Amendment 2.3 Cover letter -05/01/2005 Substantial amendment form — 05/01/2005 REC opinion letter - 02/02/2005PACE Trial Centre, 3‘ Floor Dominion House, St Bartholomew's Hospital, London, EC 1A 7BE Telephone: 020 7601 8160 Facsimile 020 7600 5901 Email: pace@gmul.ac.uk Mrs Anne McCullough Administrator, West Midlands Muti-centre Research Ethics Commitee PE CE) Ve, 27 Highfield Road, D Edgbaston, . ansse ~2L3/89 5° January 2005 Dear Ms McCullough, Full title of study: The PACE trial — A randomised controlled trial of adaptive pacing, cognitive behaviour therapy, end 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 MREC reference: 02/7/89 Amendment: 2.3, 5” January 2005 | would be grateful if you would consider a “notice of substantial amendment” for this trial, which was originally approved on 24" October 2002. This is amendment ‘umber 2.3 in reSponse to your letter of 15 December 2004, and to the email sent by Mr Nigel Ballantine, 4" January 2005. The Patient Clinic Leafiet and Participant Information Sheet have been modified according to your recommendations, Please find enclosed, four copies of the following documents with ‘tracked changes’ included: Four copies of each of the following have been supplied with this letter: + Pariicipant Information Sheet, Version 16, 5" January 2005 * Patient Clinic Leaflet, Version 9, 5" January 2005 * Notice of substantial amendment 2 3, 5" January 2005 = Chee DWP uitzittn Focing, graded Actvily ond Cogulve behovlou! harap): © roncontised Evaluation mol oceeamuloc.uk Te PACE Vos nde by he Mectea esenc Counc. Dapariner Hacc, Dozernent fr Wok ond Ren the Sect Cit Een OeREC: 08 Zanuery 2008, aot? IsReTusezasope Please note that the alieration nm the dates and version numbers of these documents will be reflected in the consent forms for the trial Please also note that the tral has not yet startled and no patient has been entered. ook forward to hearing your final decision With good wishes, Yours sincerely, MS Protessor Peter D White On behalf of Professors Michael Sharpe and Trudie Chalder Principal investigators5 Central Office for Research Ethics Committees (COREC) NOTICE OF SUBSTANTIAL AMENDMENT For use in the case of all research other than clmical trials of investigational medicinal products (CTIMPs) For substantial amendments fo CTIMPs, applicants should use the EU-approved notice of amendment form available at www.corec.org.uk/amendments.him. This form cannot be eccepted for CTIMPs. To be completed in typesorist by the Chief investigator and submitted to the Research Ethics Commitee that gave a favourable opinion of the research ("the main REC’). In the case of multisite studies, do not send copies to other RECs unless specifically notified (0 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 Schoo! of Medicine and Dentistry Department of Psychiatry Institute of Community Health Sciences Room 3 112 31d Floor, Dominion House St Bartholomew's Hospital London EC1A 7BE Telephone: Direct line: 020 7801 8108 PACE tal centre number: 020 7601 8160 E-mail: .d.white@amul.ac.uk Fax: 020 7800 5901 ‘Short ttle of tral Pacing, graded Activity, and Cognitive behaviour, therapy: 2 randomised Evaluation Long ttie of trial: ‘A randomised controlled trial of adaptive paang, cognitive behaviour therapy, and graded exercise, as supplements fo standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome / myelgic encephalomyelitis or encephalopathy Research sponsor: ‘Queen Mary, University of London, with other local sponsorship arrangements at each centre. Notice of amendment (non-CTIMP), Version 1.0, May 2004Name of main REC: West Midlands MREC Main REC reference number: MREC/02/7/89 Date study commenced: The trial aims to open to rand: tion on the 17" January 2006. Protocol reference (if applicable), | ISRCTN number: ISRCTN54285094 current version and date: MRC code number G020043.4 Final protocol Protocol version number 2 0 Protocol date: 18.11.2004 A further full protocol (version 3.0), particularly including therapist and participant manuals was submitted on 3 December 2004 for which we are awaiting approval/comments from the MREC. Amendment number and date: Protocol Amendment 2.3, 05 January 2005 Type of amendment (indicate all that apply) (2) Amendment to information previously given on the REC application form Yes O No g tyes, please refer to relevant sections of the REC applicetion in the “summary of changes” below. (0) Amendment to the protoco! Yes O Ne g tyes, please submit either the revised protocol with a new version number and date, highlighting changes in bold, ot a document listing the changes and giving both the previous and revised text (c) Amendment to the information sheet(s) and consent form(s) for participants, or to any ther supporting documentation for the study Yes & No Oo Iryes, please submit all revised documents with nev version numbers and dates, highlighting new text in bold Notice of amendment (non-CTIMP), Version “.0, May 2004Summary of changes Briefly summarise the main changes proposed in this amendment. 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. We are grateful for the opinion of the Research Ethics Committee sub-committee, from the meeting held on the 14" December 2004, regarding amendment 2.2, dated 24" November 2004. We are pleased to respond to these suggestions and have modified the Patient Information Sheet and Patient Ciinic Leaflet accordingly. These are attached with tracked changes. Any other relevant information Applicants may indicate any specific ethical issues relating to the amendment, on which the opinion of the REC is sought. List of enclosed documents Indicate revised version numbers and dates and highlight all changes in bold or underline. «Participant information Sheet, Version 16, 5" January 2005 © Patient Clinic Leaflet, Version 9, 5" January 2005 Declaration © | confirm that the information in this form is accurate to the best of my knowledge and I take full responsibility for it. | consider that it would be reasonable for the proposed amendment to be implemented. Signature of Chiet Investigator: Print name: Notice of meniment (non-CTIMP), Version 1.0, May 2004Date of submission: Notice of amendment (non-CTIMP), Version 1.0, May 2004Vasens ouberz0ar meron IES West Midlands Multi-centre Research Ethics Committee 2 February 2005 27 Highfield Road igbaston Professor Peter D White Birminghern Clo Julia DeCesare 815 30P PACE Trial Manager ae Barts and the London eas Queen Mary's School of Medicine & Dentstry Department of Psychiatry Institute of Community Health Sciences Room 3.112 3° Floor, Dominion House St Bartholomew's Hospital London EC1A 7BE Deer Professor White Study title: A randomised, controlled trial of adding cognitive behaviour therapy, graded exercise therapy, or adaptive pacing therapy to usual medical care, compared fo usual medical eare alone for the chronic fatigue syndrome [ME] PACE trial REC reference: MRE/02/7/89 Thank you for submitting the 2bove protocol amendment, which was recerved on 7 January 2005. [tis noted that this is a modification of an amendment previously rejected by the Committee. The modified amendment was considered at the meeting of the Amendment Sub Committed held on 1 February 2005. A list of the members who were present at the meeting is attached Ethical opinion | am pleased to confirm that the Committee has given a favourable ethical opinion of the modified amendment on the basis described in the notice of amendment form and supporting documentation, Approved documents The documents reviewed and approved are: Amendment 2.1, 22/10/2004 + Protocol version 2.1, 22 October 2004 ~ superceded in Amendment 3.1, however the majority of the appendix remains the same. This appendix includes the following items: Appendix 4: Patient/participant information, * A14 Eligibility Assessment / Baseline Consent Form, version 3.1 (cligibilty/baseline),22 10.2004 + AY. Full trial Consent Form, version 3.2 (full ral),22. 10.2004 + A1.6 Eligibility Assessment / Baseline Consent Form, version 3.3 (cligibility/baseline ~ missing therapy),22 10 2004 + A17 Full Trial Consent Form, version 3.1 (full trial — missing therapy), 22.10.2004 4, The Central Offce for Research Ethics Committees is responsible for the ‘Operational management of Muli-centre Research Ethic: CommitteesSL34 Favourable opinicn of arrendment ‘Version 2, October 2004 Appendix 3: General Practitioner Letters + Participant entry to trial, version 2,22. 10.2004 * Participant completion of supplementery therapy, version 1, 22.10.2004 * Participant completion of triel, version 1, 22.10.2004 «Participant withdrawal from treatment, version 1, 22.10.2004 + Participant drop-out frarr trial, version 1, 22.10.2004 Appendix 4: Letters to the participant from the Research Nurse © Participant initial letter from 1esearch nurse, version 1, 22.10.2004 * Participant follow-up appointments, version 1, 22.10.2004 + Participant letter for final follow-up wsit, version 1, 22.10.2004 «Participant withdrawal from treatment, version 1, 22 10.2004 * Participant drop-out from tral, version 1, 22.10.2004 Appendix 5: Medical Screening Standard Operating Procedure © Version?, 22.10.2004 Appendix 6: Case Report forms (all version 1, 22.10.2004, unless indicated) © Actigraphy instructions © Borg Scale © Centers for Disease Control enteria 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) * Clinical Global Impression change scale (CG)) for participants (previously MREC approved: formatting changes only) + CGifortherapists and doctors (previously MREC approved; now filled in by both therapist and doctor) Chalder Fatigue Questionnaire (previously MREC approved; formatting changes only) Co morbid medical conditions Concomitant medications Client Service Receipt Inventory (CSRI) (previous version MREC approved) Demographic information including self-help group and patient organisation membership Eligibility criteria Euroqo| EQ5d (previously MREC approved; formatting changes only) Exercise and Activity Scale Expectation of therapeutic oulcome Fibromyalgia assessment Hospital and Depression Scale (HADS) (previously MREC approved; formatting changes only) Jenkins Sleep Scale London criterta for ME Oxford criteria for CFS (previous use agreed by MREC; formatting changes only) Past medical history Preferred treatment group Therepy satisfaction scale (previously MREC approved; formatting changes only) Self-efficacy scale Standardised Clinical Interview for DSM (SCID) summary form (previously MREC approved; formatting changes only) ‘SF-36 physical function sub-scale (previously MREC approved; formatting changes only} Self paced step test of fitness Symptom Interpretation Questionnaire Six minute walking test 2S34 Favourable opinion of amencmant Version 2. October 2004 ‘SSMC monitoring interview Work and Social Adjustment Scale Adverse Event report form Drop-out report form This submission also included the following items for information only: + Appendix 7: PACE policy on ancillary studios, version 1, 22.10.2004 © Appendix 8: Consort Diagram, version 1, 22.10 2004 Amendment 3.1, 06/12/2005 ‘Adaptive Pacing Therapy (APT) Manual for Therapists’, Version 2, 11/2004 ‘Adaptive Pacing Therapy (APT) Manual for Participants’, Version 2, 11/2004 ‘Cogniive Behaviour Therapy (CBT) Manual for Therapists’ Version 2, 11/2004 ‘Cognitive Behaviour Therepy (CBT) Manual for Participants’, Version 2, 11/2004 ‘Graded Exercise Therapy (GET) Manual for Therapists’, Version 2, 16/11/2004 ‘Graded Exercise Therapy (GET) Manual for Participants’, Version 1, 16/11/2004 ‘Standardise Specialist Medical Care (SSMC) Manual’, Version 1, 02/12/2004 Protocol version 3, 02/12/2004, which includes further minor amendments to the study design (detailed in tracked chenges' format). The significant alterations to this document are listed in the Notice of Substantial Amendment Form. Amendment 2.3, 05/04/2005 Participant Information Sheet, Version 16, 5° January 2005 * Patient Clinic Leaflet, Version 9, 5” January 2005 Membership of the Committee The members of the Ethics Committee who were present at the meeting are listed on the attached sheet Management approval All investigators and research collaborators in the NHS should notify the R&D Department for the relevant NHS care organisation of this amendment and check whether it affects local management approval of the research. Statement of compliance 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. TREC reference number: MRECIO2I7I8G.__ Please quote this number on all correspondence Yours sincerely, nc Anne Mcullough [Mrs] | wae Committee Administrator Enclosures _ List of names and professions of members who were present at the meeting and those who submitted written commentsComposition of MREC West Midlands Members1 February 2005 Attondance_| Name Profession Dr Jammi Rao Chairman Director of Public Health Dr Steve Bain Reader in Diabetic Medicine vs Mr Nigel Ballantine fice Chairman ‘Specialist Clinical Pharmacist vs Dr Harshad Desai Consultant Physician Ms Debra Easlea Oncology Research Sister Clinical Research Associate Mr Timothy James ‘Senior Lecturer in Law Dr R Jubb Consultant Rheumatologist Rev Dorrie Johnson Lay Member Miss Nancy Lestie Lay Member Prof Alexander McNeish__| Retired Consultant Paediatrician vs Mrs Pat Mosatey Lay Member Ms Christiane Neumann —_| Clinical Nurse Specialist Dr A Roddam Senior Statistician KEY: vos Member attended W = _ Member submitted written comments S$ = Member of Sub Committee