ziekte- en invaliditeitsverzekering) en de Referentiecentra voor het Chronisch vermoeidheidssyndroom (CVS). 2006. Available online:https://drive.google.com/file/d/0BxnVj9Z... (accessed: January 17, 2015) (Dutch language version)

26. Stordeur S, Thiry N, Eyssen M. Chronisch Vermoeidheidssyndroom: diagnose, behandeling en zorgorganisatie. Health Services Research (HSR). Brussel: Federaal Kenniscentrum voor de Gezondheidszorg (KCE); 2008. KCE reports 88A (D/2008/10.273/58)https://kce.fgov.be/sites/default/files/... (accessed: January 17, 2015)

Competing interests: I am a committee member of the Irish ME/CFS Association and perform various types of voluntary work for the Association.

Gadawodd Kathryn Dickenson anodiad ()

http://journals.sagepub.com/doi/full/10....

PACE trial claims for recovery in myalgic encephalomyelitis/chronic fatigue syndrome – true or false?

It’s time for an independent review of the methodology and results
Charles Bernard Shepherd
First Published April 9, 2017

PACE trial claims for recovery in myalgic encephalomyelitis/chronic fatigue syndrome ; true or false? It's time for an independent review of the methodology and results

The PACE trial set out to discover whether cognitive behaviour therapy and graded exercise therapy are safe and effective forms of treatment for myalgic encephalomyelitis/chronic fatigue syndrome. It concluded that these interventions could even result in recovery.

However, patient evidence has repeatedly found that cognitive behaviour therapy is ineffective and graded exercise therapy can make the condition worse. The PACE trial methodology has been heavily criticised by clinicians, academics and patients. A re-analysis of the data has cast serious doubts on the recovery rates being claimed. The trust of patients has been lost. The medical profession must start listening to people with myalgic encephalomyelitis/chronic fatigue syndrome if trust is going to be restored.

Keywords activity, behavioural medicine, chronic fatigue syndrome, cognitive behaviour therapy, dissatisfaction, efficacy, exercise, graded exercise therapy
Keith Geraghty’s (2016) editorial has identified and discussed most of the key reasons why both the PACE trial methodology and the results are not regarded as reliable.

PACE – an acronym for Pacing, graded Activity, and Cognitive behaviour therapy, a randomised Evaluation – compared the effectiveness of four separate inteventions: specialist medical care (SMC) to SMC plus adaptive pacing therapy, cognitive behaviour therapy and graded exercise therapy in patients with myalgic encephalomyelitis/chronic fatigue syndrome. However, those involved in the PACE trial have responded by stating that these criticisms are based on misunderstandings and misrepresentations (White, 2017).

I would like to use this commentary to examine controversies surrounding how two of the PACE trial interventions – cognitive behaviour therapy (CBT) and graded exercise therapy (GET) – originated, why the PACE trial was bound to run into difficulties, and why the patient community is so at odds with the medical establishment over their promotion of CBT and GET.

As a physician who has spent much of the past 35 years helping patients with myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS), I have a strong desire to find safe, acceptable and effective forms of treatment that are aimed at the underlying disease process – rather than just trying to relieve some of the key symptoms. The same position is taken by most ME/CFS patients.

However, uncertainties and disagreements among doctors and patients as to how we should name, define and diagnose this illness, what causes it and how it should be managed make this a very challenging task.

The failure to accept that ME/CFS is a very heterogeneous condition in both clinical presentations and underlying disease mechanisms has meant that the two ‘rehabilitative’ approaches to management – CBT and GET – which were assessed in the PACE trial have become the only forms of treatment for ME/CFS recommended by NICE (National Institute for Health and Clinical Excellence, 2011). At the same time, CBT and GET are consistently rejected by a substantial proportion of people with ME/CFS for being either ineffective (in the case of CBT) or harmful (in the case of GET).

This conflict over the management of ME/CFS largely dates back to a decision taken in the 1980s to rename and redefine what had previously been known as ME as CFS. By relaxing the diagnostic criteria, CFS brought in a much wider group of people who had some form of undiagnosed chronic fatigue that, in some cases, primarily involved psychological or psychiatric factors.

Based on a new and seriously flawed hypothesis that CFS was largely being maintained by abnormal illness beliefs and behaviours, along with inactivity and deconditioning, CBT and GET became the two main recommended forms of treatment in both the United Kingdom and the United States.

Prior to publication of the PACE trial results, a small number of clinical trials had supported the use of CBT and GET, almost all of which had been carried out by health professionals who promoted a psychosomatic model of causation and management. However, patient survey evidence, as collected by the ME Association (ME Association, 2015) along with most other patient surveys (Kindlon and Baldwin, 2015), told a very different story. The majority of people with ME/CFS consistently reported that CBT was ineffective. And around 50 per cent consistently reported that GET had made their condition worse.

The largest and most recent ME Association survey (ME Association, 2015) of patient evidence on the acceptability, efficacy and safety of CBT, GET and Pacing involved 1428 respondents. In this case, 73 per cent of respondents reported that CBT had no effect on their symptoms and 74 per cent reported that their symptoms were made worse by GET.

Surveys carried out by patient support groups have a number of limitations and these are listed in detail in section 6 of The ME Association survey results. In particular, it should be noted that people who belong to patient support groups, or use their websites, are going to produce a bias towards those who have been ill for a longer period of time and/or have a more severe form of illness. At the same time, those who have recovered, or have largely recovered, are less likely to belong to a support group or take part in surveys. So the respondents in these sort of surveys are not necessarily a representative sample of the whole ME/CFS population who have tried these therapies.

And while entry to this survey was on the basis of having a diagnosis of ME/CFS, we did not collect any clinical details or contact the health professional involved for confirmation.

So the PACE trial was essentially set up to provide robust evidence of both safety and efficacy for graded activity (i.e. GET), CBT and a modified version of pacing known as adaptive pacing. But PACE was a study that selected patients using a flawed diagnostic criteria (i.e. Oxford) and only assessed a limited number of subjective outcome measures focusing on fatigue and disability – a design that required strict vigilance in order to prevent the possibility of bias. Not surprisingly, PACE met with widespread criticism right from the very start.

The MEA argued that PACE was not taking account of the clinical heterogeneity of the illness and was ignoring the complex interaction between central (brain) and peripheral (muscle) factors in the causation of fatigue in ME/CFS.

With specific reference to graded exercise, muscle performance and the observation that exercise often makes symptoms worse, Brown et al. (2015) have used magnetic resonance spectroscopy to demonstrate that there are at least two muscle phenotypes involved in ME/CFS. This finding, along with other research evidence on abnormal exercise physiology (VanNess et al., 2003), that is not consistent with a deconditioning/inactivity model of causation, emphasises the need to fully characterise muscle phenotypes, as well as muscle biochemical abnormalities, before generically prescribing exercise as an effective intervention.

The MEA therefore argued that PACE was unlikely to tell us anything we did not already know from previous clinical trials involving CBT and GET. The charity also argued that PACE was a colossal waste of money that should be far better spent on much needed biomedical research – which the main funder of PACE, the Medical Research Council, had always been reluctant to do.

When the first PACE trial results were published (White et al., 2011), they once again failed to convince people with ME/CFS that CBT and GET were the most effective ways of managing everyone with mild or moderate ME/CFS.

But it was the follow-up paper on recovery in Psychological Medicine (White et al., 2013) – where it was claimed that CBT and GET led to ‘recovery’ in 22 per cent – that really intensified the debate into the methodology of the trial, the way recovery had been defined, and the manner in which the results were portrayed to clinicians, patients and the media. Key criticisms included the following:

Recovery figures were based on a definition of recovery that differed from that specified in the trial protocol. In fact, the final definition of recovery was so lax that on some criteria it was possible to score below the level required for entry to the trial, yet still be counted as ‘recovered’.

Participants were not even asked whether they had recovered in relation to normal aspects of daily living.

Information on overall receipt of state sickness or disability benefits failed to support a recovery – with the PACE trial cost analysis study (McCrone et al., 2012) reporting: ‘Receipt of benefits due to illness or disability increased slightly from baseline to follow-up’.

Information on return to some form of meaningful employment or education status was never sought. This was dismissed by the investigators as not being relevant.

Information on ability to mobilise failed to support a recovery. Overall results for all treatments relating to changes in the 6-minute walking test from baseline to 52 weeks did not represent a return to normal levels of activity. In fact, data for all the treatment groups at 52 weeks indicated that they were below the 402 m achieved by patients with class three heart failure. In addition, rejecting the use of electronic activity monitors meant no objective assessment of mobility was carried out.

The term ‘recovery’ implies a sustained return towards symptom-free health along with the ability to repeatedly and reliably participate in all aspects of normal life – employment, education, social activities and so on. Without this information, it was impossible to conclude that any of the patients in the PACE trial had usefully recovered.

Not surprisingly, criticism of the PACE trial continued and intensified. There was a debate in the House of Lords (UK House of Lords, 2013) and 36 academics and clinicians signed an open letter to The Lancet (ME Association, 2016) calling for an independent re-analysis of the data.

Several requests by academics, clinicians and patients asked for unpublished data to be made available so that it could be subjected to independent analysis. These demands were consistent with the growing acceptance by the scientific community that there should be far more transparency in clinical trials, including the sharing of data. The investigators refused to give way even when asked to do so by the Information Commissioner. Queen Mary University of London, which oversaw the trial, then spent almost £250,000 of public money on legal fees by taking the case to an appeal tribunal – which they lost.

When the unpublished PACE trial data was re-analysed by Wilshire et al. (2017), the authors found that if recovery was defined according to the original trial protocol, recovery rates in the CBT and GET groups were low and not significantly higher than in the control group (4%, 7% and 3%, respectively). The authors concluded, The claim that patients can recover as a result of CBT and GET is not justified by the data, and is highly misleading to clinicians and patients considering these treatments.

I conclude with some observations on what we can learn from the mistakes of the PACE trial. Because if lessons are not learned, distrust of the medical and scientific community by the people with ME/CFS will only continue and intensify.

This is not an argument with psychiatry. Mental and physical illness are equally real and horrible. As with any long-term illness, some people with ME/CFS will develop comorbid depression and other mental health problems – where CBT can be of help alongside good quality general management. The argument here is with a flawed model of causation assuming efficacy for CBT and GET while taking no significant account of varying clinical presentations and disease pathways.

First, on behalf of all the journals that have so far published 16 papers from the trial, The Lancet must now set up an independent re-analysis of the PACE trial data, along with appropriate sensitivity analysis. This re-analysis should be carried out by well respected independent reviewers with expertise in statistics and study design. If any results are found to be significantly inaccurate or unreliable, the possibility of a retraction will have to be considered.

Second, if a drug treatment was found to be making a significant proportion of people worse, as is the case with patient evidence relating to the use of GET, the treatment would be withdrawn and would not form part of a NICE recommendation. As there is now both consistent and extensive patient evidence relating to the harmful effects of GET, the NICE guideline recommendation on GET must be reviewed as a matter of urgency. The generic prescribing of progressive and inflexible exercise programmes is not an acceptable form of treatment for people with ME/CFS.

Third, the enormous amount of public money spent by the Medical Research Council and Department of Work and Pensions on funding the PACE trial, along with legal costs met by Queen Mary University of London in appealing against the Freedom of Information requests, merits a formal inquiry, possibly at a parliamentary level.

Finally, there is a desperate need for clinical trials of activity management that examine the heterogeneity of ME/CFS, the fact that underlying disease processes involve both central and peripheral fatigue, and the consistent evidence from patients that inflexible or progressive exercise programmes aggravate symptoms in the majority of patients who come under the ME/CFS umbrella.

Declaration of conflicting interests The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Funding The author(s) received no financial support for the research, authorship and/or publication of this article.

References
Brown AE, Jones DE, Walker M, . (2015) Abnormalities of AMPK activation and glucose uptake in cultured skeletal muscle cells from individuals with chronic fatigue syndrome. PLoS ONE 2015; 10: e0122982. Google Scholar
Geraghty KJ (2016) PACE-gate: When clinical trial evidence meets open data access. Journal of Health Psychology. Epub ahead of print 1 November. DOI: 10.1177/1359105316675213. Google Scholar CrossRef
Kindlon T, Baldwin A (2015) Response to: Reports of recovery in chronic fatigue syndrome may present less than meets the eye. Evidence Based Mental Health 18(2): e5. Google Scholar CrossRef, Medline
McCrone P, Sharpe M, Chalder T, . (2012) Adaptive pacing, cognitive behaviour therapy, graded exercise, and specialist medical care for chronic fatigue syndrome: A cost-effectiveness analysis. PLoS ONE 7(8): e40808. Google Scholar CrossRef, Medline
ME Association (2015) ME/CFS illness management survey results: ‘No decisions about me without me’. Available at:http://www.meassociation.org.uk/2015/05/... / Google Scholar
ME Association (2016) Clamour grows for independent inquiry into PACE trial: Open letter to The Lancet republished. Available at: http://www.meassociation.org.uk/2016/02/... Google Scholar
National Institute for Health and Clinical Excellence (2011) Review of clinical guideline (CG53) – Chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy): Diagnosis and management of chronic fatigue syndrome, myalgic encephalomyelitis (or encephalopathy) in adults and children. Available at: https://www.nice.org.uk/guidance/cg53/ev... Google Scholar
UK House of Lords (2013) PACE trial: Chronic fatigue syndrome/myalgic encephalomyelitis. Available at: http://www.publications.parliament.uk/pa... Google Scholar
VanNess JM, Snell CR, Strayer DR, . (2003) Subclassifying chronic fatigue syndrome through exercise testing. Medicine and Science in Sports and Exercise 35(6): 908–913. Google Scholar CrossRef, Medline
White PD (2017) Response to editorial by Dr Geraghty. Journal of Health Psychology. Epub ahead of print 24 January. DOI: 10.1177/1359105316688953. Google Scholar CrossRef
White PD, Goldsmith KA, Johnson AL, . (2011) PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): A randomized trial. The Lancet 377: 823–836. Google Scholar CrossRef, Medline
White PD, Goldsmith K, Johnson AL, . (2013) Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychological Medicine 43(10): 2227–2235. Google Scholar CrossRef, Medline
Wilshire C, Kindlon T, Matthees A, . (2017) Can patients with chronic fatigue syndrome really recover after graded exercise or cognitive behavioural therapy? A critical commentary and preliminary re-analysis of the PACE trial. Fatigue: Biomedicine, Health & Behavior 5: 43–56. Google Scholar CrossRef

Gadawodd Kathryn Dickenson anodiad ()

http://www.virology.ws/2017/03/13/an-ope...

An open letter to Psychological Medicine about “recovery” and the PACE trial
13 MARCH 2017
Sir Robin Murray and Dr. Kenneth Kendler
Psychological Medicine
Cambridge University Press
University Printing House
Shaftesbury Road
Cambridge CB2 8BS
UK

Dear Sir Robin Murray and Dr. Kendler:

In 2013, Psychological Medicine published an article called “Recovery from chronic fatigue syndrome after treatments given in the PACE trial.”[1] In the paper, White et al. reported that graded exercise therapy (GET) and cognitive behavioural therapy (CBT) each led to recovery in 22% of patients, compared with only 7% in a comparison group. The two treatments, they concluded, offered patients “the best chance of recovery.”

PACE was the largest clinical trial ever conducted for chronic fatigue syndrome (also known as myalgic encephalomyelitis, or ME/CFS), with the first results published in The Lancet in 2011.[2] It was an open-label study with subjective primary outcomes, a design that requires strict vigilance to prevent the possibility of bias. Yet PACE suffered from major flaws that have raised serious concerns about the validity, reliability and integrity of the findings.[3] Despite these flaws, White et al.’s claims of recovery in Psychological Medicine have greatly impacted treatment, research, and public attitudes towards ME/CFS.

According to the protocol for the PACE trial, participants needed to meet specific benchmarks on four different measures in order to be defined as having achieved “recovery.”[4] But in Psychological Medicine, White et al. significantly relaxed each of the four required outcomes, making “recovery” far easier to achieve. No PACE oversight committees appear to have approved the redefinition of recovery; at least, no such approvals were mentioned. White et al. did not publish the results they would have gotten using the original protocol approach, nor did they include sensitivity analyses, the standard statistical method for assessing the impact of such changes.

Patients, advocates and some scientists quickly pointed out these and other problems. In October of 2015, Virology Blog published an investigation of PACE, by David Tuller of the University of California, Berkeley, that confirmed the trial’s methodological lapses.[5] Since then, more than 12,000 patients and supporters have signed a petition calling for Psychological Medicine to retract the questionable recovery claims. Yet the journal has taken no steps to address the issues.

Last summer, Queen Mary University of London released anonymized PACE trial data under a tribunal order arising from a patient’s freedom-of-information request. In December, an independent research group used that newly released data to calculate the recovery results per the original methodology outlined in the protocol.[6] This reanalysis documented what was already clear: that the claims of recovery could not be taken at face value.

In the reanalysis, which appeared in the journal Fatigue: Biomedicine, Health & Behavior, Wilshire et al. reported that the PACE protocol’s definition of “recovery” yielded recovery rates of 7 % or less for all arms of the trial. Moreover, in contrast to the findings reported in Psychological Medicine, the PACE interventions offered no statistically significant benefits. In conclusion, noted Wilshire et al., “the claim that patients can recover as a result of CBT and GET is not justified by the data, and is highly misleading to clinicians and patients considering these treatments.”

In short, the PACE trial had null results for recovery, according to the protocol definition selected by the authors themselves. Besides the inflated recovery results reported in Psychological Medicine, the study suffered from a host of other problems, including the following:

*In a paradox, the revised recovery thresholds for physical function and fatigue–two of the four recovery measures–were so lax that patients could deteriorate during the trial and yet be counted as “recovered” on these outcomes. In fact, 13 % of participants met one or both of these recovery thresholds at baseline. White et al. did not disclose these salient facts in Psychological Medicine. We know of no other studies in the clinical trial literature in which recovery thresholds for an indicator actually represented worse health status than the entry thresholds for serious disability on the same indicator.

*During the trial, the authors published a newsletter for participants that included glowing testimonials from earlier participants about their positive outcomes in the trial.[7] An article in the same newsletter reported that a national clinical guidelines committee had already recommended CBT and GET as effective; the newsletter article did not mention adaptive pacing therapy, an intervention developed specifically for the PACE trial. The participant testimonials and the newsletter article could have biased the responses of an unknown number of the two hundred or more people still undergoing assessments—about a third of the total sample.

*The PACE protocol included a promise that the investigators would inform prospective participants of “any possible conflicts of interest.” Key PACE investigators have had longstanding relationships with major insurance companies, advising them on how to handle disability claims related to ME/CFS. However, the trial’s consent forms did not mention these self-evident conflicts of interest. It is irrelevant that insurance companies were not directly involved in the trial and insufficient that the investigators disclosed these links in their published research. Given this serious omission, the consent obtained from the 641 trial participants is of questionable legitimacy.

Such flaws are unacceptable in published research; they cannot be defended or explained away. The PACE investigators have repeatedly tried to address these concerns. Yet their efforts to date—in journal correspondence, news articles, blog posts, and most recently in their response to Wilshire et al. in Fatigue[8]—have been incomplete and unconvincing.

The PACE trial compounded these errors by using a case definition for the illness that required only one symptom–six months of disabling, unexplained fatigue. A 2015 report from the U.S. National Institutes of Health recommended abandoning this single-symptom approach for identifying patients.[9] The NIH report concluded that this broad case definition generated heterogeneous samples of people with a variety of fatiguing illnesses, and that using it to study ME/CFS could “impair progress and cause harm.”

PACE included sub-group analyses of two alternate and more specific case definitions, but these case definitions were modified in ways that could have impacted the results. Moreover, an unknown number of prospective participants might have met these alternate criteria but been excluded from the study by the initial screening.

To protect patients from ineffective and possibly harmful treatments, White et al.’s recovery claims cannot stand in the literature. Therefore, we are asking Psychological Medicine to retract the paper immediately. Patients and clinicians deserve and expect accurate and unbiased information on which to base their treatment decisions. We urge you to take action without further delay.

Sincerely,

Dharam V. Ablashi, DVM, MS, Dip Bact
Scientific Director
HHV-6 Foundation
Former Senior Investigator
National Cancer Institute
National Institutes of Health
Bethesda, Maryland, USA

James N. Baraniuk, MD
Professor, Department of Medicine
Georgetown University
Washington, D.C., USA

Lisa F. Barcellos, MPH, PhD
Professor of Epidemiology
School of Public Health
California Institute for Quantitative Biosciences
University of California, Berkeley
Berkeley, California, USA

Lucinda Bateman, MD
Medical Director
Bateman Horne Center
Salt Lake City, Utah, USA

Alison C. Bested, MD, FRCPC
Clinical Associate Professor
Faculty of Medicine
University of British Columbia
Vancouver, British Columbia, Canada

Molly Brown, PhD
Assistant Professor
Department of Psychology
DePaul University
Chicago, Illinois, USA

John Chia, MD
Clinician and Researcher
EVMED Research
Lomita, California, USA

Todd E. Davenport, PT, DPT, MPH, OCS
Associate Professor
Department of Physical Therapy
University of the Pacific
Stockton, California, USA

Ronald W. Davis, PhD
Professor of Biochemistry and Genetics
Stanford University
Stanford, California, USA

Simon Duffy, PhD, FRSA
Director
Centre for Welfare Reform
Sheffield, UK

Jonathan C.W. Edwards, MD
Emeritus Professor of Medicine
University College London
London, UK

Derek Enlander, MD
New York, New York, USA

Meredyth Evans, PhD
Clinical Psychologist and Researcher
Chicago, Illinois, USA

Kenneth J. Friedman, PhD
Associate Professor of Physiology and Pharmacology (retired)
New Jersey Medical School
University of Medicine and Dentistry of New Jersey
Newark, New Jersey, USA

Robert F. Garry, PhD
Professor of Microbiology and Immunology
Tulane University School of Medicine
New Orleans, Louisiana, USA

Keith Geraghty, PhD
Honorary Research Fellow
Division of Population Health, Health Services Research & Primary Care
School of Health Sciences
University of Manchester
Manchester, UK

Ian Gibson, PhD
Former Member of Parliament for Norwich North
Former Dean, School of Biological Sciences
University of East Anglia
Honorary Senior Lecturer and Associate Tutor
Norwich Medical School
University of East Anglia
Norwich, UK

Rebecca Goldin, PhD
Professor of Mathematics
George Mason University
Fairfax, Virginia, USA

Ellen Goudsmit, PhD, FBPsS
Health Psychologist (retired)
Former Visiting Research Fellow
University of East London
London, UK

Maureen Hanson, PhD
Liberty Hyde Bailey Professor
Department of Molecular Biology and Genetics
Cornell University
Ithaca, New York, USA

Malcolm Hooper, PhD
Emeritus Professor of Medicinal Chemistry
University of Sunderland
Sunderland, UK

Leonard A. Jason, PhD
Professor of Psychology
DePaul University
Chicago, Illinois, USA

Michael W. Kahn, MD
Assistant Professor of Psychiatry
Harvard Medical School
Boston, Massachusetts, USA

Jon D. Kaiser, MD
Clinical Faculty
Department of Medicine
University of California, San Francisco
San Francisco, California, USA

David L. Kaufman, MD
Medical Director
Open Medicine Institute
Mountain View, California, USA

Betsy Keller, PhD
Department of Exercise and Sports Sciences
Ithaca College
Ithaca, New York, USA

Nancy Klimas, MD
Director, Institute for Neuro-Immune Medicine
Nova Southeastern University
Director, Miami VA Medical Center GWI and CFS/ME Program
Miami, Florida, USA

Andreas M. Kogelnik, MD, PhD
Director and Chief Executive Officer
Open Medicine Institute
Mountain View, California, USA

Eliana M. Lacerda, MD, MSc, PhD
Clinical Assistant Professor
Disability & Eye Health Group/Clinical Research Department
Faculty of Infectious and Tropical Diseases
London School of Hygiene & Tropical Medicine
London, UK

Charles W. Lapp, MD
Medical Director
Hunter-Hopkins Center
Charlotte, North Carolina, USA
Assistant Consulting Professor
Department of Community and Family Medicine
Duke University School of Medicine
Durham, North Carolina, USA

Bruce Levin, PhD
Professor of Biostatistics
Columbia University
New York, New York, USA

Alan R. Light, PhD
Professor of Anesthesiology
Professor of Neurobiology and Anatomy
University of Utah
Salt Lake City, Utah, USA

Vincent C. Lombardi, PhD
Director of Research
Nevada Center for Biomedical Research
Reno, Nevada, USA

Alex Lubet, PhD
Professor of Music
Head, Interdisciplinary Graduate Group in Disability Studies
Affiliate Faculty, Center for Bioethics
Affiliate Faculty, Center for Cognitive Sciences
University of Minnesota
Minneapolis, Minnesota, USA

Steven Lubet
Williams Memorial Professor of Law
Northwestern University Pritzker School of Law
Chicago, Illinois, USA

Sonya Marshall-Gradisnik, PhD
Professor of Immunology
Co-Director, National Centre for Neuroimmunology and Emerging Diseases
Griffith University
Queensland, Australia

Patrick E. McKnight, PhD
Professor of Psychology
George Mason University
Fairfax, Virginia, USA

Jose G. Montoya, MD, FACP, FIDSA
Professor of Medicine
Division of Infectious Diseases and Geographic Medicine
Stanford University School of Medicine
Stanford, California, USA

Zaher Nahle, PhD, MPA
Vice President for Research and Scientific Programs
Solve ME/CFS Initiative
Los Angeles, California, USA

Henrik Nielsen, MD
Specialist in Internal Medicine and Rheumatology
Copenhagen, Denmark

James M. Oleske, MD, MPH
François-Xavier Bagnoud Professor of Pediatrics
Senator of RBHS Research Centers, Bureaus, and Institutes
Director, Division of Pediatrics Allergy, Immunology & Infectious Diseases
Department of Pediatrics
Rutgers New Jersey Medical School
Newark, New Jersey, USA

Elisa Oltra, PhD
Professor of Molecular and Cellular Biology
Catholic University of Valencia School of Medicine
Valencia, Spain

Richard Podell, MD, MPH
Clinical Professor
Department of Family Medicine
Rutgers Robert Wood Johnson Medical School
New Brunswick, New Jersey, USA

Nicole Porter, PhD
Psychologist in Private Practice
Rolling Ground, Wisconsin, USA

Vincent R. Racaniello, PhD
Professor of Microbiology and Immunology
Columbia University
New York, New York, USA

Arthur L. Reingold, MD
Professor of Epidemiology
University of California, Berkeley
Berkeley, California, USA

Anders Rosén, MD
Professor of Inflammation and Tumor Biology
Department of Clinical and Experimental Medicine
Division of Cell Biology
Linköping University
Linköping, Sweden

Peter C. Rowe, MD
Professor of Pediatrics
Johns Hopkins University School of Medicine
Baltimore, Maryland, USA

William Satariano, PhD
Professor of Epidemiology and Community Health
University of California, Berkeley
Berkeley, California, USA

Ola Didrik Saugstad, MD, PhD, FRCPE
Professor of Pediatrics
University of Oslo
Director and Department Head
Department of Pediatric Research
University of Oslo and Oslo University Hospital
Oslo, Norway

Charles Shepherd, MB, BS
Honorary Medical Adviser to the ME Association
Buckingham, UK

Christopher R. Snell, PhD
Scientific Director
WorkWell Foundation
Ripon, California, USA

Donald R. Staines, MBBS, MPH, FAFPHM, FAFOEM
Clinical Professor
Menzies Health Institute Queensland
Co-Director, National Centre for Neuroimmunology and Emerging Diseases
Griffith University
Queensland, Australia

Philip B. Stark, PhD
Professor of Statistics
University of California, Berkeley
Berkeley, California, USA

Eleanor Stein, MD, FRCP(C)
Psychiatrist in Private Practice
Assistant Clinical Professor
University of Calgary
Calgary, Alberta, Canada

Staci Stevens, MA
Founder, Exercise Physiologist
Workwell Foundation
Ripon, California, USA

Julian Stewart, MD, PhD
Professor of Pediatrics, Physiology and Medicine
Associate Chairman for Patient Oriented Research
Director, Center for Hypotension
New York Medical College
Hawthorne, NY, USA

Leonie Sugarman, PhD
Emeritus Associate Professor of Applied Psychology
University of Cumbria
Carlisle, UK

John Swartzberg, MD
Clinical Professor Emeritus
School of Public Health
University of California, Berkeley
Berkeley, California, USA

Ronald G. Tompkins, MD, ScD
Summer M Redstone Professor of Surgery
Harvard Medical School
Boston, Massachusetts, USA

David Tuller, DrPH
Lecturer in Public Health and Journalism
University of California, Berkeley
Berkeley, California, USA

Rosemary A. Underhill, MB, BS, MRCOG, FRCSE
Physician and Independent Researcher
Palm Coast, Florida, USA

Rosamund Vallings, MNZM, MB, BS
General Practitioner
Auckland, New Zealand

Michael VanElzakker, PhD
Research Fellow, Psychiatric Neuroscience Division
Harvard Medical School & Massachusetts General Hospital
Instructor, Tufts University Psychology
Boston, Massachusetts, USA

Mark VanNess, PhD
Professor of Health, Exercise & Sports Sciences
University of the Pacific
Stockton, California, USA
Workwell Foundation
Ripon, California, USA

Mark Vink, MD
Family Physician
Soerabaja Research Center
Amsterdam, Netherlands

Frans Visser, MD
Cardiologist
Stichting Cardiozorg
Hoofddorp, Netherlands

Tony Ward, MA (Hons), PhD, DipClinPsyc
Registered Clinical Psychologist
Professor of Clinical Psychology
School of Psychology
Victoria University of Wellington
Wellington, New Zealand
Adjunct Professor, School of Psychology
University of Birmingham
Birmingham, UK
Adjunct Professor, School of Psychology
University of Kent
Canterbury, UK

William Weir, FRCP
Infectious Disease Consultant
London, UK

John Whiting, MD
Specialist Physician
Private Practice
Brisbane, Australia

Carolyn Wilshire, PhD
Senior Lecturer
School of Psychology
Victoria University of Wellington
Wellington, New Zealand

Michael Zeineh, MD, PhD
Assistant Professor
Department of Radiology
Stanford University
Stanford, California, USA

Marcie Zinn, PhD
Research Consultant in Experimental Electrical Neuroimaging and Statistics
Center for Community Research
DePaul University
Chicago, Illinois, USA
Executive Director
Society for Neuroscience and Psychology in the Performing Arts
Dublin, California, USA

Mark Zinn, MM
Research Consultant in Experimental Electrophysiology
Center for Community Research
DePaul University
Chicago, Illinois, USA

ME/CFS Patient Organizations

25% ME Group
UK

Emerge Australia
Australia

European ME Alliance:

Belgium ME/CFS Association
Belgium

ME Foreningen
Denmark

Suomen CFS-Yhdistys
Finland

Fatigatio e.V.
Germany

Het Alternatief
Netherlands

Icelandic ME Association
Iceland

Irish ME Trust
Ireland

Associazione Malati di CFS
Italy

Norges ME-forening
Norway

Liga SFC
Spain

Riksföreningen för ME-patienter
Sweden

Verein ME/CFS Schweiz
Switzerland

Invest in ME Research
UK

Hope 4 ME & Fibro Northern Ireland
UK

Irish ME/CFS Association
Ireland

Massachusetts CFIDS/ME & FM Association
USA

ME Association
UK

ME/cvs Vereniging
Netherlands

National ME/FM Action Network
Canada

New Jersey ME/CFS Association
USA

Pandora Org
USA

Phoenix Rising
International membership representing many countries

Solve ME/CFS Initiative
USA

Tymes Trust (The Young ME Sufferers Trust)
UK

Wisconsin ME and CFS Association
USA

[1] White PD, Goldsmith K, Johnson AL, et al. 2013. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychological Medicine 43(10): 2227-2235.

[2] White PD, Goldsmith KA, Johnson AL, et al. 2011. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. The Lancet 377: 823–836

[3] Racaniello V. 2016. An open letter to The Lancet, again. Virology Blog, 10 Feb. Available at: http://www.virology.ws/2016/02/10/open-l... (accessed on 2/24/17).

[4] White PD, Sharpe MC, Chalder T, et al. 2007. 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 7: 6.

[5] Tuller D. 2015. Trial by error: the troubling case of the PACE chronic fatigue syndrome trial. Virology Blog, 21-23 Oct. Available at: http://www.virology.ws/2015/10/21/trial-... (accessed on 2/24/17)

[6] Wilshire C, Kindlon T, Matthees A, McGrath S. 2016. Can patients with chronic fatigue syndrome really recover after graded exercise or cognitive behavioural therapy? A critical commentary and preliminary re-analysis of the PACE trial. Fatigue: Biomedicine, Health & Behavior; published online 14 Dec. Available at: http://www.tandfonline.com/doi/full/10.1... (accessed on 2/24/17)

[7] PACE Participants Newsletter. December 2008. Issue 3. Available at: http://www.wolfson.qmul.ac.uk/images/pdf... (accessed on 2/24/17).

[8] Sharpe M, Chalder T, Johnson AL, et al. 2017. Do more people recover from chronic fatigue syndrome with cognitive behaviour therapy or graded exercise therapy than with other treatments? Fatigue: Biomedicine, Health & Behavior; published online 15 Feb. Available at: http://www.tandfonline.com/doi/full/10.1... (accessed on 2/24/17).

[9] Green CR, Cowan P, Elk R. 2015. National Institutes of Health Pathways to Prevention Workshop: Advancing the research on myalgic encephalomyelitis/chronic fatigue syndrome. Annals of Internal Medicine 162: 860-865.

Gadawodd Kathryn Dickenson anodiad ()

http://www.thelancet.com/pdfs/journals/l...

Correspondence
www.thelancet.com/psychiatry Vol 3 February 2016

PACE: CBT and GET are not rehabilitative therapies
In a recent Article Michael Sharpe and colleagues report on findings of a follow-up study of the PACE trial of
proposed rehabilitative interventions
for chronic fatigue syndrome: graded
exercise therapy (GET) and cognitive
behavioural therapy (CBT).
Their main finding is that the beneficial effects
of CBT and GET were maintained at follow-up (median: 2·5 years). Both CBT and GET have been qualified by the PACE trial investigators as “moderately effective treatments”.2
However, looking at the data of the follow-up study1 and other PACE
trial studies,2,3 CBT and GET do not
qualify as rehabilitative therapies for
chronic fatigue syndrome or myalgic
encephalomyelitis, as defi ned by the
London criteria.1

First, the PACE trial investigated
the eff ects of CBT and GET in chronic
fatigue, as defined by the Oxford
criteria, not in chronic fatigue
syndrome, let alone myalgic encephalomyelitis,
as defi ned by the Ramsay criteria.

The Oxford criteria have
been criticised often. For that reason
“consensus groups and researchers
should consider retiring the Oxford
case defi nition”.4

Second, the positive eff ect of CBT and GET in subjective measures, fatigue and physical functioning, cannot be qualified as sufficient.

Mean short form-36 physical functioning scores in the CBT group (62·2) and the GET group (59·8) at follow-up were below the inclusion cutoff score for the PACE trial (≤65)3
and far below the objective for recovery as defined in the PACE protocol (≥85).5

The mean fatigue scores in the CBT group (18·4)
and GET group (19·1) were above subnormal (<18)4
and far above the entry criterion for the PACE trial
(>12, recalculated)3 and the recovery
criterion in the PACE protocol (≤6).5

Third, the PACE trial follow-up study1
concluded that outcomes
with specialist medical care alone
or adaptive pacing therapy (APT)
were similar to CBT and GET at
follow-up. The authors suggest that
”it is important to note that many
of the participants had received
additional treatment for CFS since
completing the trial”. Looking at the
data,1
23 (20%) of the patients in the
specialist medical care arm received
an adequate number of sessions
(n=10) of CBT after the PACE trial and
14 (12%) received GET, while 20 (17%)
of the patients in the APT group
received CBT and 7 (6%) received GET
afterwards. This fi nding implies that
the vast majority of patients improved
subjectively by specialist medical
care and APT to the same level as by
CBT and GET, without any additional
therapies, including CBT and GET, or
by other therapies.1
Finally, looking at subjective
outcomes at follow-up1
and objective
outcomes in earlier studies, such
as physical fitness,2
return to
employment,3
social welfare benefi ts,3
and health-care usage,3
CBT and GET,
like specialist medical care and APT,
cannot be qualifi ed as eff ective.
In conclusion, CBT and GET are
moderately effective in subjective
terms in chronic fatigue, but looking
at the patients studied and the
(subjective and objective) outcomes
of the PACE trial,1,3–5 CBT and GET
do not meet the requirements for
rehabilitative or eff ective therapies for
chronic fatigue syndrome, let alone
myalgic encephalomyelitis.
I am associated with a Dutch ME/CFS patient
foundation in a voluntary (non-paid) capacity.
Frank Twisk
frank.twisk@hetnet.nl
Research, ME-de-patiënten Foundation, Limmen,
1906HB, Netherlands
1 Sharpe M, Goldsmith KA, Johnson AL,
Chalder T, Walker K, White PD. Rehabilitative
treatments for chronic fatigue syndrome:
long-term follow-up from the PACE trial.
Lancet Psychiatry 2015; 2: 1067–74.
2 Twisk F. Post-exertional malaise in chronic
fatigue syndrome. Lancet Psychiatry 2015;
2: e8–9.
3 McCrone P, Sharpe M, Chalder T, et al. Adaptive
pacing, cognitive behaviour therapy, graded
exercise, and specialist medical care for chronic
fatigue syndrome: a cost-eff ectiveness
analysis. PLoS One 2012; 7: e40808.
4 Haney E, Smith ME, McDonagh M, et al.
Diagnostic methods for Myalgic
Encephalomyelitis/chronic fatigue syndrome:
a systematic review for a national institutes of
health pathways to prevention workshop.
Ann Intern Med 2015; 162: 834–40.
5 White PD, Sharpe MC, Chalder T, DeCesare JC,
Walwyn R; PACE trial group. Protocol for the
PACE trial: a randomised controlled trial of
adaptive pacing, cognitive behaviour therapy,
and graded exercise, as supplements to
standardised specialist medical care versus
standardised specialist medical care alone for
patients with the chronic fatigue
syndrome/myalgic encephalomyelitis or
encephalopathy. BMC Neurol 2007; 7: 6.
Results of the PACE
follow-up study are
uninterpretable
The PACE follow-up study 1
is
something of a curate’s egg,
admirable in ambition, but
i n t e r p r e t a t i v e l y i n d i g e s t i b l e .
Although the PACE programme
of cognitive behavioural therapy
(CBT) or graded exercise therapy
(GET) led patients to report less
fatigue or greater physical function
than patients in the adaptive
pacing therapy and specialist
medical care groups in the short
term, evidence in the long-term
follow-up is unconvincing. The lack
of between-group differences at
follow-up takes precedence over
within-group differences, which
are inflated by attribution of any
change associated with non-specifi c
factors to the specifi c interventions.
Re-assignment to new treatment also
makes between-group comparisons
uninterpretable, as we will see.
Although the investigators made
heroic efforts to correct for attrition
using linear mixed-effects regression
models, such efforts depend on their
unjustified assumptions of random
missing data and of treatment
received at follow-up not distorting
any signal of effects of the earlier
Published Online
January 18, 2016
http://dx.doi.org/10.1016/
S2215-0366(15)00554-4
Published Online
January 18, 2016
http://dx.doi.org/10.1016/
S2215-0366(15)00551-9
Correspondence
e7 www.thelancet.com/psychiatry Vol 3 February 2016
Patient reaction to the
PACE trial
The long-term follow-up of the
PACE trial,1
which originally reported
that cognitive behavioural therapy
(CBT) and graded exercise therapy
(GET) produced a significant and
sustained improvement, even
recovery, for some people with
myalgic encephalomyelitis/chronic
fatigue syndrome (ME/CFS)2
should,
in theory, have been greeted positively
by patients. However, Michael Sharpe
and colleagues1
found very little
diff erence in outcomes at long-term
follow-up between any of the four
interventions (which also included
adapted pacing therapy and specialist
medical care) and the patient
community has expressed both anger
and despair.
Anger because the media, along
with many health professionals, has
concluded that people can recover from
ME/CFS through a simplistic approach
to management involving exercise and
positive thinking.3
Despair because the
fi ndings from the PACE trial have not
been supported by patient evidence
on CBT, GET, and pacing, which dates
back to the 2002 Chief Medical Offi cer’s
Working Group report4
on ME/CFS.
The largest and most recent
survey5
of patient evidence on the
acceptability, efficacy, and safety of
CBT, GET, and pacing was carried out
by The ME Association and involved
1428 respondents. In this case, 73% of
respondents reported that CBT had
no effect on their symptoms and
74% that their symptoms were made
worse by GET.
As a result, The ME Association
has recommended that the National
Institute for Health and Care
Excellence should withdraw their
recommendation that everyone with
mild or moderate ME/CFS should be
off ered GET. And while accepting that
some people may find CBT helpful
when there are comorbid mental
health problems, as can occur with any
short-form 36 (SF-63) physical
functioning score is less than 60. It is
useful to put this number in context.
77% of the PACE trial participants were
women, and the mean age of the trial
population was 38 years, with no other
disabling medical conditions. Patients
with lupus have a mean physical
functioning score of 63,2
patients
with class II congestive heart failure
have a mean score lower than 60,3
and
normal controls with no long-term
health problems have a mean score
of 93.4
Lastly, the PACE investigators
have previously complained in
The Lancet Psychiatry of “the apparent
campaign to bring the robust fi ndings
of the trial into question”.5
We think
the further scrutiny that the follow-up
study has brought casts further doubt
on whether there ever were “robust
findings”. The investigators should
get more accustomed to rigorous
post-publication peer review, which
is not a campaign, but a reality of the
21st century.
We declare no competing interests.
*James Charles Coyne, Keith R Laws
jcoyne@mail.med.upenn.edu
Department of Health Psychology,
University Medical Center, University of
Groningen, Groningen 9700 AD, Netherlands
(JCC); and Department of Psychology,
University of Hertfordshire, Hatfi eld,
Hertfordshire, UK (KRL)
1 Sharpe M, Goldsmith KA, Johnson AL,
Chalder T, Walker J, White PD. Rehabilitative
treatments for chronic fatigue syndrome:
long-term follow-up from the PACE trial.
Lancet Psychiatry 2015; 2: 1067–74.
2 Tench CM, McCurdie I, White PD, D’Cruz DP.
The prevalence and associations of fatigue in
systemic lupus erythematosus. Rheumatology
2000; 39: 1249–54.
3 Juenger J, Schellberg D, Kraemer S, et al.
Health related quality of life in patients with
congestive heart failure: comparison with
other chronic diseases and relation to
functional variables. Heart 2002; 87: 235–41.
4 Bowling A, Bond M, Jenkinson C, Lamping
DL. Short Form 36 (SF-36) Health Survey
questionnaire: which normative data should
be used? Comparisons between the norms
provided by the Omnibus Survey in Britain,
the Health Survey for England and the Oxford
Healthy Life Survey. J Pub Health 1999;
21: 255–70.
5 Chalder T, Goldsmith KA, White PD, Sharpe
M, Pickles AR. Methods and outcome
reporting in the PACE trial–Author’s reply.
Lancet Psychiatry 2015; 2: e10–e11.
randomisation. Various covariates
are introduced for statistical control,
but without adequate rationale
and documentation of diagnostics.
It is therefore doubtful that the
complexly adjusted results are
reliable.
Several other unfortunate decisions
further undermine the findings.
Foremost, the unregulated crossover
between treatments during follow-up.
The follow-up outcome data1
in
table 3 and fi gure 2 are uninterpretable
because they refer to initial
randomisation, without reflecting
the—quite different treatments—
received during follow-up.
The authors argued: “In so far
as the need to seek additional
treatment is a marker of continuing
illness, these findings support
the superiority of CBT and GET
as treatments for chronic fatigue
syndrome”.1
More participants in
the specialist medical care alone
and the adaptive pacing therapy
(APT) groups received additional
treatments during follow-up than did
those in the CBT and GET groups, but
this fi nding is hardly surprising when
half of participants in the specialist
medical care group rated it as not
being a logical treatment for them
and only 41% were confi dent about
being helped by specialist medical
care.1
This lack of equipoise was
facilitated by the initial description
of treatments investigators off ered
to patients and compounded by a
mid-trial Newsletter for patients
praising the PACE interventions. It
is easy to see how specialist medical
care effectively became a waitlist
control of frustrated suff erers, who
naturally awaited re-assignment.
This limitation casts doubts not only
on the validity of the follow-up data,
but on the integrity of the trial itself.
Putting doubts about the validity
of the PACE follow-up aside, let’s
take a close look at the unadjusted
physical functioning follow-up
data in fi gure 2.1
There are no group
differences, and the overall mean
Published Online
January 18, 2016
http://dx.doi.org/10.1016/
S2215-0366(15)00546-5

Gadawodd Kathryn Dickenson anodiad ()

http://journals.sagepub.com/doi/pdf/10.1...

David Tuller on the PACE trial authors failure to address flaws in the trial.

https://doi.org/10.1177/1359105317703788
Journal of Health Psychology 1–5

Other commentaries in this Special Section focus on specific methodological aspects of the PACE trial. (The study’s full name: “Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome: A randomised trial.”)
I would like to examine how the PACE investigators, in their response to the troubling questions about their research raised in Geraghty’s editorial (Geraghty, 2016), have strategically avoided providing direct answers (White et al., 2017). Instead, they have provided non-answers—persuasive-sounding arguments that fall apart quickly under scrutiny. This approach is consistent with their earlier efforts to rebut legitimate criticism.
The PACE investigators note that they have “repeatedly addressed” the various concerns about the trial, citing journal correspondence as well as popular forums such as blog posts and news articles. A review of some of these publications confirms their point. But “addressing” concerns is not the same as offering credible explanations, and the investigators have failed this test each time they have responded.

Gadawodd Kathryn Dickenson anodiad ()

The USA Centre for Disease Control

https://www.cdc.gov/features/cfsawarenes...

Gadawodd Kathryn Dickenson anodiad ()

The Invest in ME Research 2017. IIMEC12 Pre-conference dinner. David Tuller will be our guest presenter.

David Tuller DrPh, is academic coordinator of University of California Berkeley's joint masters program in public health and journalism. He was a reporter and editor for 10 years at the San Francisco Chronicle, served as health editor at Salon.com and frequently writes about health for The New York Times.

David's presentation - #TearItUp - will include his work in exposing the flaws in the PACE Trial.

His analysis of the PACE (Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome) Trial, and its aftermath, will probably be seen as a pivotal moment when the history of research into ME is written.

By bringing investigatory and scientific analysis to the PACE Trial and exposing and documenting the faults in what has taken place with this trial David Tuller has also brought awareness to how research into ME has been so flawed in the past.

The results of his thorough journalism has brought hope to people with ME and their families who have long called for independent review of the PACE trial, and related research.

David Tuller received the Special Service Award at the October 2016 IACFS/ME conference in Fort Lauderdale, USA and this high-quality and dedicated journalism will surely receive more awards in the future.

References for David Tuller

Undark
Undark Podcast
Virology Blog: TRIAL BY ERROR: The Troubling Case of the PACE Chronic Fatigue Syndrome Study
TRIAL BY ERROR: The Troubling Case of the PACE Chronic Fatigue Syndrome Study (second installment)
TRIAL BY ERROR: The Troubling Case of the PACE Chronic Fatigue Syndrome Study (final installment)
PACE trial investigators respond to David Tuller
David Tuller responds to the PACE investigators
Trial By Error, Continued: Did the PACE Study Really Adopt a ‘Strict Criterion’ for Recovery?
Trial By Error, Continued: Why has the PACE Study’s “Sister Trial” been “Disappeared” and Forgotten?
An open letter to Dr. Richard Horton and The Lancet
Trial by error, Continued: PACE Team’s Work for Insurance Companies Is “Not Related” to PACE. Really?
A request for data from the PACE trial
Revisiting the PLoS One economics analysis of PACE
Trial By Error, Continued: Questions for Dr. White and his PACE Colleagues
Trial By Error, Continued: Did the PACE Trial Really Prove that Graded Exercise Is Safe? (with Julie Rehmeyer)
Trial By Error, Continued: More Nonsense from The Lancet Psychiatry
Trial By Error, Continued: A Few Words About “Harassment”
Trial By Error, Continued: My Questions for Lancet Editor Richard Horton
Trial By Error, Continued: The Real Data

Gadawodd Kathryn Dickenson anodiad ()

Key websites:
Press & research
Added in 2017

TED TALK: Jen Brea describes the obstacles she’s encountered in seeking treatment for her condition: What happens when you have a disease doctors can’t diagnose
Disability News Service:

PIP INVESTIGATION: Assessment reports show widespread dishonesty by nurses

BBC: Research in Norwich could offer ME/CFS breakthrough: Researchers in Norwich are teaming up with researchers from Norway to collaborate on ME/CFS research
Jennifer Brea’s Sundance Winner “Unrest” Acquired by PBS: PBS has bought the U.S. broadcast rights to “Unrest”
The ‘all in the mind’ myth of ME/CFS: From Nursing in Practice – 27 June 2016

PACE Trial latest | MEA to pay for open access to independent reanalysis paper: PACE Trial latest-MEA to pay for open access to independent reanalysis paper

Novel Gene Variants in ME/CFS and Fibromyalgia: From the Bateman Horne Centre Feb 2017

Queensland Scientists Make Chronic Fatigue Syndrome Research Breakthrough: Minister describes a small study showing link to abnormal immune system cells

Centre for Welfare reform essay: In the Expectation of Recovery

Ronald W. Davis, Research update Feb 21st 2017: Significant breakthroughs towards understanding the molecular mechanisms of the disease.. now ready for testing
Ronald W. Davis, PhD, Scientific Advisory Board Director: About Professor Davis

Severe ME left me in a world of pain and darkness. 26 years on, why is it still so poorly understood?: Article on Open Democracy

Pathological mechanisms in ME from Bergen research group : A new study, partly funded by the Kavli Trust
Webinar led by Anthony L. Komaroff, MD, professor of medicine at Harvard Medical School: Useful overview of the state of ME science from late 2016

Impressions from IACFS/ME 2016 : Take-home messages from this conference?

Dr. Mark Van Ness, “Expanding Physical Capability in ME/CFS” Part 1 (of 2) : First of a two-part 2016 ME awareness presentation

Dr. Mark Van Ness, “Expanding Physical Capability in ME/CFS” Part 2 (of 2) : Second of a two-part 2016 ME awareness presentation
Workwell Foundation : Latest news

Added to our website in 2016
Health rising: The IACFS/ME Preconference: ME/CFS and GWI – The Complex Neuroinflammatory Conditions
Open Medicine Foundation: UPDATED: Metabolic Features of Chronic Fatigue Syndrome – Q & A with Robert Naviaux, MD

Open Medicine Foundation: Ronald W. Davis, PhD, Scientific Advisory Board Director

Invest In ME charity discuss the MEGA study, and the Omega counter petition: Find out more about objections to this proposed UK study

From 2015 – but worth watching: scientist dad searches for cure for ill son

Dr Lucinda Bateman from the Bateman Horne Center USA: Global report of progress lecture

Part 1 of three talks given at the Watershed in Bristol: Prof. Mark VanNess on exercise and CFS/ME

Part 2 of three talks given at the Watershed in Bristol: Dr. Nigel Speight on exercise and CFS/ME

Part 3 of three talks given at the Watershed in Bristol: Erina Bowman on exercise and ME/CFS
Workwell Foundation USA: Staci Stevens & Mark VanNess video’s
US Neuroscientist says exercise worsens ME/CFS Symptoms: Prof. J. Mark VanNess from the Californian University of the Pacific
The National Academies of SCIENCES, ENGINEERING, MEDICINE, USA: Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness
Virology blog: Trial By Error, Continued: The Real Data
PLOS blog: Before you enroll your child in the MAGENTA chronic fatigue syndrome study: Issues to be considered
A thoughtful piece relating to education, sick children, and the attitudes of the state: Independent Living and Education
Naviaux’s Metabolism Paper: Researcher at Uni of California publishes a ‘landmark’ paper
US Representatives support letter to NIH in USA for ME/CFS research: 55 members of Congress have signed the letter…
ME Research UK’s Forward ME Group meeting minutes: Reports on their meeting in the House of Lords
ME Research UK publishes a magazine called Breakthrough: Features updates on projects funded by the charity
Parliamentary Question regarding steps to be taken to encourage research into ME: 13th Sept 2016 – politician asks the question..
The Lancet rejects Scientists’ Pace Letter: Update on the letter written to the Lancet by 43 scientists
Soft Tissue Therapy for Fibromyalgia: Clinical trial recruiting participants
Timeline, Torture and Tragedy: Valerie Eliot Smith writes about the case of Karina
FREE Karina: The tragic and ongoing case of Karina Hansen in Denmark
PIP assesment: Dept for Work and Pensions
QMUL RELEASES THE PACE DATA: ME ACTION reports:
Hyperbaric oxygen use in fibromyalgia: Does HBO reduce the symptoms of ME/CFS and firbomyalgia?:
Posts by Valerie Eliot Smith who writes about Law and Health: Here you can see a variety of posts written by Valerie on the subject of QMUL, PACE and the law:
Article in the Proceedings of the National Academy of Sciences of the USA: Metabolic Features of chronic fatigue syndrome:
Article in the Proceedings of the National Academy of Sciences of the USA: Metabolic Features of chronic fatigue syndrome:
Trial By Error, Continued: My questions for Lancet Editor Richard Horton: By David Tuller, DrPH written 1-9-16:
Hope for CFS: Article by Julie Rehmeyer who is also making a documentary about ME/CFS called Canary in a Coal Mine:
Tribunal orders University to release data: From the BMJ news Hub, reported on ME Association website:
You look too well presented to be sick: Poem written after rising a government agency…:
Research paper about Leptin and Fibromyalgia: Association of Leptin with Body Pain in Women:
Invest in ME Research International ME Conference – 2nd June 2017: Running ME Biomedical Research conferences since 2006:
ME Association article: Tribunal orders release of PACE Trial data (courtesy of Valerie Eliot Smith)
Occupy ME article: AHRQ Evidence Review Changes its Conclusions
ME Association article: Tribunal orders university to release data from PACE chronic fatigue study- from BMJ news hub
The Information Tribunal – Government website: The QMUL appeal of 20-22 April 2016 – details of the appeal.
The Centre For Welfare Reform, article: Major breakthrough on PACE trial
USA TODAY. New research sheds light on mysterious fibromyalgia
Columbia Magazine. New hope for those with chronic fatigue syndrome
Occupy ME. Exercise Testing and Using a Heart Rate Monitor
Scientifically Redefining ME/CFS. The Other MEGA Chronic Fatigue Syndrome (ME/CFS) Project: Dr. Hornig Talks
Harvard and Tufts neuroscientist Dr. Michael Van ElZakker shares his fascinating new paper Chronic Fatigue from Vagus Nerve Infection:
A Psychoneuroimmunological Hypothesis. His hypothesis proposes that an infection of the vagus nerve can cause greatly exaggerated chronic sickness responses like fatigue, pain and more. Research paper
Vincent Racaniello speaks to guest journalist David Tuller about the flaws in the UK’s PACE trial, and the efforts to have the trial data release. Excellent for practitioners in the NHS and the general public to listen to, if you wish to be informed. Interview
Invest In ME event. Conference 2016
GMC impose conditions on Dr Speight’s licence to practice. ME Association reports..
Nigel Speight speaks at the Watershed in Bristol. Advisor to ME charities speaks.
New research on Fibro pain. USA Today – report.
The Big Sleep for ME. Invest in ME charity annual event
Search for aetiology of ME/CFS. Search for a rational diagnostic system.
Scientists find clues into cognitive dysfunction in CFS. Research from Columbia University USA.
USA. National Institute for Health – ME news release from 29-10-15. NIH Take action…
Missing Millions international protest – London event. Evening standard report
BBC Radio Bristol programme. The truth about living with ME – 3 women’s stories
ME related petition on a UK government website. Invest more money into scientific research to find the cause of ME/CFS
ME Association CBT, GET, PACING REPORT. No decisions about me – without me
A hard hitting article about what lies behind the attack on disability benefits. The Misleading Research at the Heart of Disability Cuts

Guardian article titled: Is chronic fatigue syndrome finally being taken seriously?
Virtual protest: Missing Millions

Dr Speight speaks at Bristol Watershed

Gadawodd Kathryn Dickenson anodiad ()

http://journals.sagepub.com/doi/10.1177/...

Relevant article regarding PACE

Once again, the PACE authors respond to concerns with empty answers
David Tuller
Abstract
In their response to Geraghty, the PACE investigators state that they have “repeatedly addressed” the various methodological concerns raised about the trial.
While this is true, these responses have repeatedly failed to provide satisfactory explanations for the trial’s very serious flaws.
This commentary examines how the current response once again demonstrates the ways in which the investigators avoid acknowledging the obvious problems with PACE and offer non-answers instead—arguments that fall apart quickly under scrutiny.

Journal of Health Psychology 1–5 ©
The Author(s) 2017 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1359105317703788 journals.sagepub.com/home/hpq
http://journals.sagepub.com/doi/10.1177/...

Gadawodd Kathryn Dickenson anodiad ()

David Tuller - podcast regarding the flaws and faults with PACE and the FOI release ordered by the First Tribunal and International and Worldwide concern about the trial.

No statistical recovery and subjective outcome only. No verifiable objective data released.

http://www.microbe.tv/twiv/twivs-tuller3/

David Tuller returns to discuss the continuing saga of the UK’s PACE trial for chronic fatigue syndrome, including the accusation that he is engaging in libelous blogging.

Dear QM FOI Enquiries,

I refer to my request for a copy of non-identified objective data, from the 5 million pound PACE study.

I am writing to remind you that it is nearly a month since I wrote to you and to advise that I have attached a series of annotations to my request.

The annotations highlight some of the problems with the PACE trial. They help explain the need for transparency and perusal of the objective outcome data from the PACE trial by independent scientists including but not limited to exercise physiologists, exercise cardiologists, exercise neuroscientists.

Independent scientists are those who are NOT connected to, or chosen by the PACE principal investigators Peter White, Michael Sharpe, Trudi Chaldler their adviser Simon Wessley, ardent supporter Ester Crawley or persons who may be unduly under the influence of these mental health professionals.

Further, given that the insurance industry directly benefits from the PACE authors misleading claims it is essential that independent scientists, NOT connected to the insurance industry are able to review the raw data.

I look forward to your response.

Yours sincerely,

Kathryn Dickenson

QM FOI Enquiries, Queen Mary University of London

FOI 2017/F158
 
Dear Kathryn Dickenson
 
Thank you for your email of 6^th May.
 
Firstly, not all of the information you have requested is held. Many of
the measures specified seem to be based on being listed in the trial’s
manuals. However, this has no bearing on what was measured in the trial
and you should refer to the protocol. We do not hold data on VO2 max,
TUAG, sit-stand test, 2 minute walk. We hold the actometer measures, but
only at baseline, not at the other time points requested. The only measure
for which we hold Borg and end heart rate is the step test. There are no
data measured direct after randomisation, at 10 weeks, separately at mid
assessment (this is the 12 week data), separately at the final assessment
(this is the 52 week data) or 39 week time points. No exercise data were
measured at long term follow-up, so these data are not held.
 
With regards to the rest of the data that we do hold, we estimate - given
the time already expended ascertaining what is held as well - that to
provide all of the information would exceed the appropriate limit as
defined by the Freedom of Information and Data Protection (Appropriate
Limit) Regulations 2004. For your information this is £450, calculated as
the estimated cost of one person spending 18 hours in determining whether
the information is held, then locating, retrieving and extracting the
information. Section 12 of the Freedom of Information Act 2000 therefore
makes provision for public authorities to refuse such requests.
 
If you are dissatisfied with this response, you may ask QMUL to conduct a
review of this decision.  To do this, please contact the College in
writing (including by fax, letter or email), describe the original
request, explain your grounds for dissatisfaction, and include an address
for correspondence.  You have 40 working days from receipt of this
communication to submit a review request.  When the review process has
been completed, if you are still dissatisfied, you may ask the Information
Commissioner to intervene. Please see [1]www.ico.org.uk for details.

Yours sincerely
 
Paul Smallcombe
Records & Information Compliance Manager
 

References

Visible links
1. http://www.ico.org.uk/

Dear QM FOI Enquiries,

I note your advice that the protocols described in the PACE manual, have “no bearing on what was measured in the trial”.

On the basis of your advice I have modified my information request to the information that QMUL states was measured, and make the following amendments, to my request for objective physiological/physical data :

1/ Actometer results (BMC reference 18) – QMUL advise that the actometer results were only measured at baseline. Request raw data actometer, baseline measurements.
2/ VO2 max (manual page 40) - QMUL advise this is not held.
3/ TUAG (timed up and go. Chair-stand-walk 3 metres-turn- walk back -sit down (manual page 88) - QMUL advise this is not held.
4/ Sit-stand test (count number in one minute – manual page 88)) - QMUL advise this is not held - QMUL advise this is not held.
5/ 2-minute walk (manual page 88)- QMUL advise this is not held.
6/ 6 minute walk objective measure of recovery (BMC reference 31) – Request raw data.
7/ Self-paced step. Test of fitness (BMC reference 43) - QMUL advise have Borg test (scale of perceived exertion) and end heart rate – Request raw data.
8/ Exercise and activity scale (BMC reference 36) – Request raw data.

9/ For each physiological measure I require, The time, End heart rate and Borg measure. (Borg Scale of perceived physical exertion [BMC reference 44], is used to measure effort with exercise.) QMUL advise that the “only measure for which we hold Borg and end heart rate is the step test” – Request raw data for the heart rate and Borg measure for the step test.

Time periods, that the PACE authors specified they would collect, objective measurements of physical functioning:
10/ Baseline (PACE manual) – request the raw data
After randomisation (BMC) – QMUL advise this measurement did not take place.
10 weeks - QMUL advise this measurement is the 12 week data.
11/ 12 weeks (authors response to review) – request the raw data
Mid assessment (PACE manual) - QMUL advise was not measured
12/ 24 weeks - request the raw data
13/ Final assessment (PACE manual) – request the raw data
14/ 39 weeks - QMUL advise data was not measured at this time point.
15/ 52 week data - QMUL advise this measurement time point is the same as the 39 week time point and the final assessment time point.
16/ One year follow up - request the raw data.
17/ 2.5 year follow up - QMUL advise that data was not obtained at long term follow up.

Hence my modified request is as follows:

i/ Actometer results (BMC reference 18) – raw data actometer, baseline measurements.
ii/ 6 minute walk objective measure of recovery (BMC reference 31).
iii/ Self-paced step. Test of fitness (BMC reference 43), including the Borg test (scale of perceived exertion) and end heart rate.
iv/ Exercise and activity scale (BMC reference 36).

At the specified time periods, that the PACE authors specified they would collect the data:
v/ Baseline
vi/ 12 weeks
vii/ 24 weeks
viii/ Final assessment – 52 week/39 week time point
ix/ One year follow up

I request, that the data is provided in a manner that enables me to distinguish between data from patients with CFS and those with mental health disorders:
(i) Patients diagnosed with CFS and no mental health disorders
(ii) Patients diagnosed with psychiatric disorder
(iii) Patients diagnosed with depressive disorder

Yours sincerely

Kathryn Dickenson

QM FOI Enquiries, Queen Mary University of London

Dear Kathryn Dickenson

You do not appear to have understood our response. Where we do hold data, this has been refused under s.12 of the Freedom of Information Act.

Please accept our email of 5th June as a refusal notice under s.17.

Yours sincerely

Queen Mary University of London

Dear QM FOI Enquiries,

Thank you, for getting back to me.

Yours sincerely,

Kathryn Dickenson

Dear QM FOI Enquiries,

Thank you for your assistance, further to your comments, I have reduced my information request to asking for even less information.

I have reduced the number of time points, removed the request for the exercise and activity scale data and removed, the request for a copy of the data in a format that separated the patients without depressive or psychiatric disorders from those with the mental health issues.

My reduced information request is as follows:
i/ Actometer results (BMC reference 18) – raw data actometer, baseline measurements.
ii/ 6 minute walk objective measure of recovery (BMC reference 31).
iii/ Self-paced step. Test of fitness (BMC reference 43), including the Borg test (scale of perceived exertion) and end heart rate.

At the specified time periods, that the PACE authors specified they would collect the data:
iv/ Baseline
v/ Final assessment – 52 week/39 week time point

Yours sincerely,

Kathryn Dickenson

Dear QM FOI Enquiries,
I refer to my amended FOI request in which I significantly reduced the amount of information requested.
I have not received a response.
Is QMUL proceeding with the amended FOI request?

Yours sincerely,

Kathryn Dickenson

QM FOI Enquiries, Queen Mary University of London

Dear Kathryn Dickenson

We are proceeding with this request now that it has been narrowed. We will be in touch in due course.

Yours sincerely

Queen Mary University of London

Dear QM FOI Enquiries,
After I didn't receive a response to my reduced request for information. I submitted a fresh request. In part as it appears quite likely that this FOI could follow the footsteps of Alem Mattews one and end up before the Information Commissioner, in which case it might be clearer to have the request as a "fresh start".
Hence, I refer you to my request entitled:
"CFS - a small % of the objective physical and physiological data from PACE trial"

Yours sincerely,

Kathryn Dickenson