Amendment 2.1 Cover letter - 22/10/2004 Substantial amendment form ~ 22/10/2004 REC opinion letter — 3/11/2004oe ‘farts and The London Q¥ Barts and The London Serer : ‘4 Mist Smite Queen Mary's School of Medicine and Dentistry London FCIA 76E “eephore. 020 7601 8108 Faesimile C20 7601 7969 Department of Paschiaty Protesso Stephen Stansted Heed af Depaancert Miss Nikki Murphy, Administrative Assistant, West Midlands Multi-centre Research Ethics Committee 27 Highfield Road, Edgbaston, Birmingham, B15 3DP 22 October 2004 Dear Ms Murphy, Full title of study: A randomised, controlled trial of adding cognitive behaviour therapy, graded exercise therapy, or adaptive pacing therapy to usual medical care, compared to usual medical care alone for the chronic fatigue syndrome [ME] PACE trial REC reference number 02/7/89 Further to my telephone call of last week and your last letter of 19" October, | would be grateful if you would consider a “notice of substantial amendment” for this trial, which was originally approved on 24" October 2002 Please note that the trial has not yet started and no patient has been entered. We hope to randomise the first participants on 29" November 2004. | enclose the following documents: Trial identifier (Protocol) version 2.1, 22 October 2004. (previous version MREC approved) This includes the appendix which contains the following items Appendix 4: Participant information A1.3 Participant Information Sheet, version 10, date 22.10.2004 (previous version MREC approved) 1.4 Eligibility Assessment / Baseline Consent Form, version 3.1. (Cligibility/baseline) date 22.10.2004 (previous version MREC approved) Patrons Her Majesty The Queen Incorprated by Reya Char Quoc Mary & Wertvid Calege, Universty at Londenfate and The London z \Qy Barts and The London oo Queen Mary's School of Medicine and Dentistry teense AIRE a. rome of Payehity Stephen Stanstels Head of Department Miss Nikki Murphy, Administrative Assistant, West Midlands Multi-centre Research Ethics Committee 27 Highfield Road, Edgbaston Birmingham, B15 3DP 22" October 2004 Dear Ms Murphy, Full title of study: A randomised, controlled trial of adding cognitive behaviour therapy, graded exercise therapy, or adaptive pacing therapy to usual medical care, compared to usual medical care alone for the chronic fatigue syndrome [ME] PACE trial REC reference number 02/7/89 Further to my telephone call of last week and your last letter of 19!" October, | would be grateful if you would consider a ‘notice of substantial amendment” for this trial, which was originally approved on 24" October 2002. Please note that the trial has not yet started and no patient has been entered. ‘We hope to randomise the first participants on 28" November 2004 lenclose the following documents: Tnal identifier (Protocol) version 2.1, 22 October 2004 (previous version MREC approved) This includes the appendix which contains the following items: Appendix 1: Participant information A1.3 Participant information Sheet, version 10, date 22.10 2004 (previous version MREC approved) A1.4 Eligibility Assessment / Baseline Consent Form, version 3.1 (cligibilityfoaseline) date 22.10.2004 (previous version MREC approved) Fatt: Her Majesty The Queen Incerporeted by Royal Ohare se Queen Mary & WestheldColege, Uniersity 9! Loncor1.5 Full tral version MREC approved) The next two centre for an Consent Form, version 3.2 (full trial) date 22.10.2004 (previous -~ documents are only for use when one therapist is unavailable at a extended period: A16 Eligibility Assessment / Baseline Consent Form, version 3.37 (cligibility/baseline — missing therapy) date 22.10.2004 A1_7 Full Trial Consent Form, version 3.1 (full trial - missing therapy) dated 22.10.2004 Appendix 3: Aat General Practitioner Letters Perticipant entry to trial, version 2 dated 22.10.2004 (previous version MREC approved) A3.2___ Participant completion of supplementary therapy, version 1,“ 22.10.2004 3.3 Participant completion of trial, version 1, 22.10.2004. A3.4 Participant withdrawal from treatment, version 1, 22.10.2004 A3.§ Participant drop-out from trial, version 1, 22.10.2004. —~ Appendix 4: Letters to the participant from the Research Nurse Ad.) Participant initial letter from research nurse, version 1, 22.10.2004 A42 Participant follow-up appointments, version 1, 22.10.2004 A4.3 Participant letter for final follow-up visit, version 1, 22.10.2004 A4.4 Participant withdrawal from treatment, version 1, 22.10.2004 A45 Participant drop-out from tial, version 1, 22.10.2004 ~ Appendix 5: Medical Screening Standard Operating Procedure, Version1,.~ 22.10.2004 Appendix 6: Case Report forms, all version 1, 22.10.2004, unless indicated 41 —— Actigraphy instructions ~ A42 Borg Scale ~ A4.3 __ Centers for Disease Control criteria for Chronic Fatigue Syndrome .~ (CFS) (previous version (Fukuda et al, 1994) MREC approved: no change ‘made to symptoms, but more detailed update (Reeves et al, 2003) to be used) 44 Clinical Global Impression change scale (CGI) for participants (previously MREC approved, no change made) AGS CG for therapists and dociors (previously MREC approved; now ~~ filled in by both therapist and doctor) ALS Chalder Fatigue Questionnaire (previously MREC approved; now change made) ALT Co morbid medical conditions -~‘48 Concomitant medications A4.9 Client Service Receipt Inventory (CSRI) (previous version MREC\ approved) ‘4.10 Demographic information including self-help group and patient organisation membership ~~ A411 — Eligibility criteria A412 Eurogol EQ5d (previously MREC approved, no change made) A413 Exercise and Activity Scale —~ A414 Expectation of therapeutic outcome ~ A415 Fibromyalgia assessment .~ A416 Hospital and Depression Scale (HADS) (previously MREC —~ approved; no change made) A417 Jenkins Sleep Scale ~~ A448 — London criteria for ME ~~ A418 Oxford criteria for CFS (previous use agreed by MREG; no change -—~ made) A4.20 Past medical history ~ A421 Preferred treatment group ~~ A4.22 Therapy satisfaction scale (previously MREC approved; no change — made) A423 Self-efficacy scale ~ A4.24 Standardised Clinical Interview for DSM (SCID) summary form (previously MREC approved; no change made) A425 SF-36 physical function sub-scale (previously MREC approved; no change made) A426 — Self paced step test of fitness A427 Symptom Interpretation Questionnaire .~ A428 Six minute walking test ~ ‘A429 SSMC monitoring interview ~ A430 Work and Social Adjustment Scale” A431 Adverse Event report forme A432 Drop-out report form Appendix 7: PACE policy on ancillary studies, version 1, 22.10.2004 Appendix 8: Consort Diagram, version 1, 22.10.2004 ““ A further and separate notice of substantial amendment As previously discussed over the telephone, the following items will be enclosed ina further submission to be made within the next two to three weeks. This delay will allow a further piloting of the manuals and their therapies before consideration of MREC approval for the emendments to the previously approved manuals. We are grateful to you for suggesting that MREC can consider these matters separately to prevent delay in starting the trial.1.1 Patient clinic appointment letter A1 2 Patient Clinic Leaflet ‘These two documents are essentially the adverts for the patients who will be approached for the trial Appendix 2: Therapy Manuals A21 APT Therapist Manual A22 APT Patient Manual A23 CBT Therapist Manual A24 CBT Patient Manual A25 GET Therapist Manual A26 GET Patient Manual A2T SSMC Doctors’ Manual With good wishes, Yours sincerely, eter D White, On behalf of Professors Michael Sharpe and Trudie Chalder Principal Investigators5 Central Office for Research Ethics Committees (COREQ) NOTICE OF SUBSTANTIAL AMENDMENT For use in the case of all research other than clinical trials of investigational medicinal products (CTIMPs). For substantial amendmonts to CTIMPs, applicants should use the EU-spproved notice of amendment form available at www.corec.oro.uk/amendments him. This form cannot be accepted for CTIMPS. To be completed in typescript by the Chief Investigator and submitted fo the Research Ethics Committee that gave a favourable opinion of the research (“the main REC’) in the case of multi-site studies, do not send capies to other RECs unless specifically notified fo do so by the main REC. Details of Chief Investigator: Name: Professor Peter D White Address: Clo Julia DeCesare PACE Trial Manager Barts and the London Queen Mary's School of Medicine and Dentistry Department of Psychiatry | Institute of Community Health Scences Room 3.112 3rd Floor, Dominion House St Bartholomew's Hospital London EC1A 7BE Telephone: Direct line: 020 7601 8108 PACE trial centre number: 020 7601 8160 E-mail: p.d.white@qmul.ac.uk Fax: 020 7600 5901 Notice of emendment (non-CTIMP), Version 1.0, May 2004Full title of study: Short title of tral: Pacing, graded Activity, and Cognitive behaviour therapy; a randomised Evaluation PLEASE NOTE. Minor amendment to trial long title below Long title of 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 Research sponsor: Queen Mary, University of London, with other local sponsorship arrangements at each centre Name of main REC: West Midlands MREC Main REC reference number: MRECIO2/7/69 Date study commenced: The trial aims to open to randomisation on the 20" November 2004. Protocol reference (if applicable), current version and date: ISRCTN number: ISRCTN54285084 MRC code number: G0200434 Final protocol Protocol version number 2 1 Protocol date: 22 10.2004 Amendment number and date: Protocol Amendment 2, 22 October 2004 Notice of amendment (non-CTINP), Version 1.0, May 2004Type of amendment (indicate all that apply) (@) Amendment to information previously given on the REC epplication form Yes No oO If yes, please refer to relevant sections of the REC application in the “summary of changes” below (b) Amendment to the protoco! Yes No oO Jf yes, please submit either the revised protocol with a new version number and date, highlighting changes in bold, or a document listing the changes and giving both the previous and revised text (©) Amendment to the information sheet(s) and consent form(s) for participants, or to any ‘other supporting documentation for the study Yes & No oO If yes, please submit all revised documents with new version numbers and dates, highlighting new text in bold Notice of amendment (non-CTIMP), Version 1.0, May 2004Summary of changes Brefly summarise the main changes proposed in this amendiment. Explain the purpose of the changes and their significance for the study. Supporting scientific information should be given (or enclosed separately) where the amendment significantly alters the research design or methodology, or could otherwise affect the scientific value of the study. Please note: Due to the extent of alteration to the trial protocol and Patient Information Sheet, it is neither practical nor possible to present the original document with ‘tracked changes’ or new text highlighted in boid. Please note that this trial has not yet opened to recruitment and therefore the alterations made will not affect participants since none have been entered. Summary of changes The main change has been to provide more detail of what we will do, and we have made no significant changes to the goals or aims or design of the study. We have made some minor changes to the protocol with the addition of measures in order to: properly measure meaningful outcome (the addition of the Work and Social adjustment scale); to ensure we are measuring predictors that other studies have shown (self-efficacy) or that patient organisations believe are important (London criteria for myalgic encephalomyelitis), and to be sure that all likely mediators of change are measured (sleep disturbance scale) The CSRI now gives more accurate financial measures to enable us to accurately measure cost-utilily of the different treatments The symptoms interpretation questionnaire will give more pertinent information about the illness beliefs that may affect prognosis, and yet may change in the process of treatment. There have been changes to the initial protocol, considered by the MRC, and the version approved by MREC. These are listed below: 1. A two stage consent to separate baseline assessment from full participation in the trial We have done this in order to ensure participants are eligible before they are randomised. Otherwise they may have given consent for randomisation before we know whether they are eligible. 2. A two stage baseline assessment (with visits a week apart) in order to avoid unnecessary fatigue for participants by too long assessments. 3. Stratification for randomisation to ensure equal disinbution of participants with mood disorders, and two different criteria for defining CFSME (the London and Centers for Disease Conto! criteria). 4. No research or therapeutic staff being blind to treatment allocation, in order to optimise clinical care, apart from the CTU staff. 5. A more detailed definition of adverse events and reactions, as well as operationalising clinical deterioration. This will ensure we are able to define and pick up adverse events quickly end efficiently. Notice of amendment (non-CTIMP), Version 1.0, May 20046 A modification to the primary outcome, by the addition of a 50% reduction in fatigue and physical disability being a positive outcome, alongside the previously approved categorical outcome. 7. An additional primary outcome of needing both fatigue and physical disability to improve ©@ 1) 2) 3) 4 3) 8) ” 8) Operationalised criteria for recovery The addition of the following questionnaire measures: Jenkins Sleep Questionnaire (4 items) Self-efficacy (5 items) Work and social edjustment scale (5 items) Therapeutic plausibility (1 item) The London criteria for ME (3 items) The Symptom Interpretation Questionnaire (43 items) Revision of the CSRI Therapist and doctor rated CGIs (1 item) All these amendments have been approved by the independent Trial Steering Committee (TSC) and the independent Data Monitoring and Ethics Committee at its jeint meeting on 27" September 2004. Any future amendments fo the protocol will be issued by the Trial Management Group after discussion with the TSC, and with the West Midlands MREC. Amendments will be circulated to all centres and incorporated into a revised version of the protocol. Notice of amendment (ron-CTIMP), Version 1.0, May 2004Any other relevant information Applicants may indicate any specific ethical issues relating to the amendment, on which the opinion of the REC is sought. The Structured Clinical Interview for DSM IV (SCID) will now be audio-recorded. This request has been added in a separate paragraph to the first consent form We believe this is necessary in order for a psychiatrist to review psychiatne exclusions from the trial and in order to train and supervise research nurses. In order to avoid embarrassment of participants by directly asking financial information, we have designed a coded (alphabetical) method of answering We have been careful to weigh up the advantage of adding another measure against the risk of measurement overload. We have rejected saveral measures (of social participation for instance) for this reason We will now provide further treatment for all participants who require further treatment after their involvement in the study has ceased, We have asked permission in the consent form to follow up participants up to five years, at the suggestion of the TSC, in order to measure long-term outcome, assuming proper research ethics approval is given for further studies. In the unlikely event of a centre not having all three supplementary therapies available for several months, we would recruit new participants to the trial with a contingent consent form making clear what therapies are available. See Appendices A1.6 and A1 7 Notice of amendment (non-CTIMP), Version “.0, May 2004List of enclosed documents Indicate revised version numbers and dates and highlight all. changes in bold or underine. Protocol version 2.1, 22 October 2004 This includes the appendix which contains the following items: Appendix 1: Participant information A1 3 Participant Information Sheet, version 10, date 22.10 2004 1.4 Eligibility Assessment / Baseline Consent Form, version 3.1 (eligibilityioaseline) date 22.10.2004 ‘1.5 Full trial Consent Form, version 3.2 (full trial) date 22.10.2004 Only for use when one therapist is unavailable at a centre for an extended period: A16 Eligibility Assessment / Baseline Consent Form, version 3.3 (cligibility/baseiine — missing therapy) date 22.10.2004 A1,7 Full Trial Consent Form, version 3.1 (full rial — missing therapy) date 22 10.2004 Appendix 3: GP Letters A3 1 Participant entry to trial, version 2, 22.10.2004 3.2 Participant completion of supplementary therapy, version 1, 22.10.2004 A3.3 Participant completion of trial, version 1, 22.10.2004 A3.4 Participant withdrawal from treatment, version 1, 22.10.2004 A3.5 Participant drop-out from trial, version 1, 22.10.2004 Appendix 4: Letters to the participant from Research the Nurse ‘A4.1 Participant initial letter from research nurse, version 1, 22.10.2004 A4.2 Participant follow-up appointments, version 1, 22.10.2004 ‘A4.3 Participant letter for final follow-up visit, version 1, 22.10.2004 A4.4 Participant withdrawal from treatment, version 1, 22.10.2004 A4.5 Participant drop-out from trial, version 1, 22.10.2004 Appendix 5: Medical Screening SOP, Version‘, 22.10.2004 Appendix 6: Case Report forms, all version 4, 22.10.2004 4.1 Actigraphy instructions A42_ Borg Scale A43 CDC A4.4 CGI for participants 45 CGl for therapists and doctors 4.6 Chalder Fatigue Questionnaire 4.7 Co morbid medical conditions 4.8 Concomitant medications A49_ CSRI ‘A410 Demographic information including seif-help group and pationt organisation membership Notice of amencment (non-CTIMP), Version 1.0, May 2004A447 Eligibility criteria ‘A412 Eurogol EQSd A4.13 Exercise and Activity Scale [now omitted] ‘A4.14 Expectation of therapeutic outcome A4.15 Fibromyalgia assessment ‘A418 Hospital and Depression Scale (HADS) A4.17 Jenkins Sleep Scale A418 London criteria for ME A4 19 Oxford criteria for CFS ‘4.20 Past medical history A421 Preferred treatment group 4.22 Satisfaction scale A4.23 Self-efficacy scale A424 SCID summary form ‘A4.25 SF-36 physical function sub-scale ‘A426 Self paced step test of fitness ‘A4.27 Symptom Interpretation Questionnaire A4.28 Six minute walking test A429 SSMC monitoring interview ‘4.30 Work and Social Adjustment Scale A431 Adverse Event report form 4.32 Drop-out report form Appendix 7: PACE policy on ancillary studies, version 1, 22.10.2004 Appendix 8: Consort Diagram, version 1, 22.10.2004 As previously discussed over the telephone, the following items will be enclosed in a further submission to be made within the next two weeks: 1.4 Patient clinic appointment letter 1.2 Patient Clic Leaflet These two documents are essentially the adverts for the patients who will be approached for the trial Appendix 2: Therapy Manuals A2.1 APT Therapist Manual (see separate document) ‘A2.2 APT Patient Manual (see separate document) A2.3 CBT Therapist Manual (see separate document) ‘A2.4 CBT Patient Menual (see separate document) A2.5 GET Therapist Manual (see separate document) 2.6 GET Patient Manual (see separate document) 2.7 SSMC Doctors’ Manual (see separate document) Notice of amendment (non-CTIMP), Version 1.0, May 2004Declaration + | confirm that the information in this form is accurate to the best of my knowledge and | take full responsibility for it * I consider that it would be reasonable for the proposed amendment to be implemented Signature of Chiet Investgator: Print name: ROP Dae, if Date of submission: Be hrolos., . Notice of emendment (nor-GTIMP), Version 1 0, May 2004INS} West Midlands Multi-centre Research Ethics Committee 3 November 2004 27 Wighfield Read Professor Peter D White Edgbarion oo Julia DeCesare irminghar | PACE Trial Manager B15 307 Barts and the London Queen Mary's School of Medicine and Dentistry Depariment of Psychiatry Institute of Community Health Sciences Room 3.112 3° Floor, Dominion House St Bartholomews Hospital London EC1A 7BE Tel: 0129 245 2548 Fax: 0121 245 2519, Dear Professor White A randomised, controlied trial of adding cognitive behaviour therapy, graded exercise therapy, or adaptive pacing therapy to usual medical care, compared fo usual medical care alone for the chronic iatigue syndrome [ME] PACE trial REC reference number: 02/7/89 Amendment number: 2.1 Amendment date: 22 October 2004 The above amendment was reviewed by the Research Ethics Committee Sub Committee at the meeting held on 25 October 2004. Ethical opinion The members of the Committee present decided that it could not give a favourable ethical opinion of the amendment, for the following reasons: 4 The members were unable to understand the need for a two stage consent procedure. It is typical of many studies that the subject's consent fo the study is obtained prior to eligibility screening — which might then find them to be ineligible. This is appropriate since it ensure that no trial-related procedures are performed without consent. They did not feel that you had adequately justfied a more complex procedure and consent and do nat believe that the second stage consent form adds anything to the consent obtained at the first stage. 2 There sno information in the Petient Information Sheet about what will happen to recordings of interviews after the 20 year storage period hes elapsed. 3 It was felt that the Patient Information Sheet is potentially coercive in that the peragraph entitled ‘Will my treatment stop suddenly at the end of the trial, [Page 90] it suggests that the three additional procedures may only be available to subjects who have participated. 4 It was thought that there is a case for the inclusion/exclusion entena, or some information about them being included in the Patient Information Sheet particularly in viow of th use of the two stage consent procedure. regret to inform you that the amendment is therefore not approved. The study should continue in accordance with the documentation previously approved by the Commitee. SOPs version 1.0 dated February 2004 $130 Unfavourable epinion of amendment The Central Olfice for Research Fthics Committees is responsible for the operational management of Mult: centre Research Ethics CommitteeModifying the amendment If you think that it would be possible for you to modify or adapt the amendment in such a way 2 to address the Committee's conoerns, it is open to you to submit a revised notice of amendment on the standard form. The form shouid indicate that this 1s a modification of the above amendment. [Clinical trials of investigational medicinal products only] A revised notice of amendment must be submitied at least 14 days before you plan to implement the emendment. The Committee will then have 14 days from the date of receiving the notice in which to notfy the sponsor in writing that the amendment is rejected, otherwise the amendment may be implemented.) Documents reviewed ‘The documents reviewed at the meeting were Note. As the amendment has not been approved at this stage the documents have not been spectfically iternised as in your letter. Appenaix 1: Participant information Appendix 3: General Practitioner Letters Appendix 4: Letters to the participant from the Research Nurse Appendix 5: Medical Screening Standard Operating Procedure Appendix 6: Case Report Forms Appendix 7: PACE Policy on ancillary studies Appendix 8: Consort Diagram Membership of the Committee The members of the Ethics Committee who were present at the meeting ere listed on the attached sheet. This Committee is recognised by the United Kingdom Ethics Committee Authority under the Medicines for Human Use (Clinical Trials) Regulations 2004, and is authorised to carry out the ethical review of clinical trials of medicinal produets. ‘The Committee is fully compliant with the Regulations as they relate to ethics committees and the conditions and principles of good clinical practice The Committee is constituted in accordance with the Governance Arrangements for Research Ethics Committees (July 2001} and complies fully with the Standard Operating Procedures for Research Ethics Committees in the UK. REC reference number: MRECIO2I7/69.__ Please quote this number on all correspondence One Anne McCullough [Mrs] Administrator Enclosures List of names and professions of members who were present at the meeting SOPs version 1.0 dated February 2004 S130 Unfavourable opinion of amendmentComposition of MREC West Midlands Members: 25 October 2004 | Attendance _| Name Profession | DrJammi Rao Chairman Director of Public Health Dr Steve Bain Reader in Diabetic Medicine ] YS | Mr Nigel Ballantine Vice Chairman - Ee Specialist Clinical Pharmacist Dr Harshad Desai Consultant Physician | Ms Debra Easlea Oncology Research Sister Clinical Research Associate Mr Timothy James Sonior Lecturer in Law DrR Jubb Consultant Rheumatologist Rev Dorrie Johnson Lay Member Miss Nanoy Leslie Lay Member vs Prof Alexander McNeish__| Retired Consultant Paedietrician vs Mrs Pat Moseley Lay Member Ms Chnstiane Neumann _| Clinical Nurse Specialist Dr A Roddam Senior Statistroran KEY: vf Member attended w Member submitted written comments S = _ Member of Sub Committee