Wikipedia

PACE (Studie)

umstrittene Studie zu Therapien bei ME/CFS
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Vorlage:Short description

The PACE trial was a large and controversial trial which compared the effects of cognitive behavioural therapy (CBT), graded exercise therapy (GET), adaptive pacing therapy, and specialist medical care for people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).[1][2]

The investigators reported that both CBT and GET were “moderately” effective at treating ME/CFS. The results have been questioned due to methodological weaknesses in the study design. For instance, the definition of recovery was weakened after the data was collected, leading to a larger share of recovered participants. Analyses under the original protocol did not find significant effects.[1][3][2] As of 2021, graded exercise therapy and cognitive behavioural therapy (intended as a treatment) are no longer recommended by the National Institute for Health and Care Excellence for people with ME/CFS.[4]

Initial study and findings

The $8 million trial was funded by various branches of the UK government, including the Department for Work and Pensions.[5][6] Notable authors include psychiatrists Micheal Sharpe and Peter White, along with psychotherapist Trudie Chalder.[1]

Study design

641 patients were selected based on the Oxford Criteria (which is much broader than modern definitions of ME/CFS, only requiring chronic fatigue as a symptom) and divided into four groups. The first group only received specialist medical care (SMC). The second group received SMC and cognitive behavioural therapy (CBT). The third group received SMC and graded exercise therapy (GET). The fourth group received SMC and adaptive pacing therapy (APT), not to be confused with pacing (a recommended management strategy for people with ME/CFS).[5][1]

SMC consisted of specialists giving advice to patients, such as “to avoid extremes of activity and rest”, and the prescription of drugs to help manage symptoms. CBT was done on the basis of a theory that regards ME/CFS as being reversible and that “fear of engaging in activity” and “avoidance of activity” are linked and interact with physiological processes to perpetuate fatigue. APT consisted of telling patients not to do activity, if it increases their symptoms; however, patients were encouraged to increase activity if their symptoms were manageable. GET was done on the basis of theories that assumed that ME/CFS is perpetuated by reversible physiological changes of deconditioning and avoidance of activity.[1]

Outcome measures were assessed at the beginning of the trial, and then at 12, 24, and 52 weeks. Subjective outcome measures included self-rated fatigue and physical functioning questionnaires. Objective outcome measures were a six minute walking test, a fitness test, reception of benefits due to illness, and number of days out of work due to illness.[7] Two and a half years later, there was another follow up using only subjective measures.[8]

The study design had various strengths. The large sample size and randomised allocation of patients into groups of near equal size, increased the precision of findings and, therefore, the likelihood of finding statistically significant outcomes. Additionally the subjects received a substantial amount of therapy (GET or CBT), over an extended duration, which contributed increased precision in the findings.[2]

Initial findings

 
Subjective outcomes at 52 weeks reported by the PACE trial

The findings were published in 2011 and concluded GET and CBT were “moderately effective” treatments. 52 after the beginning of the trial, self-reported fatigue scores were significantly lower and self-rated physical function scores significantly higher for the GET and CBT groups than for the SMC and APT groups. The average scores on a 6-minute walking distance test were higher for the GET group than for the other groups. However, the mean distance walked (334 metres) was still well below the mean for healthy elderly people (631 metres) and over 30% of patients in the GET group did not do the test at 52 weeks.[9] The CBT group did not perform significantly differently from the SMC and APT groups on this measure.[10] A subsequent paper presented results from a step fitness test, but at 52 weeks, there were no significant differences in performance across groups on this measure.[11]

A 2013 paper examined the proportion of patients who could be classified as “recovered” after the trial. A patient was considered recovered if they obtained a specified threshold score on the fatigue and physical function self-report scales, if they rated their health as "much better" or "very much better", and if they also failed to meet the authors' case definition of CFS. According to the primary measures of recovery reported in the paper, 22% recovered after CBT, 22% after GET, but only 8% after APT and 7% after SMC.[12]

A follow-up conducted 2.5 years after the commencement of the trial reported no significant differences between the various treatment groups on the primary self-report measures. That is, the treatment-specific effects evident at 52 weeks were no longer evident at 2.5 years.[8]

Controversies and criticism

After being published, the trial generated considerable criticism and concerns which were voiced through letters to the editor, patient groups, and groups of researchers and healthcare professionals.[13][14][15][16][17] Lancet Editor Richard Horton defended the trial, calling the critics "a fairly small, but highly organized, very vocal and very damaging group of individuals who have, I would say, actually hijacked this agenda and distorted the debate so that it actually harms the overwhelming majority of patients."[18][19]

The study continued receiving criticism from within the scientific community. Ronald Davis of Stanford University wrote, "I'm shocked that the Lancet published it... The PACE study has so many flaws and there are so many questions you'd want to ask about it that I don't understand how it got through any kind of peer review".[3] In an analysis of the study's design, the mathematician Professor Rebecca Goldin wrote that "There were problems with the study on almost all levels... the flaws in this design were enough to doom its results from the start."[20]

Outcome switching

Vorlage:See also Midway through the trial the primary outcome measures were switched.[2] In particular, there was a change in how recovery was defined. One of the original requirements was that patients would need to score over 85 on a survey of physical functioning, indicative of what healthy working-age people score. This was changed to a score of over 60.[21] This meant that some were counted as recovered on this metric at the start of the trial, as the criterion for entry was a score of under 65.[22][21] The authors defended this switch, saying it was “approved by the independent PACE Trial Steering Committee and Data Monitoring and Ethics Committee”.[23] However, a reanalysis of the PACE trial using the original primary outcome measures, found no statistically significant difference between the GET, CBT, and control groups.[2]

Subjective primary outcome measures and placebo

There has been considerable criticism due to the original findings only being supported by subjective (participant reported) primary outcome measures.[3][22][2] Professor Jonathan Edwards of University College London wrote that “[the use of subjective outcome measures in an unblinded trial] makes [the PACE trial] non-starter in the eyes of any physician or clinical pharmacologist familiar with problems of systematic bias in trial execution."[24]

Additionally, the patient newsletter given throughout the study was said to have subtly praised CBT and GET by saying a government committee had approved them as treatments, while critiquing biomedical research in ME/CFS.[25][26] This raised concerns of a possible placebo effect, especially given the subjective outcome measures.[25][3] Biostatistician Bruce Levin of Columbia University, an expert in clinical trial design, said, "To let participants know that interventions have been selected by a government committee 'based on the best available evidence' strikes me as the height of clinical trial amateurism".[27]

Multiple authors of the PACE trial noted potential conflicts of interest in their scientific publications, having worked for or received royalties from disability insurance companies who would benefit from there being a treatment for ME/CFS.[1] These potential conflicts of interest, however, were not disclosed to trial participants. 42 scientists criticised this in an open letter saying it meant there was a lack of informed consent and breached the Helsinki Protocol.[22]

Request for data and allegations of harassment

The full research data for the PACE trial was requested by both patients acting as citizen scientists, and by other researchers, in order to verify the results through reanalyses.[28] However, the request was initially denied and several of the researchers involved in the PACE trial, reported to the press that they had been verbally abused by patients.[29][28] This was criticised by patients and advocates as being a coordinated effort to dismiss legitimate concerns about the methodology behind psychosocial studies into ME.[30][31] However, these allegations continued to gain traction, and some of the authors began saying they were harassed on Twitter (now X).[32]

The argument that ME/CFS patients and their organisations were militant and using methods of harassment was used by the authors to argue against a release of the trial’s data. The Information Commissioner dismissed these claims as "wild speculations" and the tribunal found them to be “grossly exaggerated”. The judge subsequently ordered a release of the data.[28][33]

Reanalysis

After the data was made public, several researchers published a reanalysis of the PACE trial data, but drawing the conclusion that the CBT and GET treatments were not effective and possibly not safe.[34][35][36][2] The full PACE trial data showed that the treatments did not result in patients being able to return to work or study,[37] and that they were not able to walk significantly further after treatment.[2]

The reanalysis using the original primary outcome measures still showed there was a small improvement in one of the two subjective measures at 52 weeks for the GET and CBT groups. However, this difference was not sustained in the long-term follow-up. Additionally, there was no statistically significant difference in recovery rates, with all being low (>10%). The GET group experienced twice the rate of adverse outcomes compared to controls, hence the conclusion that the treatment may be unsafe.[2]

Legacy and influence

The PACE trial was a major piece of evidence used by influential health authorities to recommend cognitive behavioural therapy and graded exercise therapy for people with ME/CFS, such as the CDC (US) and NICE (UK).[38][39] After many years of controversy and criticism of the trial, the CDC (in 2017), then NICE (in 2021) stopped recommending graded exercise therapy and cognitive behavioural therapy (as a treatment).[4][39] As of 2024, the Cochrane guidelines conclude that GET likely reduces fatigue for those diagnosed under older criteria sets, partially based on evidence from the PACE trial.[40]:3

Modern definitions of ME/CFS differ significantly from the 1991 Oxford criteria used by the PACE trial authors. This, along with methodological flaws and reanalyses with different conclusions, puts into question whether their findings are applicable to current ME/CFS patients.[41]

References

Vorlage:Reflist

  1. ↑ a b c d e f White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL, Bavinton J, Angus BJ, Murphy G, Murphy M, O'Dowd H, Wilks D, McCrone P, Chalder T, Sharpe M: Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. In: Lancet. 377. Jahrgang, Nr. 9768, März 2011, S. 823–36, doi:10.1016/S0140-6736(11)60096-2, PMID 21334061, PMC 3065633 (freier Volltext).
  2. ↑ a b c d e f g h i Wilshire CE, Kindlon T, Courtney R, Matthees A, Tuller D, Geraghty K, Levin B: Rethinking the treatment of chronic fatigue syndrome-a reanalysis and evaluation of findings from a recent major trial of graded exercise and CBT. In: BMC Psychology. 6. Jahrgang, Nr. 1, März 2018, S. 6, doi:10.1186/s40359-018-0218-3, PMID 29562932, PMC 5863477 (freier Volltext).
  3. ↑ a b c d An open letter to Dr. Richard Horton and The Lancet. In: www.virology.ws. 13. November 2015, abgerufen am 2. Mai 2016.
  4. ↑ a b Mark Vink, Alexandra Vink-Niese: The Updated NICE Guidance Exposed the Serious Flaws in CBT and Graded Exercise Therapy Trials for ME/CFS. In: Healthcare (Basel, Switzerland). 10. Jahrgang, Nr. 5, 12. Mai 2022, ISSN 2227-9032, S. 898, doi:10.3390/healthcare10050898, PMID 35628033, PMC 9141828 (freier Volltext).
  5. ↑ a b Peter D. White, Trudie Chalder, Michael Sharpe: The planning, implementation and publication of a complex intervention trial for chronic fatigue syndrome: the PACE trial. In: BJPsych Bulletin. 39. Jahrgang, Nr. 1, Februar 2015, ISSN 2056-4694, S. 24–27, doi:10.1192/pb.bp.113.045005, PMID 26191420, PMC 4495840 (freier Volltext) – (englisch).
  6. ↑ David Tuller: TRIAL BY ERROR: The Troubling Case of the PACE Chronic Fatigue Syndrome Study (final installment) | Virology Blog. 23. Oktober 2015, abgerufen am 1. Mai 2024 (amerikanisches Englisch).
  7. ↑ Peter D. White, Michael C. Sharpe, Trudie Chalder, Julia C. DeCesare, Rebecca Walwyn, the PACE trial group: Protocol for the PACE trial: A randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. In: BMC Neurology. 7. Jahrgang, Nr. 1, 8. März 2007, ISSN 1471-2377, S. 6, doi:10.1186/1471-2377-7-6, PMID 17397525, PMC 2147058 (freier Volltext).
  8. ↑ a b 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. In: The Lancet. Psychiatry. 2. Jahrgang, Nr. 12, Dezember 2015, S. 1067–74, doi:10.1016/S2215-0366(15)00317-X, PMID 26521770 (kcl.ac.uk [PDF]).
  9. ↑ Mark Vink: Assessment of Individual PACE Trial Data: in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Cognitive Behavioral and Graded Exercise Therapy are Ineffective, Do Not Lead to Actual Recovery and Negative Outcomes may be Higher than Reported. In: J Neurol Neurobiol. 3. Jahrgang, Nr. 1, Januar 2017, S. 5 (researchgate.net).
  10. ↑ Kewley AJ: The PACE trial in chronic fatigue syndrome. In: Lancet. 377. Jahrgang, Nr. 9780, Mai 2011, S. 1832; author reply 1834–35, doi:10.1016/S0140-6736(11)60681-8, PMID 21592552.
  11. ↑ Chalder T, Goldsmith KA, White PD, Sharpe M, Pickles AR: Rehabilitative therapies for chronic fatigue syndrome: a secondary mediation analysis of the PACE trial. In: The Lancet. Psychiatry. 2. Jahrgang, Nr. 2, Februar 2015, S. 141–52, doi:10.1016/S2215-0366(14)00069-8, PMID 26359750 (kcl.ac.uk).
  12. ↑ White PD, Goldsmith K, Johnson AL, Chalder T, Sharpe M: Recovery from chronic fatigue syndrome after treatments given in the PACE trial. In: Psychological Medicine. 43. Jahrgang, Nr. 10, Oktober 2013, S. 2227–35, doi:10.1017/S0033291713000020, PMID 23363640, PMC 3776285 (freier Volltext).
  13. ↑ IACFS/ME Statement on the PACE Trial: The Issue of Illness 'Reversal'. In: The International Association for Chronic Fatigue Syndrome/ME (IACFS/ME). 24. Februar 2011, archiviert vom Original am 18. Juli 2011; abgerufen am 3. August 2011.
  14. ↑ PACE: 'surprising and disappointing'. In: Action for ME. 18. Februar 2011, abgerufen am 3. August 2011.
  15. ↑ Tony Britton: ME Association press statement about the results of the PACE study. In: ME Association. 18. Februar 2011, abgerufen am 3. August 2011.
  16. ↑ Kimberly McCleary: Falling off the PACE. In: The CAA (CFIDS) Association of America. Archiviert vom Original am 25. Juni 2011; abgerufen am 26. Juli 2011.
  17. ↑ P. D. White, K. Goldsmith, A. L. Johnson, T. Chalder, M. Sharpe: Letter to the Editor: Response to correspondence concerning 'Recovery from chronic fatigue syndrome after treatments in the PACE trial'. In: Psychological Medicine. 43. Jahrgang, Nr. 8, August 2013, ISSN 0033-2917, S. 1791–1792, doi:10.1017/S0033291713001311, PMID 23866117 (englisch, cambridge.org).
  18. ↑ Comparison of treatments for chronic fatigue syndrome - the PACE trial. In: ABC Radio National. 15. April 2011, abgerufen am 24. Mai 2020 (australisches Englisch).
  19. ↑ Julie Rehmeyer: The Debate Over Chronic Fatigue Syndrome Is Suddenly Shifting. In: Slate Magazine. 13. November 2015, abgerufen am 24. Mai 2020 (englisch).
  20. ↑ Rebecca Goldin: PACE: The research that sparked a patient rebellion and challenged medicine. In: Sense About Statistics. 21. März 2016, archiviert vom Original am 21. Dezember 2016;.
  21. ↑ a b Keith J Geraghty: Further commentary on the PACE trial: Biased methods and unreliable outcomes. In: Journal of Health Psychology. 22. Jahrgang, Nr. 9, 2017, ISSN 1359-1053, S. 1209–1216, doi:10.1177/1359105317714486, PMID 28805517 (englisch, sagepub.com).
  22. ↑ a b c Vincent Racaniello: An open letter to The Lancet, again | Virology Blog. 10. Februar 2016, abgerufen am 27. April 2024 (amerikanisches Englisch).
  23. ↑ Vincent Racaniello: PACE trial investigators respond to David Tuller | Virology Blog. 30. Oktober 2015, abgerufen am 27. April 2024 (amerikanisches Englisch).
  24. ↑ Edwards J: PACE team response shows a disregard for the principles of science. In: Journal of Health Psychology. 22. Jahrgang, Nr. 9, August 2017, S. 1155–1158, doi:10.1177/1359105317700886, PMID 28805520.
  25. ↑ a b Coyne, James (October 29, 2015), Uninterpretable: Fatal flaws in PACE Chronic Fatigue Syndrome follow-up study, PLoS One Blog, archived from the original on May 6, 2016
  26. ↑ PACE Trial Management Group(December 2008), PACE trial participants' newsletter #3,https://www.qmul.ac.uk/wiph/media/the-wolfson-institute-of-population-health-wiph/documents/participantsnewsletter3.pdf, access-date 27-04-2024
  27. ↑ David Tuller: TRIAL BY ERROR: The Troubling Case of the PACE Chronic Fatigue Syndrome Study | Virology Blog. 21. Oktober 2015, abgerufen am 27. April 2024 (amerikanisches Englisch).
  28. ↑ a b c Blease C, Geraghty KJ: Are ME/CFS Patient Organizations "Militant"? : Patient Protest in a Medical Controversy. In: Journal of Bioethical Inquiry. 15. Jahrgang, Nr. 3, September 2018, S. 393–401, doi:10.1007/s11673-018-9866-5, PMID 29971693.
  29. ↑ Hawkes N: Dangers of research into chronic fatigue syndrome. In: BMJ. 342. Jahrgang, Juni 2011, S. d3780, doi:10.1136/bmj.d3780, PMID 21697226.
  30. ↑ Tuller D: Trial By Error, Continued: A Few Words About Harassment | Virology Blog. 1. Februar 2016, abgerufen am 15. April 2024 (amerikanisches Englisch).
  31. ↑ George Monbiot: 'You don't want to get better': the outdated treatment of ME/CFS patients is a national scandal In: The Guardian, 12. März 2024. Abgerufen am 30. April 2024 (britisches Englisch). 
  32. ↑ Katie Kelland: Online activists are silencing us, scientists say In: Reuters, 13. März 2019. Abgerufen am 30. April 2024 
  33. ↑ TRIBUNAL ORDERS RELEASE OF WITHHELD DATA FROM CONTROVERSIAL £5 MILLION CHRONIC FATIGUE SYNDROME STUDY In: ME Action Press Release, 16. August 2016, S. 1–2. Abgerufen am 1. Mai 2024 
  34. ↑ Vink M: PACE trial authors continue to ignore their own null effect. In: Journal of Health Psychology. 22. Jahrgang, Nr. 9, August 2017, S. 1134–1140, doi:10.1177/1359105317703785, PMID 28805519.
  35. ↑ Vink M, Vink-Niese A: Graded exercise therapy for myalgic encephalomyelitis/chronic fatigue syndrome is not effective and unsafe. Re-analysis of a Cochrane review. In: Health Psychology Open. 5. Jahrgang, Nr. 2, 8. Oktober 2018, S. 2055102918805187, doi:10.1177/2055102918805187, PMID 30305916, PMC 6176540 (freier Volltext).
  36. ↑ Twisk FN, Maes M: A review on cognitive behavorial therapy (CBT) and graded exercise therapy (GET) in myalgic encephalomyelitis (ME) / chronic fatigue syndrome (CFS): CBT/GET is not only ineffective and not evidence-based, but also potentially harmful for many patients with ME/CFS. In: Neuro Endocrinology Letters. 30. Jahrgang, Nr. 3, 2009, S. 284–99, PMID 19855350.
  37. ↑ Vink M, Vink-Niese F: Work Rehabilitation and Medical Retirement for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. A Review and Appraisal of Diagnostic Strategies. In: Diagnostics. 9. Jahrgang, Nr. 4, September 2019, S. 124, doi:10.3390/diagnostics9040124, PMID 31547009, PMC 6963831 (freier Volltext).
  38. ↑ NICE guideline committee (February 2014), NICE guidelines (CG53) - Chronic fatigue syndrome / myalgic encephalomyelitis (or encephalopathy): review decision
  39. ↑ a b David Tuller: Trial By Error: The CDC Drops CBT/GET | Virology Blog. 10. Juli 2017, abgerufen am 30. April 2024 (amerikanisches Englisch).
  40. ↑ Lillebeth Larun, Kjetil G Brurberg, Jan Odgaard-Jensen, Jonathan R Price: Exercise therapy for chronic fatigue syndrome. In: Cochrane Database of Systematic Reviews. 2021. Jahrgang, Nr. 3, 2. Oktober 2019, S. CD003200, doi:10.1002/14651858.CD003200.pub8, PMID 31577366, PMC 6953363 (freier Volltext) – (englisch).
  41. ↑ NG206 Evidence reviews underpinning recommendations and research recommendations in the NICE guideline. In: National Institue for Health and Care Excellence. Oktober 2021, S. 63, abgerufen am 30. April 2024.
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