PACE trial TSC and TMG minutes released

Lucibee · Mar 31, 2018

More evidence that the SMC group wasn't a control group (from TMG #15):

*facepalm*

Indigophoton · Mar 31, 2018

According to the TMG minutes, the PACE trial sessions were to be blind reviewed by nurses from the FINE trial, whose views regarding ME/CFS patients were recorded during FINE as being very hostile at times:

https://twitter.com/user/status/980081272918814723

https://twitter.com/user/status/980086277172277250

Lucibee · Mar 31, 2018

Does anyone have back issues of the ME Association magazine from 2004? I'm trying to find the article that mentions the PACE trial from that time. It's mentioned in the TSC/TMG minutes, with accusations of a "concerted campaign" against the trial.

Esther12 · Mar 31, 2018

Lucibee said: ↑

Does anyone have back issues of the ME Association magazine from 2004? I'm trying to find the article that mentions the PACE trial from that time. It's mentioned in the TSC/TMG minutes, with accusations of a "concerted campaign" against the trial.
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I don't, but I know these TSC minutes were previously released, so it could have been referring to these? [two sets of minutes posted in three posts]:

The PACE Trial

First Meeting of Trial Steering Committee

Held on 22" April 2004

at

St Bartholomew's Hospital, London Draft Minutes

Present: Janet Darbyshire (Chair), Trudie Chalder, Peter White and Michael Sharpe (Principal Investigators), Rebecca Walwyn (Trial Statistician), Stella Harris, Tom Sensky and Meirion Llewelyn (Independent Members), Clare Chilvers (Observer Department of Health R & D), Robin Buckle (Observer MRC). Dawn Duncan and Elizabeth Mitchell (MRC) attended the item regarding PR policy.

Apologies Recelved: Peter Craig (Observer, Scottish Chief Scientists Oﬂice), Susan Lonsdale (Observer, DH), Mansel Aylward (Observer, Department for Work and Pensions). '

INTRODUCTION Professor Darbyshire welcomed everyone to the meeting and clariﬁed that the function of the meeting was ensure that everything was in place for the beginning of the trial.

PROPOSED MEMBERSHIP OF THE TSC

The membership of the existing TSC was agreed but it was also suggested that it would be worth inviting additional members. It was suggest that Chris Clark, CEO of Action for ME should be invited as observer, and that we should also invite an independent physiotherapist and occupational therapist to ensure that these views were represented on the committee. It was suggested that these individuals ought to be from outwith the field of CFS/ME and have experience in a complementary area such as cardiac rehabilitation or chronic pain. Endorsement of their membership by the appropriate professional bodies was desirable but we would not require that they would be regarded as representative.

Action: PW to invite Chris Clark, as an observer.

Action: PW to suggest names of a physiotherapist and occupational therapist for approval by the TSC Chair.

REMIT OF THE TSC

The remit of the TSC and the MRC guidance were discussed. It was noted that the TSC's terms of reference were as follows:

1. To monitor and supervise the progress of the trial towards its objectives.

2. To review relevant information from other sources (e.g. other related trials)

3. To consider the recommendations of the data monitoring committee.

4. In the light of l, 2, and 3, to inform MRC Council and the relevant research boards on the progress of the trial.

5. To advise MRC Council on publicity in the presentation of all aspects of the trial.

To the above Janet Darbyshire suggested we add oversight of the publication and presentations plans and ancillary study policy. It was suggested that the TSC did not have to `micro manage' this, but would like to be informed, and would also act as a court of appeal in the case of dispute that was irresolvable at the TMG level.

Action: Pls to keep TSC informed of proposed publications Action: Pls to keep TSC informed of all TMG approved ancillary studio

Conflicts of Interest All members of the committee present at the meeting were asked to declare any conflict of interest. No ﬁnancial conflicts of interest were declared and it was agreed that no one present had any other substantial or material conﬂict relevant to their work on the committee.

Action: PW to write to all members outlining potential conflicts of interest, and invite replies.

MEMBERSHIP OF DATA MONITORING COMMITTEE

It was noted that Dr Charlotte Feinmann (UCL), and Professor Astrid Fletcher (London School of Hygiene and Tropical Medicine) had agreed to be members of the data monitoring committee. Professor Sharp was unable. It was noted that the DMC required a remit based on the MRC guidance but tailored to the individual trial. The MRC CTU was currently writing a charter for DMCs, and it was hoped this would be available for the PACE DMC. It was suggested that the DMC meet before the trial begins, possibly with the TSC.

Action: Pls to identify possible Chair. Action: RB would send on the MRC charter for DMCs to the members, once available.

TRIAL MANAGEMENT STRUCTURE Peter White outlined the management structure consisting of the TSC, DMC, TMG, six clinical centres, and the CTU. The target date for first randomisation is 11th October 2004.

The TSC commented on the importance of ensuring trial procedure and data quality, particularly eligibility criteria and consent, primary outcome data, and treatment received. Various strategies for checking quality were discussed, including site visits and auditing of hard copies against the electronic database.

Action: The TMG will oversee the establishment of standard operating procedures (SOPs) to check the quality of all these data.

TRIAL SPONSORSHIP

The MRC's change in policy regarding trial sponsorship was noted. The importance of ensuring indemnity was noted.

Action: The Pls would ensure that each trial centre has local sponsorship with Queen Mary taking overall sponsorship responsibility for the trial. Action: PW will invite a representative from Queen Mary to sit as an observer on the TSC. Action: Each centre leader would ensure proper indemnity cover was available, to be checked by the PIs. Action: All these decisions would be checked by the TSC.

PUBLIC RELATIONS STRATEGY

The need for active public relations strategy that involved the PIs, TMG, MRC, and Action for ME was strongly endorsed. Elizabeth Mitchell and Dawn Duncan from the MRC attended for this part of the meeting. A discussion paper was circulated. It was agreed that the MRC wished to address PACE in the context of their general scientific programme and particularly within public education concerning clinical trials. The TSC advised that PACE should be considered in relation to other similar studies, such as the FINE study, rather than stand alone. The TSC suggested that the PR policy for potential and actual participants was particularly important. It was also agreed that there needed to be a specific working group to plan the public relation strategy and that this would have the following elements.

a) Positive public education and information about the trial.

b) Ensuring accurate information reaches the potential and actual participants who took part in the trial.

c) The correction of disinformation being circulated about the trial.

Dawn Duncan and Elizabeth Mitchell were thanked for their involvement so far in answering media enquiries, parliamentary questions, and queries from private individuals. The MRC was already writing answers to frequently asked questions which could be placed on their web site. It was agreed that the principal investigators would meet with the MRC and Action for ME to develop a media strategy.

The TSC suggested that it would be willing to act as an advisory body and even an authoritative source for PR on behalf of the trial.

The issue of making the names of members of the TSC and DMC conﬁdential was discussed, but it was thought that this could be counter-productive.

Action: Pls and the MRC will meet to agree a PR strategy and policy, as suggested above.

REVIEW OF THE PROTOCOL

page by page review of the protocol was undertaken.

Major points were as follows:

1. It was noted that the MRC will no longer be the sponsor of the trial, and that this needed to be clariﬁed. It was likely that the trial sponsor would be Queen Mary's College with functions delegated to the other centres. It is noted that research governance (but not sponsorship rules) is a devolved function regarding the Scottish centre.

Action: PI: and centre leaders

2. There was a discussion about the trial aims and the extent to which it would be able to determine the predictive value of speciﬁc CFS/ME diagnostic criteria. It was suggested that we stratify by type of diagnosis if we wished to do this. This will need to be discussed with the trial statistician.

Action: TMG agenda item

3. It was agreed that a detailed screening Standard Operating Procedure (SOP) was required in the appendix. In particular a policy for screening for coeliac disease was required.

Action: T MG agenda item

4. The recruitment estimates were noted and these need to be reviewed. It was particularly noted that it may be worth training the clinicians who would be recruiting patients into the trial in recruitment strategies and procedures. Action: Protocol change and TMG agenda item

5. The issue of blindness to treatment allocation was discussed. It was agreed after discussion that in practice it was not possible to keep the research nurses truly blind to treatment allocation, and therefore it was recommended not to attempt this. It was noted that there was no plan to keep the doctors giving usual specialist care (USC) blind to treatment allocation.

Action: Protocol change and TMG agenda item

6. Because of this it was argued that consideration should be given to an independent "objective" examination of outcome for example by video or audio-taping interviews. However, as the outcomes are self rated it was unclear that this would add additional data in particular, as there were already walking and ﬁtness tests. This matter was let for further consideration by the principal investigators.

Action: TMG agenda item

7. The outcome measures were discussed. It was noted that they may need to be an adjustment of the threshold needed for entry to ensure improvements were more than trivial. For instance a participant with a Chalder score of 4 would enter the trial and be judged improved with an outcome score of 3. The TSC suggested one solution would be that the entry criteria for the Chalder scale score should be 6 or above, so that a 50% reduction would be consistent with an outcome score of 3. A similar adjustment should be made for the SF -36 physical function sub-scale. It was also suggested that as well as measuring the proportions of participants who improved in fatigue and functioning separately, we ought to also look at the proportions who improve on both. Action: Protocol change and TMG agenda item

8. The need to review the content of therapy sessions was discussed and it was noted that we did not need a sample from every patient but merely from every therapist, in order to judge therapy discrimination.

Action: Protocol change and TMG agenda item

9. It was noted that when monitoring quality control of therapy and data that it would worth being ﬂexible, scrutinising more intensively at early stages in the trial. Action: PIs and Trial Manager

10. It was noted that severe adverse events (SAEs)(e.g. a patient having a stroke) was not necessarily severe adverse reaction (SARs) to treatment. Therefore, the procedure for notifying every one of severe adverse reactions did not apply to all severe adverse events. It was also noted that SARs need to be operationalised into mild, moderate d severe. Finally, it was important to discriminate SARs of the supplementary therapies from SARs to USC. The deﬁnition of SARs in this trial is complex and requires further consideration

Action: Protocol change and TMG agenda item

Action: Agenda item for next TSC

11. The data monitoring committee safety role would require it to monitor for deterioration of partcicipants in a particular group, as judged by outcome data. It was noted that there needs to be agreement between the Pls, the Chair of the TSC, and the DMC about under which circumstances the trial might be stopped. Action: Pls, JD and DMC to meet in September

Action: Pls to include in DMC remit

12. It was noted that if patients were found to have signiﬁcant psychiatric disorder requiring treatment (e.g. major depressive disorder) as a consequence of the psychiatric interview at the beginning of the trial, it would be desirable and ethically necessary to inform the doctor providing USC.

Action: SOP for Research Nurse to be written by PI: and trial manager

13. SUSMC needs describing in more detail (Since SUSMC will not be standardised, SUSMC should really be Usual Specialist Care (USC)) Action: TMG agenda item

A number of minor comments were made on the protocol which will be amended accordingly. These included:

1. Making the abstract understandable by a lay audience

2. Making the aim of the trial explicitly to : " improve informed choice for patients by increasing evidence about treatments"

3. Consider training participant recruiters

4. Measure the plausibility of therapy for the participant after the first session 5. Ask the therapist to rate the response to treatment (Added note: This is is something we could ask the USC doctor to do.)

6. Add the fact that three centres will start recruitment in year 1 and three in year 2.

7. The CRF needs to be in the appendix 8. Measure the likely power of the trial to ﬁnd statistically signiﬁcant differences in the walking test as an objective outcome measure

THERAPY MANUALS The therapy manuals were tabled, but there was insufficient time to discuss them. It was agreed that members and observers with comments should pass them on to the principal investigators. Action: All and Pls

NEXT MEETING OF THE TSC It was agreed that the ﬁnal protocol can be signed off by the chairman of the TSC unless issues arise that require a further meeting. It is anticipated that the TSC would need to meet every six to twelve months throughout the trial but would only need to meet again before patient recruitment started (estimated in October 2004) should there be difficulty in resolving any of the above issues.

Action: PW to arrange next meeting in liaison with JD

Action: JD to be sent ﬁnal protocol and to decide if she can sign off as above

FIRST MEETING OF THE DMC This will be held in September, attended by the Chair of the TSC, the trial statistician, the trial manager and the three Pls. Action: PW to arrange this meeting once membership of the DMC is conﬁrmed

MS, PW and TC 24/4/04 Minutes revised I6/5/04
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Esther12 · Mar 31, 2018

(This set of minutes needed to be split over two posts itself - part 1)

Joint meeting of the Trial Steering Committee and Data Monitoring and Ethics Committee
2pm to 5pm, Monday 27th September. 2004
Treasurer's Room, North Wing. St Bartholomew's Hospital. West Smithfield, London, EC1A 7BE

1. Present
TS members
TSC Chair Independent Members
Janet Darbyshire
Je'nny Butler
Patrick Doherty
Stella Harris
Meirion Llewelyn

Observers
Robin Buckle (MRC)
Clair Chilvers (DH R&D) Chris Clark (AfME)
Peter Craig (Scottish CSO) Stephen Stansfeld (QMUL)

Principal Investigators
Trudie Chalder
Michael Sharpe
Peter White

Trial Statisticians
Tony Johnson
Rebecca Walwyn

Administrator to TSC
Julia Decesare

DMEC members DMEC Chair
Paul Dieppe

2. Apologies received

TSQ Members Independent Members

Tom Sensky

Observers

Mansel Aylward (DWP) Susan Lonsdale (DH)

DMEC Members

Charlotte Feinmann Astrid Fletcher

3. Introduction

Professor Darbyshire welcomed everyone to the meeting and clariﬁed that the function of the meeting was to have ﬁnal discussions about the trial

Version 1.2 27/09/2004

lSRCTN54285094

documentation before it is sent to MREC, after which the trial will hopefully begin.

4. New members of the TSC

All members present introduced themselves. giving their affiliation and function within the TSC.

5. Members of the DMEC

The DMEC membership was conﬁrmed. Unfortunately only Paul Dieppe, the Chair of the DMEC, was available to attend this meeting.

8. Revisions to draft agenda

It was noted that the standardised Specialist Medical Care (SSMC) manual would also be discussed at this meeting. Professor White also noted that two documents had been tabled for discussion at this meeting which had not been previously discussed; these were the Diagnostic Criteria and the Trial Schedule.

Professor White also took this opportunity for thanking everyone for their time and support. and to apologise for the large volume of paperwork that accompanies this particular trial.

7. Previous minutes of TSC # 1

Only one amendment was requested to the previous minutes, to correct the spelling of Professor Clair Chilvers.

Professor Darbyshire led with a review of the action points from the last meeting.

Summary of matters discussed:

a) TSC remit

The remit of the TSC was reviewed for the benefit of new members.

b) Annual reports It was determined that annual reports from the TSC to the MRC should be submitted annually from the date of this meeting.

c) Ancillary studies The policy on ancillary studies was conﬁrmed by the TSC. The TMG will review applications submitted for ancillary studies, and will inform the TSC of applications accepted. The TSC request a running list of such studies, with information of how much extra burden this will place on the participants. The TSC might still choose to reject a study, and the wording of Appendix 5 should reﬂect this.

ACTION 1: Julia Decesare to complete: Amendment to be made to Appendix 5 of the protocol to reflect this decision.

d) Conflicts of interest

Professor White conﬁrmed that letters had been received from all TSC members confirming no one had any conﬂict of interest.

e) Sponsorship Queen Mary University of London (QMUL) is conﬁmied as the overall Sponsor for PACE. Local sponsorship for each Centre is being arranged. Professor Stephen Stansfeld as Head of Psychiatry attended the TSC as an observer for QMUL.

f) Protocol It was noted t at all suggested amendments to the protocol had been made, however, discussion of the objectives and adverse events would be discussed further at this meeting.

8. Remit of DMEC and trial stopping policy

The remit of the DMEC as laid out in MRC GCP Guidelines (1998) was reiterated, and Professor Darbyshire confirmed that PACE is working in line with this guidance. Professor Dieppe confirmed that he is happy with this and stated that very few SAEs would be expected for this trial. Interim analyses would only be conducted if required. and in the ﬁrst instance. the analysis would be a blinded analysis.

ACTION 2: The TSC request that the DMEC monitor patient safety, harm and disability for each treatment arm.

9. Schedule of approvals and start of randomisation

a) Professor White talked through the schedule of activities to be completed before the trial may open to patient randomisation. In particular, the piloting of the manuals was discussed, with particular reference to the Adaptive Pacing Therapy (APT) manual. As this is a therapy being designed speciﬁcally for PACE that has never previously been tested in a randomised trial for patients with CFS/ME, this manual requires slightly more thorough piloting than the more established therapies. As a consequence, the manual might be altered even after the MREC submission has been made. The TSC then gave advice to the Pls, and this is summarised below:

b) Professor Jenny Butler advised the Pls to make direct contact with the MREC chairman to explain this issue, and request a rapid approval process for ﬁnal amendments to the manuals so that the start of trial is not subject to significant delays. For example minor amendments could be sent to the MREC for their information only.

c) Professor Patrick Doherty stated that new procedures would be of more concern to the MREC rather than new information on procedures already described.

10. Approval of PACE protocol ﬁnal version 2, revised in the light of previous TSC

Professor Darbyshire led a page-by-page review of the protocol.

a) Stella Harris asked for an explanation as to why the name of the medical care treatment for the trial had now been altered to standardised Specialist medical Care (SSMC). It was explained that the clinic doctors would be working within a remit of what advice and medications they could give. The term `specialist' refers to the fact that the patient will be seen by a CFS specialist in the clinics.

b) Professor Chilvers identiﬁed a discrepancy between the hypotheses stated in section 5.2.3, and those listed in 12.3.1

ACTION 3: Professor White to complete: Protocol section 12.3.1 to be amended to reflect the hypotheses stated in section 5.2.3.

c) Professor Darbyshire asked for confirmation from the Pls that the expected recruitment graph accurately reﬂects likely recruitment rate. Professor White detailed how these ﬁgures had been devised.

d) Professor Dieppe asked for an explanation of the back loading of recruitment. Professor White explained that this was a funding issue, and that the MRC had requested spending to be back loaded, and three centres to begin recruitment in advance of the other three centres. Professor Sharpe explained the usefulness of this strategy in that it should enable much of the trial troubleshooting to be achieved in the ﬁrst year, enabling the second round of centres to have a smoother ride.

e) Professor Darbyshire recommended that the medical exclusion criteria be detailed in the appendix of the protocol.
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Esther12 · Mar 31, 2018

Part 2 of the above minutes.

ACTION 4: Professor White to complete: Medical exclusion criteria to be added to the protocol as an appendix with more detail added.

f) Professor White explained the difﬁculties with selecting diagnostic criteria for CFS/ME, and explained that there has been a certain amount of pressure from the ME Association to use the Canadian criteria over those that have been selected for the study (London. Oxford and CDC). Professor Sharpe went on to explain this stating that the criteria should be selected for their reliability, validity and feasibility. None of the available criteria can conﬁdently be described as reliable, and therefore criteria have to be selected on the basis of validity and feasibility. The London, Oxford and CDC criteria are feasible, the Canadian criteria are not. In terms of validity, the Oxford or CDC criteria have previously been used in research, but not the London or Canadian criteria. Professor Sharpe also explained that direct communication had taken place between Professor White and the authors of the Canadian criteria who confirmed that as written these are not suitable for research purposes and would require ad hoc operationalisation. This coupled with the fact that the procedures themselves can be intrusive suggests we should not use the Canadian criteria. The TSC were satisﬁed with this explanation.

9) Professor Darbyshire asked whether there was any reason why the three belief questions had been separated out and suggested that these might simply be listed as one item, `Belief questionnaire' in the protocol.

ACTION 5: Julia DeCesare to complete: The three belief questions to be described as one item throughout the protocol.

h) Professgr Dieppe asked why only two subscales of the SF36 were being used, and not the entire SF36 questionnaire. Professor White explained that this decision had been made in order to reduce the questionnaire load to patients. Items covered by other SF36 sub- scales, were already being addressed with the use of other questionnaires. e.g. three CDC asks about ﬁve different types of pain.

Professor Butler asked whether the questionnaires had been piloted to tests how long they would take to complete. Professor White stated that this was still to be done as part of research nurse training, but pointed out that a number of these questions would be asked by the research nurses and not all questionnaires listed were self report. In addition, the baseline assessments are to be divided between two visits. and questionnaires will be sent to the participant's home address in advance of any research visit thus reducing the load to the patient. Professor Sharpe reinforced this by stating that clinical experience demonstrates that this group of patients are very tolerant of testing, and visits of one to two hours were routine in normal clinical practice.

Professor Darbyshire recommended that the order of tests be set according to importance of data.

ACTION 6: Julia Decesare to complete: Case Report Form booklets to be designed with order of importance of questionnaires in mind.

k) Discussion took place about the consent and information sheet with particular reference to following patients up after they have completed the trial.

ACTION 7: Julia Decesare to complete: Item 10 on the consent form to be split into two parts; patients should give explicit consent to allow
their records to be followed up for ten years after the end of the trial, and separately, that ONS (England) and ISD (Scotland) may be used to find the patient if they are lost to follow-up. This information should be mirrored in the participant information Sheet.

I) Section 8 was discussed and recommendations for re-wording this section made.

ACTION 8: Professor White to re-write section 8 as per TSC recommendation.

m) Professor White led discussion on the outcomes, and the TMGs struggle to ﬁnd an objective outcome measure as requested by the TSC at their last meeting, particularly as CFS/ME is a subjective condition. It is proposed that the protocol does not alter from the three primary objectives already set.

n) Professor Butler recommended that an extra measure be added for participation in life, and that the ICF scales be explored.

ACTION 9: Professor Chalder to investigate the use of a five point measure of Work and Social Adjustment Scale (Marks at al) used previously In research.

ACTION 10: Professor Sharpe to contact Derrick Wade of the ICF to ask for other recommended measures.

o) Professor Darbyshire led discussion about how to define `improvement'. Professor Dieppe stated that in order to identify `damage' by any treatment arm, it would be important to know how patients receiving no treatment would be expected to progress. The question was asked `how soon will you know if a participant is getting worse?' to which Professor Chalder responded that previous research has shown that it cannot be determined if people are getting better until at least six months after the end of therapy (i.e. a year after therapy has begun). CBT and GET may both make a patient worse before they begin to improve. Professor Sharpe clariﬁed that there is a difference between transient and persistent deterioration. It was felt important that the DMEC be aware of this short term differential effect.

ACTION 11: Professor White to add into section 10.3 (monitoring adverse outcomes) a defined drop in SF36 score.

ACTION 12: DMEC: An explicit definition of deterioration should be produced before the first review by the DMEC next year. At six months and one year after the trial opens for randomisation, the DMEC (and statisticians) will review SAEs, CGI and SF36 scores to see if there Is a normal distribution. In addition, previous trials will be reviewed to aid categorisation of deterioration.

p) Professor Darbyshire asked that section 10.6 (therapeutic input) be revised.

ACTION 13: Professor Sharpe to revise the therapeutic input questions.

ACTION 14: Professor White to add in `analysis of deterioration of primary outcomes' to section 12 of the protocol.

ACTION 15: Professor Sharpe to amend section 13.2 (regarding the use of NHS number) to be relevant to the Edinburgh centre.

q) Section 14 on adverse events was carefully reviewed as this has undergone substantial revision since the last TSC meeting. It was felt that a `new' disability might be irrelevant in the context of PACE.

ACTION 18: Julia Decesare to replace `new' with `increased' in section 14.1.1

ACTION 17: Julia Decesare to remove exercise equipment from section 14.2.

ACTION 18: Julia DeCesare to reference MRC GCP Guidelines (1998) in section 17. and to add in information on indemnity as provided through NHS R&D.

ACTION 19: Robin Buckle to check under the new MRC sponsorship agreement what indemnity the MRC offer.

ACTION 20: Julia DeCesare to make minor amendments to section 18 as discussed (removal of word `annually', clarify that `significant and consistent deterioration will be quantified at the first meeting of the DMEC').

r) Professor Chilvers recommended that the publication policy (section 19) be clarified in greater detail, and that a decision should be made about order of authorship. and for the main publication, the TMG should consider authorship as the `PACE trial team`.

ACTION 21: Julia Decesare to amend section 19 to reﬂect this suggestion.

s) Professor Darbyshire noted that the term CFS/ME has not been used consistently and is absent from the trial title.

ACTION 22: Julia Decesare to amend the protocol and afﬁliated paperwork to ensure that CFS/ME is used consistently.

ACTION 23: Julia DeCesare to ensure that ISD is also mentioned (to reflect Scottish practice) where the protocol and information currently only refer to ONS.

t) Professor Chilvers recommended re-phrasing the paragraph on alternatives for treatment in the PIS.

ACTION 24: Julia Decesare to rephrase the paragraph on alternatives for treatment in the PIS `Depending on where you are, the following treatments may or may not be available'.

ACTION 25: Julia Decesare to rephrase PIS section `Benefits of taking part' according to Professor Darbyshire's suggestion: `we hope that the treatment you receive will be of help to you'.

ACTION 26: Julia Decesare to ensure that Professor Butler's suggestion to ensure that 10 year long term follow-up is included in the PIS and Consent Form.

ACTION 27: Julia Decesare to re-word paragraph three of the GP letter according to Professor Chllver's recommendation.

u) The Pls were asked why the trial was only open to patients able to speak and read English. it was explained that it would be too costly to train up and employ non-English speaking therapists for what was likely to be a very tiny minority of potential participants. The therapies could not be assured if delivered through an interpreter. As the primary outcomes are self-report measures, and many of the scales to be used have not been validated for use in other languages, it would be very difficult to fairly represent non-English speakers. The TSC were satisﬁed with this explanation but asked that this be clariﬁed in the protocol.

ACTION 28: Professor White to add a line to the protocol to explain this.

11. Participant recruitment targets

a) The TSC stated that they were happy with the proposed recruitment rate. Professor Dieppe asked whether this rate had been piloted, and expressed anxiety that recruitment might be impede by the anti- PACE/FINE lobbyists. Professor Sharpe and Professor White explained how this rate and been derived, and stated that lobby groups had not previously affected recruitment in trials of GET, which is the most controversial of the therapies to be tested.

b) Professor Butler asked whether there was a real danger of patients withdrawing from the trial after randomisation if they are not allocated their preferred treatment. Professor Dieppe reinforced this and stated that he had seen similar happen on a previous trial. Professor Sharpe stated that the two stage consent process was designed to minimise this and that the research nurses would be trained to try to prevent this occurring. Professor Chalder stated this problem might be seen as a
centre effect, with patients wanting CBT if they are being seen at King's, or GET if they go to Barts.

ACTION 29: Julia DeCesare/Barts Data Manager should carry out careful checks for duplicated participants. This should be added into the trial SOP.

12. Medical Screening Standard Operating Procedure (SOP)

a) Professor White noted that there were three changes already planned for this document: i. `Physician' should read `doctor' ii. Under medical history, patients with hyperventilation or somatization disorder would not be excluded. iii. The exclusions would be added. The TSC were happy with this document, with the addition of more detail to be added (see above).

ACTION 30: Julia DeCesare to re-word the Medical Screening Standard Operating Procedure according to Professor White's recommendations.

13. Approval of revised Adaptive Pacing Therapy (APT) therapist manual and participant manuals and hand-outs

a) Professor Butler expressed concern that the APT manual appeared to be considerably smaller than those for CBT and GET. Recommendations including copying the format of the GET manual for information on engaging the patient, the initial assessment and troubleshooting such as `what to do if your therapist is on holiday'. it was stated that APT should have equal face validity to the other therapies, and that because this was a new treatment and one advocated by the patient groups, it was important to make this treatment of equal quality. Chris Clark was asked to comment on whether there were items for pacing that could be included that reﬂect users views. Chris stated that the surveys carried out by AfME produced a wealth of complex answers and that these could not be easily included.

b) Professor Butler also expressed concern that the cognitive component of APT is not significantly different from CBT at session 3. Professor Butler noted that the GET manual included a section on `how to be sure that you are giving GET and not CBT' and again reiterated that this type of advice should be common to all four manuals.

ACTION 31: Professor Sharpe to lead Diane Cox in making the recommended alterations to the APT manual.

ACTION 32: Diane Cox should also contact Professor Butler directly for further advice.

14.Approval of revised Cognitive Behaviour Therapy (CBT) therapist manual and participant manuals and hand-outs

a) As recommended for APT. general information should be included across all the manuals. Generalisable information should also be identiﬁed from the CBT manual and copied into those for the other therapies. Professor Chalder particularly identified information on how to deal with a distressed patient, therapeutic alliance, warmth and empathy. Robin Buckle asked whether the physiological model of CFS/ME in the CBT manual could also be generalised across all the manuals.

b) It was noted that the recommendations for the CBT manual advised by Professor Sensky have already been incorporated. Professor Butler stated that she was very impressed with this manual.

15.Approval of revised Graded Exercise Therapy (GET) therapist manual and participant manuals and hand-outs

a) The GET manual was passed with only minor alterations suggested by Professor Chilvers.

ACTION 33: Julia Decesare to pass on the recommended alterations for the GET manual to Jessica Bavlnton.

16.Approval of the standardised Specialist Medical Care (SSMC) doctor's manual

a) Professor White stated that one alteration was to be made to this manual to state that every randomised patient should be seen by their SSMC doctor within two weeks. This was to help ensure that the SSMC arm was not interpreted by the participants as the `go away' arm. The TSC approved this manual.

ACTION 34: Gabrielle Murphy to ensure that the SSMC manual is modiﬁed to include a first participant appointment within two weeks of randomisation. (NB the TMG later revised this to one month in order to reduce the number of visits required by participants in the first two weeks of the trial.)

17. Approval of Patient Clinic Leaﬂet

a) Stella Harris stated that she thought this document was excellent. Minor amendments were recommended: i. `specialist medical care' should be altered to `routine medical care',

ii. Error in the title should be corrected

iii. Peter Craig recommended that the word holistic be carefully considered and changed if necessary

iv. The penultimate paragraph should be placed earlier in the document.

ACTION 35: Pls should alter the PCL as advised.

ACTION 36: Pls to ensure that the Patient Clinic Leaflet (PCL) explicitly states the different theoretical models of CFS/ME In relation to the four treatment approaches.

18. Summary of changes generalisable to all manuals

a) The question was asked as to whether the TMG had considered passing any documentation to a writing expert to ensure readability for a lay audience. Julia DeCesare stated that contact had already been made with Martin Rosser. who has been contracted to carry out this work for other MRC Trials. This was to be pursued after the meeting.

ACTION 37: The PIs in conjunction with the treatment leads should ensure that generalisable information is consistent across all four therapist manuals. A note of caution is advised to ensure that in synchronising the manuals, the therapies do not become too similar.

ACTION 38: Treatment leaders should ensure that the finalised manuals are sent to the TSC experts for final approval as advised by Professor Darbyshire.

ACTION 39: All documents should be checked to ensure that there is no tautology with the use of PIN (i.e. should always read PIN and never PIN number).

ACTION 40: Julia DeCesare to contact Martin Rosser for a review/re- write of the PCL, PIS and Consent Form.

19.Case Report Form (CRF)

a) A draft earlier version of the CRF was presented and it was explained that the ﬁnal version was still in development.

ACTION 41: Julia Decesare to send the completed CRFs to the TSC for their comments and advice before submission to MREC.

20.Public Relations

a) Professor White summarised the policy so far. All media enquiries should be directed to Dawn Duncan at the MRC Press Office in the ﬁrst instance. Dawn will contact the Pls for agreement before releasing any statement. It was noted that a policy statement and PACE/FINE Q&A page already exists. The Pls will also be writing to the MREC and LRECs to make them aware of the campaign to stop the trial. All were agreed that the names of the TSC and DMEC could be published to
retain transparency, but conﬁrmation was still required from the two DMEC members. The question was asked as to how to deal with any emails or hateful correspondence received. It was agreed that these should not be directly responded to, but should be retained as evidence for the future should it be needed. Chris Clark urged a note of caution that nothing negative should be written or emailed about the lobbyists as this could be libellous.

ACTION 42: PIs to write to the MREC and LRECs with details of the MEA campaign to stop PACE and FINE.

ACTION 43: Julia Decesare to email all TSC and DMEC members with contact details for Dawn Duncan and some information on how to deal with queries.

ACTION 44: Professor Dieppe to contact the two other members of this committee to confirm that they are happy for their names to be published.

ACTION 45: Any lobbyist mall to be forwarded to Julia Decesare for storage.

21.Next meeting and frequency of meetings of TSC

a) The next TSC meeting will take place on April 28"` or six months after recruitment begins if the trial is delayed for any reason.

22.Next meeting and frequency of meetings of DMEC

a) The first DMEC meeting will take place approximately one month in advance of the next TSC meeting.
Click to expand...

Esther12 · Mar 31, 2018

There was this on the "MEA campaign to stop PACE and FINE":

20.Public Relations

a) Professor White summarised the policy so far. All media enquiries should be directed to Dawn Duncan at the MRC Press Office in the ﬁrst instance. Dawn will contact the Pls for agreement before releasing any statement. It was noted that a policy statement and PACE/FINE Q&A page already exists. The Pls will also be writing to the MREC and LRECs to make them aware of the campaign to stop the trial. All were agreed that the names of the TSC and DMEC could be published to
retain transparency, but conﬁrmation was still required from the two DMEC members. The question was asked as to how to deal with any emails or hateful correspondence received. It was agreed that these should not be directly responded to, but should be retained as evidence for the future should it be needed. Chris Clark urged a note of caution that nothing negative should be written or emailed about the lobbyists as this could be libellous.

ACTION 42: PIs to write to the MREC and LRECs with details of the MEA campaign to stop PACE and FINE.

ACTION 43: Julia Decesare to email all TSC and DMEC members with contact details for Dawn Duncan and some information on how to deal with queries.

ACTION 44: Professor Dieppe to contact the two other members of this committee to confirm that they are happy for their names to be published.

ACTION 45: Any lobbyist mall to be forwarded to Julia Decesare for storage.
Click to expand...

Esther12 · Mar 31, 2018

In the above there was also this bit referring to "the TMGs struggle to ﬁnd an objective outcome measure as requested by the TSC at their last meeting". It would be good to find the details of the discussions referred to, but I expect that the minutes don't include them.

6. Because of this it was argued that consideration should be given to an independent "objective" examination of outcome for example by video or audio-taping interviews. However, as the outcomes are self rated it was unclear that this would add additional data in particular, as there were already walking and ﬁtness tests. This matter was let for further consideration by the principal investigators.

Action: TMG agenda item
Click to expand...

ACTION 8: Professor White to re-write section 8 as per TSC recommendation.

m) Professor White led discussion on the outcomes, and the TMGs struggle to ﬁnd an objective outcome measure as requested by the TSC at their last meeting, particularly as CFS/ME is a subjective condition. It is proposed that the protocol does not alter from the three primary objectives already set.

n) Professor Butler recommended that an extra measure be added for participation in life, and that the ICF scales be explored.
Click to expand...

Lucibee · Mar 31, 2018

Thanks @Esther12 - I have all those - I was asking for the ME Association magazine article from 2004 that they referred to.

From TMG #10 - 15 Sept 2004

14. ME Association
MEA have agreed to publish the response to their article campaigning to stop PACE and FINE. It was noted that there had been resignations of trustees due to divisions in the MEA about PACE and FINE.
Click to expand...

From TMG #12 - 12 Oct 2004

15. Unsolicited mail and MRC request for publication of protocol
The MRC have received 30-40 letters of complaint about the PACE trial. It was explained that this is a result of a concerted campaign by the MEA and others.
XX will be meeting with and anyone else who wants to may also attend.

It was suggested that the protocol be submitted for publication in a BioMed Central electronic journal. The MRC were agreeable to this. This gives open access for anyone to view. There were concerns about how estimates for improvement with each treatment might be interpreted by a lay reader. It was agreed that sections of the protocol would be re-written and edited for a lay audience before publication.

The MRC would like to print the name of the DMEC members on their website. has written to the DMEC to ask for permission to have their names printed. Some positive feedback has been received so far.

ACTION 36: XXX to explain in published protocol percentages of efficacy on different treatments.

ACTION 37: XXX to contact MRC and ask if and how power calculations are normally published on their website.

ACTION 38: XXX to circulate the MEA article and response to the TMG.

ACTION 39: XXX to ask if the PI’s can see copies of all correspondence sent to the MRC about PACE.

ACTION 40: XXX to write an explanation of all the criteria for CFS/ME used for the trial in lay language as this has been requested by XX
Click to expand...

Esther12 · Mar 31, 2018

Lucibee said: ↑

Thanks @Esther12 - I have all those - I was asking for the ME Association magazine article from 2004 that they referred to.
Click to expand...

Ugh - I misread your post. I've done that a few times recently.

I had anyway been thinking about drawing attention to those earlier releases, and seeing if they included info censroed from the new release.

ukxmrv · Mar 31, 2018

Lucibee said: ↑

Thanks @Esther12 - I have all those - I was asking for the ME Association magazine article from 2004 that they referred to.

From TMG #10 - 15 Sept 2004

From TMG #12 - 12 Oct 2004
Click to expand...

I've been searching through my emails from 2004 (this one 5th June) and was sent one from a member of the MEA. Still trying to find the statement which it refers to

""Our attention has been drawn to a public statement by the ME Association regarding the PACE trial, of which we are the principle investigators.

We regret that no-one from the MEA contacted us to discuss these matters before publication. We would be willing to discuss your questions and concerns about the trial in person.

If you would like to do this, please contact Dr. White, in the first instance.

Yours sincerely

Dr. Peter White

pp Professor Michael Sharpe

pp Professor Trudie Chalder."

++++

Plus the MEA seem to have been busy that year

(extract from another email)

....
In July we met with Peter White, Michael Sharpe, Trudie Chalder et al
to explain our objections in considerable detail. We have not had
any change of mind since that meeting.

A few weeks ago we explained our objections to the Medical Research
Council.

Last week I went up to the Department of Health to explain why the
MEA remains opposed to the PACE and FINE trials.

.....

Lucibee · Aug 10, 2018

I've tracked it down to the July 2004 issue of ME Essential - "MEA calls for PACE to be scrapped" (pages 3-4).

Does anyone have a copy? [ETA: Update - I now have a copy - see here]

It was mentioned in this extract from BJPsychBull in 2015:

PACE was affected by several external influences. First, some patient organisations expressed opposition to the trial from the time that funding was announced.18 Our understanding is that this opposition reflected the fact that the trial did not focus on a biomedical approach to CFS. Meetings with those who objected did not alter their concerns and divergent views about the illness and its management continue to this day.19 Strategies against the trial have included a public petition to the prime minister and formal complaints to our funders and publishers.20 None of these complaints have been upheld, but they did take considerable time to address.

Refs:
18. ME Association. MEA calls for PACE trial to be scrapped. ME Essential, July 2004: 91: 3–4.
19. Smith C, Wessely S. Unity of opposites? Chronic fatigue syndrome and the challenge of divergent perspectives in guideline development. J Neurol Neurosurg Psychiatry 2014; 85: 214–9. [PubMed]
20. The Lancet. Patients’ power and PACE. 2011; 377: 1808. [PubMed]
Click to expand...

There may also have been further discussion in the October 2004 issue.

Andy · Apr 1, 2018

Not sure if this is currently accurate but this page on the MEA website states that they can provide copies of past articles.
http://www.meassociation.org.uk/2007/02/index-to-articles-in-me-essential-magazine/

Lucibee · Apr 1, 2018

Andy said: ↑

Not sure if this is currently accurate but this page on the MEA website states that they can provide copies of past articles.
http://www.meassociation.org.uk/2007/02/index-to-articles-in-me-essential-magazine/
Click to expand...

Thanks Andy - that's how I found out what the page numbers were! If no-one else can help, that will be my next step - but I thought I'd ask here first.

Jonathan Edwards · Apr 1, 2018

Lucibee said: ↑

Thanks Andy - that's how I found out what the page numbers were! If no-one else can help, that will be my next step - but I thought I'd ask here first.
Click to expand...

Can @Russell Fleming advise?

JohnTheJack · Apr 1, 2018

Lucibee said: ↑

I've tracked it down to the July 2004 issue of ME Essential - "MEA calls for PACE to be scrapped" (pages 3-4).

Does anyone have a copy?

It was mentioned in this extract from BJPsychBull in 2015:

There may also have been further discussion in the October 2004 issue.
Click to expand...

Haven't read that paper in a while. It's awful in many ways, but a few things stood out:

Despite what they say when dismissing the actigraphy, they clearly set out to improve 'fatigue and disability'.

The analysis 'also addressed the potential clustering effects resulting from different numbers of patients being treated by the different therapists'.

'These very high rates of follow-up were achieved as a result of the commitment of the participants and the assiduous work by the research staff. The strategies used by the latter included offering convenient interview times (including early evenings), mailing most questionnaires to allow sufficient time to answer them before interviews, paying travel expenses, following up non-attenders expeditiously by mail and telephone, offering to see the participants at their homes and, as a last resort, recording the primary outcomes over the telephone.'
They visited patients' homes?
No wonder there was a placebo effect: travel expenses, birthday cards, home visits...

They decided 'to have the most appropriate discipline deliver each therapy' which 'ensured optimal delivery of each therapy by the therapists most likely to deliver these therapies in clinical practice', but then 'occasionally, it was necessary to train an existing therapist in a second therapy, which proved popular with those who did it'.

They also push heavily their 'CFS treatment centres' and it was presumably there they were 'providing guaranteed employment beyond the trial, when possible'.

Jonathan Edwards · Apr 1, 2018

JohnTheJack said: ↑

They decided 'to have the most appropriate discipline deliver each therapy' which 'ensured optimal delivery of each therapy by the therapists most likely to deliver these therapies in clinical practice', but then 'occasionally, it was necessary to train an existing therapist in a second therapy, which proved popular with those who did it'.
Click to expand...

I am surprised that they did not go on strike for violation of restrictive practices.
But this is interesting. I have it down in my notebook that maybe the colour of the cardigan does not matter? An important scientific finding.

Jonathan Edwards · Apr 1, 2018

It is a curious paper and presumably invited by someone? You do not normally publish a paper and then publish how you came to do the study a second time - unless of course you are testing Einstein's theory of general relativity or something. Some useful historical bits.

JohnTheJack · Apr 1, 2018

Jonathan Edwards said: ↑

It is a curious paper and presumably invited by someone? You do not normally publish a paper and then publish how you came to do the study a second time - unless of course you are testing Einstein's theory of general relativity or something. Some useful historical bits.
Click to expand...

Yes, it reads oddly and confused, part rehash of protocol, part narrative, part justification.

It reeks again of hubris.

Indigophoton · Apr 1, 2018

Jonathan Edwards said: ↑

But this is interesting. I have it down in my notebook that maybe the colour of the cardigan does not matter?
Click to expand...

According to the TSC minutes, the thinking was,

The resignation of the - was especially difficult
because of the geographical location of the centre. The PIs reported that the - GET therapist - and the - CBT therapist had both generously offered their time to overcome this problem. The - took over the - GET caseload whilst the CBT therapist acted as therapy assistant and was learning to give GET. The participants have had all of their therapy delivered by these two therapists in combination. - has either travelled to - to give sessions with - sitting in as a physiotherapy assistant and observer, or - has given telephone sessions with the participants sitting with - in the - hospital for support. As - is trained up, - will take a more supervisory role in these sessions and - will lead them. The PIs reported that the participants affected have responded well to this and are happy with the arrangement.
A new GET therapist for - - has recently been
recruited and will be trained over the coming months.

The PIs explained the original rationale in the trial design for dividing the therapies by clinical discipline (i.e. APT delivered by an occupational therapist, CBT by a psychologist or CBT nurse specialist and GET given by a physiotherapist). This was to help ensure clear distinction between the three supplementary therapies. The TMG now feel that disciplines can cross-cover; there are some core clinical skills common to all and the therapists have no difficulty differentiating between each treatment. It was felt sensible in the long term to have cross cover because if one treatment is shown to have a greater efficacy than the others then it will avoid the issue of one clinical discipline ‘owning’ the best therapy. This will require some minor amendments to the therapy manuals which currently define the discipline delivering each therapy.
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