0.E. Matthews - V.T. Farewell Institute of Peyehistry, KCL F CTU Newsletter “F The Cluial Tia ‘neue 10 The PACE Study| Using and Understanding 7 Medical Statistics 4th, completely revised and enlarged edition The CTU has collaborated in the writing of the grant and will carry out the randomisation, data management and statistical analysis for the study over the next four years. Professor Simon Wessely isthe CTU insctor Vernon Todd Farewell “““*o"*?! B. Math, M. Math (Waterloo), PhD (London); Senior Scientist MRC Biostatistics Unit, Cambridge, UK The most common organizational structure for a trial is to have three pri- mary committees. The first is often called the Trial Management Committee or Team. This group of individuals is usually headed by the principal investigator(s) for the trial, and is charged with the day-to-day running of the trial. The Trial Steering Committee, on the other hand, is chaired by an indi- vidual who is independent of the investigators who designed and are imple- menting the trial, in order to provide independent oversight of the study. The Steering Committee will have other independent representation, usually in- cluding statistical expertise, and often including lay individuals from either the general public or disease interest groups. Trial investigators may also sit on this committee. The Trial Steering Committee is vested with primary respon- sibility for the ethical running of the trial. The final committee is usually the Data Monitoring Committee (DMC). This is a group of individuals who are entirely independent of the trial, and who are charged with monitoring the trial from an ethical perspective manuscript are detailed belaw. The authors thank Professors Tom Meade, Anthony Pinching and Simon wessely for advice about design and execution. Trial Steering Committes (TSC) ‘The Thal Steenng Committee (TSC) Is responsible for the independent oversight of the progress of the trial, investigation of serious adverse events, and determining the future progress of the trial in the light of requiar reports from the DMEC. The TSC is composed of: Professor Janet Darbyshire (Chair),Neurology, psychiatry, chro - fatigue and transfusion medicine: ener ‘http: / /www.mre-bsu.cam.ac.uk/ BSUsite/Research/Section12.shtm! eee hi regress) somisaeon ‘Saved 8 times between July 14, 2006 and April 14, 2009, Contents, abstract Introduction Epilepsy National General Practice Study of Epilepsy in its early I | | Years (NGPSE) Multicentre Study of Early Epilepsy and Single Seizures (Wess) 2006 2007 2008 Longer-term clinical outcones and cost-effectiveness of standard and new antiepileptic drugs (SANAD) Multicentre trial of infantile spasms (UKISS) Denentia Controlled trial of a cholinesterase inhibitor in the -managenent of agitation in denentia that is unresponsive to psychological intervention (CALM-AD Psychiatry Clinical Trials unit (King's College London & Institute of Psychiatry at the Maudsley) Mental Health Research Network (MHRN) Adoptions Connittee Depression Neurotic Disorders Chronic Fatigue Syndrome (CFS) Transfusion Medicine Epidemiology and survival of transfusion recipients (EASTR) Transfusion alternatives preoperatively in sickle cell disease (TAPS Trial) Acknowledgenent Summary of major achievements Publications fron this progranme Links ‘Abstract I have initiated, developed, and collaborated in both clinical trials and epidemiological studies in four challenging medical specialties working with a large nunber of collaborators geographically dispersed throughout UK, Europe, and beyond. These have resulted in major advances in the understanding of dementia in the community (with Fiona Matthews), the ‘treatment of infantile spasms and epilepsy, the efficacy of cognitive therapy in both unipolar and bipolar affective disorder, and the long-term consequences of neurotic disorders. ‘Over many years my progranme has contributed to the successful completion of the three largest clinical trials, all of major international importance, in epilepsy, as well as the development of a novel method for ‘estimating years of Life lost following diagnosis of seizures. My programme will be exploited in the future in further collaborations with the pharmaceutical industry that allow head-to-head conparisons of their new ‘drugs. deleted T have enabled a successful collaboration Linking the research progranmes of this Unit with the MRC Clinical Trials Unit (HRC CTU) in London, that has resulted in the establishnent of a new Clinical Trials Unit dedicated to ental health and neurological sciences at the Institute of Psychiatry in London, and to the creation of a major research programme in transfusion medicine, a specialty that currently lacks an evidence base, that has resulted in a multitude of clinical trials and other studies. The Linkage has ‘enabled my expertise in clinical trials to be extended to chronic fatigue rome and the setting-up of a major MRC study to evaluate the efficacy four different interventions. T have advised many clinical trialists on the setting-up of organisational structures including Steering and Data Monitoring Committees, and Management Groups, against @ background of confusion partly by recent European and UK legislation. Introduction I present my eighth and final Unit review report since joining MRC Neuropsychiatric Research Unit in 1968; a period exceeding 37 years during which I have been very privileged to engage fully in the research Programmes of MRC, be a co-editor for 18 years of the firstimajor journal in medical statistics (Statistics in Medicine), found an international society (Society of Pharmaceutical Medicine), draft the!Constitution for another (International Society for Clinical Biostatistics), and contribute to UK Government, European, and International working parties and committees. In view of my retirenent in September 2008 I describe only my research Programme over the past five years without reference to the future but note that none of my projects will terminate in the near future, for they will be continued and expanded by others many of whom I have trained for that purpose. As I have worked within MRC Cognitive Function and Ageing Study since its inception, and Line-managed Fiona Matthews from her appointment as statistician to this project in 1997, this section ends with a description of her research over the last six years as well as her proposals for the next five. My role within MRC changed radically in 2661, resulting in my switching from independent band 2 to core scientist, and with secondment (26%) to ‘the Division Without Portfolio (DWP), now Division for Other Diseases, in deleted MRC CTU, London (Director: Janet Darbyshire). My expertise in clinical trials was needed to expand the activities of DWP into areas such as mental health, denentia, chronic fatigue, and transfusion nedicine, all currently the focus of government health policy. The requirement to serve two HRC Units Linking Cambridge and London has worked extremely well and T have not only fulfilled my expanded role within MRC CTU (as evidenced by their Unit review in 2984 and requests for an increased element of my time), but also through continuation and completion of the progranme set out in this Unit's previous review report; this was achievable only by virtue of the capabilities of the staff I have supervised and trained. In my expanded role I have engaged in many clinical trial consultation meetings especially to deal with the establishment of infrastructure, the complexities resulting from European and UK legislation, ‘and the changing roles of Trial Steering Committees and Data Monitoring Committees over which there is currently great variation in practice, coupled with much confusion. In this report I present activities within both Units under the main headings of epilepsy, denentia, psychiatry, chronic fatigue, and transfusion medicine, highlighting only the principal studies within each. Epilepsy Epilepsy is the third most prevalent neurological disorder (about 1 in!208) ‘after migraine and stroke, and the most serious. My research collaborations, started 38 years ago, include large clinical trials and epidemiological studies of international importance. In 2605 ny “contributions were recognised by neurologists with the Epilepsy/Lifetine Service award for *a Lifetine’s contributions to Services to statistics and epilepsy” from International League Against Epilepsy UK Chapter; T am the third recipient of this award and the first statistician. In 1996 I was appointed by the Secretary of State for Transport (Sir George Young) to his Honorary Medical Advisory Panel on Driving and Disorders of the Nervous System for a term of 5 years (the panel includes neurologists, neurosurgeons, neurophysiologists, and neuropsychologists as well as representatives from DVLA); it advises first on driving regulations for both ‘group I and group II licenses in specific disease categories, and on individual cases. My term vas extended for a further 5 years in 2002, and 1 remain the only statistician appointed to any of the Minister's six advisory deleted panels. I describe four of ay more important collaborations to epilepsy below. National General Practice Study of Epilepsy in its early Years (NGPSE) (with S. Shorvon, 0.Cockerell, S. Lhatoo, B. MacDonald, J. Sander, G. Bell (National Hospital, London), D.Goodridge (GP, Kent)) NGPSE remains the only large prospective cohort study of epilepsy in/the general population; it recruited 1260 patients during 1984-1988, with follow-up to 2001. I was responsible for the design and have undertaken analysis in a series of major papers published since 1998. We found an unexpected excess mortality [61.050] and exploited the yearly decline in SHRs from diagnosis by using a Weibull survival model to estimate annual death rates by sex, age, and seizure type; these were superimposed on ‘the English life table to estimate reductions in Life expectancy [04.043]. As far as I am aware, this methodology is original and the paper attracted a bursary award fromthe Anerican Epilepsy Association for the first author to attend their 57th Annual Meeting in Boston in 2003; the Lancet editorial fon the paper commented that “the authors have expressed earlier knowledge in a new form which serves to refine our understanding of an important prognostic aspect of epilepsy” (Tomson, 2005). Modelling of seizure recurrence using multi-state, discrete time, Markov chain and other techniques, will be used to examine factors that influence transitions betwee s free, rand re, and recurrent seizure (chronic epilepsy) states. Further follow-up of the NGPSE cohort is planned. deleted Multicentre Study of Early Epilepsy and Single Seizures (HESS) (with Lois Kim; D. Chadwick, A.Jacoby, A. Marson (Liverpool)) When and whether to start drug treatment following a seizure is/uncertain. We have now resolved this issue in the MRC funded MESS trial that randomised 1443 patients fron 13 countries to imediate or delayed drug treatment. Lois Kim's analysis denonstrated reduction of seizure ‘occurrence with immediate drug treatment but no long-term effect on emergence of chronic epilepsy; Lois Kim also produced a simple Prognostic model using the methods developed by Royston and Saverbrei (2004) to estimate risks of seizure recurrence under the two treatment policies that can be readily used in clinical practice. Results were published in Lancet [95.067] and Lancet Neurology [06.061], and attracted an editorial (McIntosh and Berkovic, 2605). Longer-term clinical outcones and cost-effectiveness! of standard and new antiepileptic drugs (SANAD) (with D. Chadwick, A. Jacoby, C. Tudor Smith, P. Williamson (Liverpool)) There is a substantial difference in costs of drugs introduced in the early 1998s and the standard first-line treatments, carbamazepine and sodium valproate, available from the 1960s. The HTAfunded SANAD trial evaluates'5 new drugs for cost-effectiveness by comparison with the two standard ones in an original design that allows drugs from different pharmaceutical companies to go head-to-head; it completed randomisation of nearly 2500 patients by mid-2004 with minimum! follow-up for an deleted additional year; results were presented in March 2006 and are of major Oe importance. I advised on design and analysis and chaired the Data Monitoring Committee. The success of this study design will be exploited in a new trial comparing the best treatments! from SANAD with a further generation of drugs Licensed in the late 1990s. Multicentre trial of infantile spasms (UKTSS) (with J. Osborne, S. Edwards, E. Hancock, ‘A. Lux, F. 0*Callaghan (Bath), C. Kennedy (Southampton), R. Newton! (Manchester) C. Verity (Department of Paediatrics, Addenbrooke's Hospital, Cambridge) ) Infantile spasms are a rare form of devastating epilepsy in childhood that is difficult to control and associated with learning disabilities, severe Psychomotor retardation, and death. Just two forms of treatment, drugs (vigabatrin) and hormones, are available, and we have compared these in the UKISS trial that recruited 167 infants throughout UK; I advised on trial design and did the analysis. Results published in Lancet [04.069] denonstrate that hormones provide better early control of spasms, while those published in Lancet Neurology [05.063] indicate no longer term differences up to age 14 months, but as conjectured suggest that better initial control of spasms in those with no identified underlying aetiology may Lead to improved development with hormones. The design of this study will now be exploited in a new Randomised Controlled Trial (RCT) comparing combined hormone and vigabatrin treatment with hormones alone. Dementia Part of my activity in dementia has been within the MRC Coanitive deletedFunction and Ageing Study Co-operative (CFAS) of which I have been a menber since its inception in 1988. Fiona Matthews was appointed as CFAS statistician in 1997 and, since my role is now mainly advisory, this part of my programe is summarised separately under her nane. Fiona Natthews's achievenents in understanding the full complexities of this study, developing the necessarily complex techniques for analysis within deleted her PhO, organising a thriving research team of 15 staff thereby demonstrating her abilities of leadership, and coordinating the publication of over 30 papers, indicate her capability for managing CFAS within the Unit by ity Colles London) and Tan Mckeith (Newcastle) that presented our bid to become the Co-ordinating Centre for the UK Denentias and Neurodegenerative Diseases Research Network at the Departnent of Health (OH); We competed successfully against two other teams and were awarded 720m. deleted Controlled trial of a cholinesterase inhibitor in the managenent of agitation in denentia that is unresponsive to psychological intervention (CALM-AD (with R. Howard, R. Brown (Institute of Psychiatry, London), C. Ballard (Newcastle) , P. Benthan (Birmingham), R. Bullock (Swindon), A.Burns (Manchester), . Holmes (Southampton), R. Jacoby, E. Juszczak (Oxford), M. Knapp (London). J. Lindesay (Leicester), J. O'Brien (Newcastle), S. Nally & S. Tebbs (MRC CTU)) Tana principal investigator (PL) for this MRC‘funded trial that was designed to compare donepezil, risperidone, and placebo in the control ot agitation in denentia, and 1 guided other investigators on design, managenent, and analysis, as well aS supervising a half-tine data anager within MRC CTU. CALM-AD suffered major problens with a delayed start due to extended negotiation of indennity agreenents with deleted sponsors, opposition to the trial by a pharmaceutical conpany, withdrawal of risperidone by Comittes on Satety of Medicines 3 months after its start, and expiry of the shelf-life of placebo. Despite these setbacks the trial was renarkably successful in randonising its target of 199 patients 6 months before the scheduled end of recruitment; at my Suggestion the chie? investigator applied for, and HRC awarded, an additional 740,000 to enable continuation of recruitent resulting in 272 patients randorised; Geteted results will be disclosed in May 2086, The research team and infrastructure brought together by this trial will be maintained in a further trial (DOMINO) comparing donepezil, memantine, and their combination, in Alzheiners disease, the outline proposal having been accepted recently by MRC Psychiatry My long-running proaranne in psychiatry has continued with the successful conclusion of two trials in depression, a series of papersitron ‘the Nottinghan neurotic disorders cohort, engagenent in the MRC Co-operative Group for the Evaluation of Interventions to Inprove Mental Health in Prinary and Secondary Care. (succeeding Simon Thompson) wherein I supervised their statistician (Ula Nur), and menbership of Steering Conmittees and Data Monitoring Committees. I have declined to _ deleted be an applicant on several grant proposals as a result of overload but have honetheless provided statistical advice. 1 have revised my chapter in the Royal College of Psychiatrists’ book on research methodology to be published (3rd edition) this year [66.405] and will update my survey of clinical trials in psychiatry (Johnson, 1998) to include 2006. Clinical Trials Unit (King's College London & Institute of Psychiatry at the Naudstey) (with S.Wessely, R. Kerwin, R. Welwyn, S. Lee, (Institute of Psychiatry, London)) A long needed Clinical Trials Unit (CTU) dedicated to RCTs in psychiatry ‘and the neurosciences has been established with an anbitious remit to advise, initiate, design, conduct, analyse, present and publish clinical trials in mental health. I have acted as a Link between this CTU and MRC CTU, Provided guidance as a menber of its steering and Management Committees, and provided supervision and managenent of its statisticians geleted {Rebecca Walwyn & Sally Lee) on a monthly basis. I have attenpted to guide the CTU towards critical mass and in addition to two statisticians it ow has a Manager, Database Manager, and secretary. Difficulties with appointing a successor to Brian Everitt as Chair of Biostatistics or a senior ‘lecturer within that department, posts that were intended to provide sone nanagenent and supervision of statisticians within the CTU, have led to ny fulfilling these roles as well as providing advice to grant applicants at ‘the Institute of Psychiatry (ToP) and King's with inevitable requests, necessarily usually declined, to become a co-applicant. Nental Health Research Network (MHRN) Adoptions Connittee (chair: T. wykes (Institute of psychiatry, London)) In March 2065, I succeeded Janet Darbyshire as a menber of this important independent subconmittee of MHRN that decides on the suitability of projects to run on the UK network provided that they have service user input, are in Line with national mental health policy, are free of major ethical and design flaws, require multiple centres, and denonstrate feasibility to run on the network. I have quided the committee towards acceptance of larger studies, documentation and monitoring of load on the network within individual hubs, by disease areas, and by patient recruitment requirements. Depression (with G Paykel, R Abbott, H Hayhurst (Departnent of Psychiatry, University of Cambridge), R Bentall (Manchester), P Kinderman, R Morriss (Liverpool), 3 Scott (Newcastle, Glasgow, London) ) Prior to 2061 we completed a ‘therapy (CT) or usual treatment for people with residual (unipolar) depression followed up for 18 months in which T advised on design and deleted Supervised analysis. We have now extended follow-up to 6 years and demonstrated (using exponential and Weibull survival models) that the effects of CT in preventing relapse were not lost until 31/2 years; we also identified 9 need to evaluate the efficacy of booster CT around 2 years [05.077]. We have extended the methods and infrastructure developed in ‘this trial to conduct a similar ACT in people with bipolar disorder. 1 wrote comprehensive analysis strategy prior to exanining any trial data that N25 Geleted becone a tenplate for trials in psychiatry, and beyond, and supervised those doing the analysis (Hazel Hayhurst & Roserary Abbott). Results indicate that by contrast to unipolar depression, CT was of little use in bipolar disorder but suggested benefit in patients with few prior episodes “196 With Giles Newton-Howes and Peter Tyrer (Imperial College, London)! have produced 2 major meta-analysis of the association between deleted personality disorder and outcome of depression incorporating every study ‘that we could find in the literature irrespective of measures used, and ‘employing the methods of Whitehead et al. (nhitehead et al. 1999), to ‘enable inclusion of both dichotomised and continuous outcomes. This is an area of major controversy over a long period and we have demonstrated Clearly that co-norbid personality disorder with depression is associated with @ doubling of the risk of poor outcone for depression irrespective of ‘type of outcone criterion, or treatnent (drugs, psychotherapy, or both) [06.080]. ‘Neurotic Disorders (with P. Tyrer, U. Nur, G. Knerer (London), H. Seivewright (nottinghan)) The Nottinghan study of neurotic disorders started as a community-based 1e-week RCT of 261 patients allocated to three treatments and then continued as_a cohort study with follow-up to 5 years. We have now conpleted a further follow-up at 12 years achieving 96% response by delted using (to my mind the fully, justified method of) cold-calling. The study is uniaue and has produced series of paterson the ethics ef cold-calting, —_ changes in personality status, cothymia, social functioning, personality ii caeeoo dea nt Setar Ties ete camen le concastostase zie 113; 85.1 {with P. White, T. Cholaer (London ), M. Sharpe (Edinburgh) FS is currently the most controversial area of medical research and characterised by vitriolic articles and websites maintained by the More Geteted extrene charities supported by sone patient groups, journalists, Menbers of Parlianent, and others, who have little tine for research investigations. Tn response t0 a ON directive HRC called for arant proposals for Lnvestigations into CFS as a result of which two RCTS (PACE and! FINE) were funded and have started despite active campaigns to halt thes. I an part of the PACE study, a multi-centre ACT conparing cognitive behaviour ‘therapy, graded exercise training, and pacing in addition to standardised specialist medical care (SSMC), with SSMC alone in 69¢ patients; it 1s funded by MRC, Chief Scientist's Office (Scotland), DH, and Departnent of Work and Pensions at an estimated cost of 72.7m. T have been fully engaged in providing advice about design of PACE and T an anenber of deleted both Trial Managenent Group and Trial Steering Comittee. I an not a PI because of fanilial involvenent with one of the charities, a perspective that has enabled me to play a vital role in ensuring that all involved in PACE maintain absolute neutrality to all trial treataents in presentation, docunentation, and assessment Transfusion Medicine (with National Blood Service (NBS) Clinical Studies Unit (CSU, Cambridge), A Casbard (MRC CTU)) Transfusion nedicine is one of the newer specialties of medicine and covers all aspects of the use of blood products and components. Since the evidence base for current practice is very limited with few high quality RCTs, NBS established in 2961 2 CSU in Cambridge, supporting a Peete’ dedicated statistician within MRC CTU, to initiate new trials and other studies. I moved into this area through involvenent in MRC CTU and have supervised the statistician (Angela Casbard) supported by the N8S grant (initially 3 years but now permanent). Location of the CSU in Canbridge has enabled ay close collaboration with excellent working relationships. Transfusion 1s challenging area because of the small number of Clinicians working in this specialty, and their lack of involvenent" in/RCTS) and also because this is a fast moving area where practices change deleted rapidly with the issuing of new guidelines; also there are no charities in transfusion. Problems are illustrated by a review of all RCTs of prophylactic peri-operative transfusion of fresh frozen plasma inpatients undergoing cardiac surgery; Just six were found, all small, of poor quality, with variable follow-up periods and outcones [04,020]. Statistically this specialty is interesting becouse the outcones of transfusion are known within a short period (48 hours, a week, or at most a month) with just one or two of prinary importance, and consequently there is scope to use the neglected (group) sequential ‘designs. Despite the problens identified above, the CSU has been successful in stimulating applications for over thirty RCTS deleted Ga Cer aviar SEies OelGP ALD Me Sieeattinied; ewiceegied deleted follow. _ ee Epidemiology and survival of transfusion recipients (EASTR) Blood banks throughout UK maintain very detailed computerised records of the donor source, processing, and destination of every item of every product they stack. By contrast very little is known of exactly what happens at the level of patients with regard to requirenents and outcone. To renedy this NBS set up a national survey in England to establish the major uses of fresh frozen plasma, red blood cells, and platelets, and the survival of patients following transfusion. A pilot study was conducted in 5 hospitals using two months data from early 2001 (4351 transfusion episodes in 2468 recipients) to establish feasibility of linking records manually fron blood bank and hospital) computers, and to classify major reasons for transfusion of the cost-effectiveness off cognitiveusing)standard TcD-10 diagnoses and Office for Population Censuses and Surveys (OPCS) procedures; the pilot study report provided a wealth of important information on the main diseases and operative procedures for which the three components were required (82.410; 04.496]. The fut survey of 29 hospitals (stratified by size and region) and surveying the period from october 2061 to September 2962 by randon sampling of transfusion recipients (stratified by product and month) but with complete annual _use of blood products over that period, was allowed to proceed in 2005 after long delays induced by the Patient Information Advisory Group as we have reported [e4.072]. Information has been obtained fron allarder yatated Sample than expected. This study 1s unique and is already the target for elete requests for information about specific patient groups; data collection, editing, and classification are complete, and I an supervising the analysis. Transfusion alternatives preoperatively in sickle cell disease (TAPS Trial) Patients with sickle cell disease (ScD) often have a blood transfusion before surgery, the efficacy of which is questionable. To ascertain whether pre-operative transfusion increases or decreases problens arising after surgery we have set up a multi-centre group sequential RCT with one month follow-up to recruit 400 patients with SCD in UK and USA, thereby establishing the first major UK-USA collaboration in transfusion medicine. TAPS has been funded by NBS and will start later this year. Acknowledgement AL the end of this my final report I gratefully acknowledge the support I have received from MRC aver a very Long period, the help and encouragement I have received from seven very eninent Unit Directors (Dr © deleted Derek Richter, Professor Sir Richard Doll, Dr Robert Balazs, Dr lan Sutherland, Professor Nicholas Day, Professor Simon Thompson, and Professor Janet Darbyshire), and the pleasure and privilege of working with hundreds of clinicians, statisticians, and other researchers scattered ‘around the world. I pay particular tribute to all the Unit staff both past and Present whose companionship, advice, and encouragenent have made my career so enjoyable and rewarding. Summary of major achievements Successful integration of diverse research progrannes across two PRC Units; Providing young statisticians with confidence and expertise to function independently; Completion of major trials and epidemiological studies in difficult medical specialties; Improving understanding of psychiatric and neurological diseases and their treatment; Lifetime achievenent award for research in epilepsy. Publications from this programme Peer-reviewed publications Books, book chapters and reports Editorials and commissioned articles Letters and conmentaries Other non-peer-reviewed publications eae:PACE trial group Go to: 4) Trial Steering Committee (independent members)—Janet Darbyshire (Chair), Jenny Butler, Patrick Doherty, Stella Law, M Llewelyn, and Tom Sensky. Observers—Sir Mansel Aylward (Department for Work and Pensions, London, UK), Sir Peter Spencer and Chris Clark (Action for ME, Bristol, UK), Stephen Stansfeld (Queen Mary University of London, London, UK), Alison Wearden (Fatigue Intervention by Nurses Evaluation trial), and members of analysis strategy group and writing and publication oversight committee. Data Monitoring and Ethics Committee—Paul Dieppe (initial Chair), Astrid Fletcher (final Chair), and Charlotte Feinmann. /ndependent assessors of the trial safety data—Hiroko Akagi, Alastair Miller, and Gavin Spickett. Independent assessors of therapy—Barbara Bowman and Deborah Fleetwood. 4. Trial management ©THE PACE TRIALIDENTIFIER — THE MEDICAL RESEARCH COUNCIL} 4.1 What are the arrangements for day to day management of the trial? The trial will be run by the trial co-ordinator who will be based at Barts and the London. , with the principal investigator (PI), and alongside two of the six clinical centres. He/she will liaise regularly with staff at the Clinical Trials Unit (CTU) who themselves will be primarily responsible for randomisation and database design and management (overseen by the centre statistician Dr Tony Johnson), directed by Professor Simon Wessely, in collaboration with Professor Janet Darbyshire at the MRC CTU. 4.4 What will be the responsibilities of the named collaborators? Prof. Anthony Pinching will lead the Baits immunology centre. Dr David Wilks will co-lead the Edinburgh centre. Prof. Tim Peto and Dr Eleanor Feldman will co-lead the Oxford centre. Dr Gabrielle Murphy will lead the Royal Free centre. Professors Peto and Pinching and Dr Wilks will advise regarding any uncertain medical exclusions, Prof. Simon Wesscly will oversee the CTU, with the support of Dr Tony Johnson and Prof. Janet Darbyshire. Prof. Martin Knapp will oversee the analysis of the health economic data, Prof. Tom Meade (London School of Hygiene and Tropical Medicine) is a senior consultant. Mr. Chris Clark, CEO of A/ME, will be a member of the TMC and help with external relations. 4.5 Who will be the trial statistician? TBA (CTU post about to be appointed) will be supervised by Dr Tony Johnson. 6 Application History 6.1 A similar application of a much smaller two arm trial (FATIMA; Grant number G9825745) was submitted in full to the MRC in 1999, rated Alpha B, but not funded. The outline proposal of this study (G010039) was approved for a full proposal in October 2001. The major innovations in this application include close collaboration with Action for ME, two new arms (APT and UMC), a much larger number of subjects and centres, and the involvement of a clinical trial unit. 6.2 We submitted a similar trial to the Department of Social Security (now Work and Pensions) in 2000, and agreement in principle to fund was given, although final funding was not forth-coming.