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THE MRC / PACE TRIAL SCANDAL
Should patients boycott this trial? We call for a Public Inquiry
By Jane Bryant, April 2004
THE PACE (PACING, ACTIVITY AND COGNITIVE BEHAVIOUR THERAPY: A RANDOMISED
EVALUATION) TRIAL
One of the worst scandals in UK medical history is set to erupt shortly over
a psychiatric clinical trial that has been approved and funded by the
Medical Research Council (MRC) ostensibly to benefit sufferers from the
neurological disease ME/CFS ICD-10 G93.3. According to one of the trial
leaders, about £4m of British taxpayers money is scheduled to be wasted in
the conduction of these trials that in the case of the PACE trial,
specifically excludes the very patient group that it is supposed to be
studying.
In February of this year the Health Minister, Lord Warner, confirmed that
the UK accepts that ME/CFS is a neurological disease and listed as such by
the World Health Organisation (WHO) under ICD-10 G93.3. And yet the PACE
trial will study only psychosocial management regimes and treatments that
have been comprehensively shown to be at best ineffective and in many
instances have made sufferers of ME/CFS considerably worse. The MRC is very
well aware of this fact.
Led by a group of psychiatrists and designed by Professor Simon Wessely who
will oversee the Clinical Trial Unit, the PACE trial is to study and compare
the psychosocial management/treatment regimes of Adaptive Pacing Therapy
(APT), Cognitive Behavioural Therapy (CBT) and Graded Exercise Therapy (GET)
for the sufferers of ME/CFS. Professor Simon Wessely who will direct the
randomisation, data base design and management of the trial is notorious
worldwide for his on the record and published views that ME is simply an
erroneous belief system and not the neurological disease that it is
recognised to be by international consensus and the WHO, listed under ICD-10
G93.3.
The doctors carrying out the research are, themselves, employed to provide
the therapies being studied. As such, they have a monetary vested interest
in showing that they are effective. This must surely explain why such
‘inclusive’ criteria were used since people with other types of chronic
fatigue who are NOT ME/CFS SUFFERERS, (CFS being the supposed subject of the
study), may well find these therapies helpful.
In a Press Release recently issued by THE 25% ME GROUP (representing the 25%
of ME/CFS sufferers who remain long term ill and severely disabled by the
disease), figures were released that showed over 90% of ME/CFS sufferers
have found these treatments to be unhelpful and a shocking 82% reported that
GET was actively harmful.
See THE 25% ME GROUP Press Release here:
http://www.bryantpr.plus.com/25%25%20Group%20Press%20Release%202.doc
Pacing as used by the ME/CFS sufferers right around the globe in no way
resembles Adaptive Pacing Therapy (APT). Pacing as used by ME/CFS sufferers
aims at a sustainable lifestyle involving the careful management of energy
output so as to promote stabilisation and healing, thus reducing relapses
and minimising symptoms. Pacing does not feature targets and goals other
than this. Pacing as used by ME/CFS sufferers is diametrically different
from APT that sets targets and goals and for which there is no apparent and
credible scientific support.
These psychosocial treatments are to be trialled at the newly operational
ME/CFS centres recently announced by the Department of Health, UK. The
combination funding for the new ME/CFS centres and the trials amounts to
some £11.1m that is currently being ring fenced and devoted to psychosocial
treatments for an organic illness; treatments that have not only failed at
best to benefit sufferers in the past, but have also actively damaged many.
THE OXFORD CRITERIA
In May 2003, the MRC announced that the Oxford criteria are to be used as
the criteria for the PACE trial. Produced by a group of UK psychiatrists in
1991, the Oxford criteria have been superseded, are outdated, have no
predictive value and are not in use by international consensus.
See full text of the Oxford criteria here:
http://www.bryantpr.plus.com/CFS%20Oxford%20Criteria%201991.pdf
The Oxford Criteria specifically *exclude* patients suffering from a
neurological disorder and therefore by definition all 240,000 sufferers of
the neurological disease ME/CFS – 40,000 of them children in the UK.
Moreover, patients suffering from the disease Fibromyalgia are to be
included in the PACE trial. Fibromyalgia is classified in the WHO ICD at M79
as a distinct entity. Fibromyalgia is a quite separate disorder from ME/CFS,
with a discrete biomedical profile that is entirely distinct from that found
in ME/CFS. There is absolutely no scientific rationale for including
Fibromyalgia patients in the PACE trial.
The Oxford criteria are so wide that anyone suffering from fatigue for six
months or more could be included in the PACE trial. On this basis it is
quite clear that the Oxford criteria have been selected so as to *enhance
the numbers recruited* and include the masses suffering from idiopathic
chronic fatigue that is classified by the WHO under F48 as a mental disorder
and totally separate to the neurological disease ME/CFS ICD- 10 G93.3.
The One Click Group asked the MRC as to who judged the use of the Oxford
criteria to be appropriate for use in this trial? The MRC answered: “The
independent experts from UK and abroad who peer reviewed the trial protocol
considered the INCLUSION criteria to be appropriate for meeting the
objective of the trial.”
When further questioned by The One Click Group as to how many of the
so-called international ‘independent’ experts who peer reviewed the trial
protocol were psychiatrists, how many were neurologists, neuropsychiatrists
or psychologists, answer came there none.
It is scientifically dishonest for the MRC to accept, approve and fund a
trial when the evidence clearly shows that is flawed from the outset by
virtue of the fact that it cannot be including ME/CFS sufferers and yet
claims to be doing so.
These ‘trials’ are quite clearly little more than job providers for certain
psychiatrists, their helpers and supporters who operate on the basis of a
misguided but entrenched illness belief that ME/CFS is a mental disorder,
not the neurological illness that it is, as recognised by the WHO, by the UK
government and by international consensus worldwide.
This is deceit and a scandal of massive proportions. How did it come about
that £4m of British taxpayers money was agreed by the MRC to be spent on a
trial that excluded the very patient population that it claims to be
studying?
THE ACTION FOR ME (AfME) INVOLVEMENT
The charity AfME has been closely involved in the development of the PACE
trial protocol and is being given government monies under Section 64 to
represent the so-called ‘best interests’ of ME/CFS patients that transpire
to be nothing of the kind.
This charity also has one of its key employees seconded to the Department of
Health Secretariat and acting as Observer on the Steering Committee. AfME is
currently under investigation because the policy, stance, direction and
workings of this charity are not supported by its subscribers and the wider
ME/CFS community. AfME has not seen fit to hold an Annual General Meeting
that involved its subscribers since 1996.
See the full text of THE AfME DOSSIER 2004 here:
http://listserv.nodak.edu/scripts/wa.exe?A2=ind0401E&L=co-cure&P=R2
When Mr. Clark, the CEO of AfME, was very recently questioned over the
psychosocial treatments on offer in the new ME/CFS centres, he maintained
that 90% of ME/CFS sufferers found Pacing to be helpful. This is entirely
correct. However, the fact of the matter is that the APT treatment in no way
resembles Pacing and this Mr. Clark knows full well. Mr. Clark also stated
that 50% of ME/CFS sufferers were helped by CBT/GET. This is demonstrably
not the case.
In March 2001, AfME itself carried out a survey of 2,338 respondents
entitled “Severely Neglected – M.E in the UK” that clearly stated **“graded
exercise was reported to be the treatment that had made most people worse.”
**
Quite how Mr. Clark manages to rationalise his charity’s stance over the
PACE trial for which AfME has obtained funds by government grant with the
results of AfME’s own survey, is a matter of intense speculation both in the
UK and abroad.
In response to massive disquiet by the ME/CFS community over the use of the
superseded and outdated Oxford criteria to be used for the PACE trial as
announced by the MRC that by definition excludes all sufferers of ME/CFS,
Mr. Chris Clark, the CEO of AfME, issued a statement on the 10th February
2004 and said that the Fukuda criteria would also be used for the PACE
trial.
See the AfME PACE trial statement here:
http://www.bryantpr.plus.com/PACE%20-%20AfME%20STATEMENT.txt
When the MRC was questioned by The One Click Group as to the validity of
announcing a separate set of criteria to be used *after* the PACE trial
proposal had been already approved, a spokesperson for the MRC responded:
“The AFME statement is correct. Patients will be entered into the trial
using the Oxford criteria but will then be further assessed against the
other criteria (Fukuda and London) for secondary analysis.”
Secondary analysis? That’s rich. The MRC went on to say: “Applying the
Fukuda and London criteria to the patients recruited under the Oxford
criteria will enable finding out about sub groups of people including those
who meet the WHO ICD-10 G93 classification.” Since *all* patients suffering
from ME/CFS have *already been excluded from the PACE trial by definition of
the use of the Oxford criteria, how can they be then analyzed a second time
when they have not been included in the first place?* The foregoing
statement by the MRC defies credibility.
The One Click Group also asked the MRC to list by name the number of trials
that had been rigorously scrutinised and approved using one set of criteria
and then other additional bolt on sets of criteria subsequently added. The
MRC refused to provide any details despite repeated request.
THE CANADIAN DEFINITION OF ME/CFS
Produced by an Expert Medical Consensus Panel of eleven physicians who have
between them treated/diagnosed over 20,000 ME/CFS sufferers worldwide, the
Canadian Definition of ME/CFS, Diagnostic and Treatment Protocols sets out
the most recent and carefully compiled criteria and seeks to rectify
problems encountered in many studies so far. Published in 2003, these
criteria most closely define those ME/CFS patients who not only suffer from
bone crushing fatigue, but also from a wide range of neurological,
immunological, and endocrinological problems, i.e. those who would come
under the WHO classification of ME/CFS ICD-10 G93.3. It is these Canadian
criteria that have international consensus that should be used for the PACE
trial and any other clinical trial in relation to ME/CFS.
See the full text of the Canadian Definition of ME/CFS here:
http://www3.sympatico.ca/me-fm.action/journal.pdf
The national UK charity Tymes Trust (The Young ME Sufferers Trust) has
enthusiastically praised the Canadian Definition of ME/CFS and recommends
its clinical use. It has stated that once these criteria are put into
widespread use, it will be much more difficult for people with idiopathic
chronic fatigue to be categorised along with those who have ME/CFS.
MERGE (Myalgic Encephalomyelitis Research Group for Education and Support),
the charity that funds and commissions biomedical scientific investigation
into the causes, consequences and treatment of Myalgic Encephalomyelitis and
related conditions is scathing over this psychiatric trial. As is stated in
the ‘Comparison of MRC-funded research and MERGE-funded research into ME/CFS
’ written by Margaret Williams in April 2004: “Despite being desperately
short of funding and thus having to devote much time and effort to
fund-raising instead of to its primary goal of biomedical research, MERGE
has achieved far more in furthering the understanding of ME/ICD-CFS since
its inception in 2000 than the MRC and Government have achieved in the last
20 years.”
See full text of the ‘Comparison of MRC-funded research and MERGE-funded
research into ME/CFS’ document here:
http://www.bryantpr.plus.com/COMPARISON%20OF%20MRC%20AND%20MERGE%20RESEARCH%
20ON%20ME-CFS.pdf
Other charities that work in the ME/CFS field such as the Myalgic
Encephalopathy Association (MEA – currently under investigation), the
Association of Young ME sufferers (AYME) and unsurprisingly AfME – also
under investigation and who has an entire conflict of interest over this
issue - have refused to even pass comment on Canadian criteria that
represent the international consensus breakthrough for ME/CFS sufferers
worldwide.
When the MRC was questioned by The One Click Group as to precisely why the
Canadian criteria were not to be used for the PACE trial, the MRC
spokesperson said: “There is no international consensus. International
reviewers were involved in reviewing PACE along with those in the UK and
they were satisfied the INCLUSION criteria was appropriate for meeting the
objective of the trial.”
From its own mouth, the MRC damns itself. The Oxford criteria are being used
so as to INCLUDE patients who will most likely respond to the treatments and
EXCLUDE those who will not – specifically sufferers of the neurological
disease ME/CFS ICD-10 G93.3.
These ME/CFS clinics are supposed to be treating patients - not recruiting
people for research. The money that they are being set up with is money for
SERVICES - NOT RESEARCH. And since this is the case, what is the point in
the clinics using anything OTHER than clinical diagnostic criteria - except
of course to provide guinea
pigs for research?
This study is clearly set up to provide jobs and prestige for the ‘boys’.
THE PACE TRIAL IDENTIFIER
Amidst this huge outcry by the ME/CFS community and the controversy of what
it is being said could well amount to scientific misconduct and fraud in
regard to the PACE trial, The One Click Group was given a copy of the PACE
Trial Identifier. The full contents of this document are published below.
The PACE Trial Identifier is also available online here:
http://www.bryantpr.plus.com/THE%20PACE%20TRIAL%20IDENTIFIER%20.pdf
This is the document that the MRC did not want you to see. It did not want
you to see it because it contains the chapter and verse protocols and costs
of the PACE trial and highlights so clearly the brain washing exercise that
is being carried out over this trial par excellence at taxpayers expense.
This PACE Trial Identifier is an insult to all severely, physically ill
patients of the neurological disease ME/CFS. This trial will do nothing to
enhance the understanding of this disease or help patients in any lasting
and fundamental way.
You will see that the PACE trial is to be designed and managed by Professor
Simon Wessely; that Dr. Peter White, Michael Sharpe and Trudie Chalder will
be centre leaders. Also involved will be Professor Anthony Pinching, Dr.
David Wilks, Professor Tim Peto, Dr. Eleanor Feldman, Dr. Gabrielle Murphy,
Dr. Tony Johnson, Professor Janet Derbyshire, Professor Tom Meade, Professor
Martin Knapp, Ms. Diane Cox, Mr. Vincent Deary, Dr. Paul McCrone, Dr Meirion
Llewelyn, Professor Anne Farmer, Professor Tom Craig, Mrs. Frankie Campling
(ex-sufferer and CFS counsellor). And last but by no means least, we have
our very own Mr. Chris Clark from AfME as part of the Management Committee.
Amongst the many nuggets in the PACE Trial Identifier it is stated that: **
“COMPLIANCE with both the treatments and the study will be maximized by the
COLLABORATION and SUPPORT of AfME…… in the trial.”** AfME compliance,
collaboration and support in relation to the psychosocial PACE trial? This
sentence is reminiscent of how collaborators behaved during the Second World
War! AfME has obtained government monies to recruit and attempt to obtain
the compliance of ME/CFS sufferers in relation to this trial that by Oxford
criteria definition precludes them from entry!
The document also states that previously found predictors of a negative
outcome with treatment include membership of a self-help group and being in
receipt of a disability pension.
It is quite clearly the case that they wish to *investigate the role of
Benefits as a predictor of poor outcome.* It will then be found of course
that if the Benefits are provided, the person has a poor outcome. Ergo, if
the Benefits are not given, the person will have to work for a living.
Subjects will be discouraged from starting over the counter medicines or
alternative treatments. This is particularly poignant since it has been
shown that it is precisely these treatments that can assist some ME/CFS
sufferers the most, even though there is no cure.
As is always the case, those most severely afflicted by ME/CFS will not be
studied because they are too ill to be able to attend these ME/CFS centres
SOME FUNDAMENTAL QUESTIONS THAT REQUIRE URGENT ANSWER
1. What gives this group of psychiatrists and their supporters the right to
impose inappropriate coping/management regimes on severely ill patients,
despite the fact that such methods have been shown to either make little or
no difference or in many cases worsen the illness, sometimes dramatically?
2. What was the purpose of setting up the Chief Medical Officer’s Working
Group, preparing a complex report, taking into account at least some of the
patients’ views and then to all intent and purposes, ignoring them
completely? And this despite the ‘Expert Patient’ initiatives currently
being touted by the UK Government?
3. Why are the Canadian criteria not being adopted for all ME/CFS clinical
trials?
4. Why are some of the UK ME/CFS charities – and especially their principal
representatives – not representing their members properly?
5. Why is £4m of taxpayer’s money being wasted on this PACE trial that by
definition and design excludes ME/CFS sufferers – the very group of patients
that is supposed to be studied?
6. Why are no funds being directed to research of the aetiology of
biomedical aspects of ME/CFS?
7. Is it ethical for people with proven commercial interests in these
studies to be designing and running these trials, given the proven evidence
of their personal commercial interests in the desired outcome of these
trials?
CONCLUSION
This PACE Trial Identifier should be as widely distributed as possible.
As the ME/CFS community UK we request that an Injunction be placed on these
psychosocial PACE and FINE trials, pending the outcome of a Public Inquiry
that is immediately required.
The ME/CFS community UK will be organising a blanket boycott of these
outrageous trials that will not assist sufferers of the neurological disease
ME/CFS ICD-10 G93.3 in any way shape or form and that are promoting
psychosocial treatments that in many cases have made sufferers considerably
worse.
Jane Bryant
THE ONE CLICK GROUP
http://health.groups.yahoo.com/group/THEONECLICKPROTEST/
April 2004
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This document is available online at:
http://www.bryantpr.plus.com/THE%20PACE%20TRIAL%20IDENTIFIER%20.pdf
THE PACE TRIAL IDENTIFIER – THE MEDICAL RESEARCH COUNCIL
1. Trial identifier
1.1 Full title of trial
RCT of CBT, graded exercise, and pacing versus usual medical care for the
chronic fatigue syndrome
1.2 Acronym
PACE: Pacing, Activity, and Cognitive behaviour therapy; a randomised
Evaluation
2. The need for a trial
2.1 What is the problem to be addressed?
The chronic fatigue syndrome (CFS) is a condition characterised by chronic
disabling fatigue and other symptoms, which is not associated with either an
identifiable disease process or a major psychiatric illness.1-3 Myalgic
encephalomyelitis (ME) is thought by most to be synonymous with CFS.1-5 The
prevalence of CFS in primary care is between 1 and 2%.3 An independent
working party, reporting to the English Chief Medical Officer, recently
concluded; “CFS/ME is a relatively common clinical condition, which can
cause profound, often prolonged, illness and disability, and can have a
substantial impact on the individual and the family.”4 As many as half the
patients are unemployed,6 and they have 10 times the amount of sick-leave of
other general medical outpatients.7 The prognosis is poor; in primary care
only a third improve by one year, and of those referred to secondary care
less than 10% return to premorbid functioning.3,8 The management of patients
with CFS consumes significant resources in both primary and secondary
cafe.2,3 CFS patients use an annual average of 13 visits to their general
practitioner and 5 visits to secondary care.6 However there is now evidence
that specific treatments can improve patient outcome. The CMO’s working
party concluded;
“Therapeutic strategies that can enable improvement include graded
exercise/activity programmes, cognitive behaviour therapy, and pacing.”4
This positive statement was balanced in the report by, first the concern of
patient organisations that graded exercise therapy (GET) and cognitive
behaviour therapy (CBT) may worsen symptoms and disability, and second that
pacing, although widely advocated by patients’ organisations, is as yet
unsupported by scientific evidence.
2.2 What are the principal research questions to be addressed?
(1) Are CBT and/or GET more effective than pacing in reducing both fatigue
and disability?
(2) Is pacing more effective than usual medical care?
(3) Are there differential predictors of response to CBT and GET and does
the mechanism of change differ?
(4) Do different treatments have differential effects on outcomes (i.e.
disability versus symptoms)?
(5) What factors predict a favourable response to treatment in general and
with specific treatments?
(6) What are the mechanisms of change with successful treatment?
(7) What are the relative cost-effectiveness and cost-utility of these
treatments?
2.3 Why is a trial needed now?
Efficacy: Two independent systematic reviews have found that rehabilitative
CBT and GET were the most promising treatments for CFS in secondary
care.5,9,10,11 Yet the authors criticised the methodology of the published
trials for being too small, too selective, and using different outcome
measures. No other treatments for CFS have been shown to be helpful in more
than one RCT.5,11 CBT is a more complex therapy than GET, requiring highly
trained therapists, and is therefore less available through the NHS. In
contrast to this evidence, 2,338 members of the patient charity Action for
ME (AfME) reported that CBT and GET were more likely to make them worse
rather than better.12 Pacing and rest were reported to be more helpful.12
Pacing has been described in the scientific literature as a lifestyle
management that allows optimal adaptation to the illness, including an
appropriate balance of rest and activity.4,13 It has been advocated by
exponents of the “envelope theory” of CFS, which states that a patient has a
fixed and finite amount, or envelope, of energy that they must adapt to by
managing activity.13 A non-randomised comparison of adaptive (rather than
rehabilitative) CBT, which included adaptive pacing therapy (APT) based on
this model, found that, although fatigue improved, this treatment was no
more effective than the control condition.14 A recent systematic review
concluded that there was insufficient evidence to recommend adaptive pacing
at present5,9,11 There is therefore an urgent need to: (a) compare CBT and
GET with both APT and usual medical care alone (UMC), seeking evidence of
both benefit and harm (b) compare APT against UMC, and (c) compare CBT and
GET to each other to clarify differential predictors and mechanisms of
change.
Differential outcomes: Because CBT and GET are based on graded exposure to
activity or exercise, they may preferentially improve disability, whilst
APT, being based on the theory of staying within the limits of a finite
amount of “energy”, may improve symptoms, but at the expense of disability.
By measuring both symptoms and disability as our primary outcomes, we will
be able to address this issue.
Process of treatment: We do not know the essential mechanism of successful
rehabilitation from CFS. Do illness beliefs or focussing of attention on
symptoms (symptom focusing) need to be changed by CBT? Or does CBT work
solely by graded exposure to avoided activity, which also occurs with GET?
Is increased physical fitness following increased physical activity,
essential to recovery or not? How important is the alliance between
therapist and patient? Is it important to adapt to the illness to allow
symptomatic relief? A greater understanding of these processes will shed
light on the nature of recovery from CFS and allow the development of more
efficient treatments.
Predictors of outcome: We also need to know which patients require the more
complex CBT rather than the simpler and more readily available GET.
Previously found predictors of a negative outcome with treatment include
mood disorder, membership of a self-help group, being in receipt of a
disability pension, focusing on physical symptoms, and pervasive
inactivity.3,15 No predictive factor has been found in more than one
published study, probably due to a type II error.
Cost-effectiveness: There are no published data on the cost-effectiveness of
treatments for CFS. CBT is relatively expensive and uses scarce therapeutic
resources: we need to know relative cost-effectiveness and cost-utility.
2.4 Systematic reviews
Two recent systematic reviews of treatments for CFS were published together,
because their conclusions were the same.11 Whiting and colleagues concluded
that RCTs had shown that CBT and GET were “promising treatments”, with
criticisms outlined in section 2.3. They found insufficient evidence to
recommend adaptive pacing. The York University guidance, stemming from their
review, recommended that a comparison of CBT, GET and pacing was
particularly needed.5
2.5 How will the results of this trial be used?
The results of this trial will: (a) allow health planners, clinicians and
patients to choose treatment on the basis of both efficacy and cost; (b)
provide evidence to either reassure or confirm patients’ doubts about the
efficacy and negative effects of the more active rehabilitation therapies
(CBT and GET) in contrast to adaptive pacing; (c) provide the first test of
pacing against usual medical care; (d) indicate which patient
characteristics predict response to which treatment; and (e) define the
essential aspects of effective treatment as a step toward the development of
more efficient therapies.
The trial will recruit from secondary care clinics run by three different
disciplines (immunology, infectious disease and psychiatry) in six different
centres in both England and Scotland to ensure sufficient heterogeneity to
allow generalisation of the findings. We will not recruit directly from
primary care because we wish to compare the efficacy of these treatments in
patients whom GPs regard as requiring additional help and who are likely to
have a worse prognosis (one of the recommendations CMO’s report4).
Furthermore, direct recruitment from primary care has been problematic in
previous studies. Two recent trials of treatment for prolonged fatigue using
large and well established primary care research networks recruited only 46
patients with CFS in three years in one study16 and 44 patients in 2.5 years
in the other (personal communication, Lucy Darbishire).
2.6 Risks to safety of the patients in the trial
There is a discrepancy between patient organisation reports of the safety of
CBT and GET and the published evidence of minimal risk from RCTs. A survey
of AfME members suggested that GET can sometimes cause a set-back in
symptoms or disability, rather than improvement.12 AfME suggests that such
set-backs probably results from rigidly applied GET that is not tailored to
the patient’s disabi|ity. Our treatment manual by being based on mutually
agreed and flexible programme that varies according to patient response. We
will also carefully monitor for any adverse effects of the treatments, and
will undertake a detailed assessment, at home if necessary, for any subject
who drops out of treatment for this reason, following which they will be
offered appropriate help.
3. The proposed trial
3.1 The proposed trial
This trial will compare the efficacy and adverse effects of four different
treatments for CFS. All subjects will receive usual medical care (UMC), and
in three arms this will be supplemented by a specific therapy. Hence the
four groups will be CBT and UMC, GET and UMC, APT and UMC, and UMC alone
while on a waiting list for treatment. We will also (a) study the process
and predictors of effective therapy and (b) compare the cost-effectiveness
of each treatment condition.
3.2 What is the proposed trial design?
A four arm, single blind, randomised controlled trial in consecutive
referrals of patients who meet operationalised criteria for CFS, with
follow-up for 12 months.
3.4 What are the planned trial interventions?
All patients will receive UMC. Those allocated to specific treatments will
all also receive 14 sessions of that treatment (CBT, GET or APT) with equal
therapist time (90 minutes in the first session, and 50 minutes thereafter)
for each therapy. We have chosen 14 sessions on the basis of the positive
trials of CBT and GET,15,17,20 as well as extensive clinical experience.
RCTs of the least effective CBT and GET used 6 and 8 sessions.20,21 Although
one study of a pragmatic rehabilitation found that only 4t sessions were
helpful,22 we believe that this result may have been related to the lack of
a treatment as usual control group, and that more than four sessions are
necessary to achieve change. All interventions will be based on manuals
apart from UMC, where guidance will be given to treat patients as usual (see
appendices).
CBT will be based on the illness model of fear avoidance, used in the three
positive trials of CBT.15,17,18 There are three essential elements: (a)
Assessment of illness beliefs and coping strategies, (b) Structuring of
daily rest, sleep and activity, with a graduated return to normal activity,
(c) Challenging of unhelpful beliefs about symptoms and activity (see
appendices 2 & 6).
GET will be based on the illness model of both deconditioning and exercise
avoidance, used in the previous trials.19,20,22 Therapy involves an
assessment of physical capacity, negotiation of an individually designed
home aerobic exercise programme with set target heart rates and times, and
sessional feedback with mutual planning of the next fortnight’s home
exercise programme (see appendices 3 & 6).
APT will be based on the illness model that CFS is an undetermined organic
disease, but that APT can improve quality of life without affecting the core
disease. APT involves assessment of the link between activity and subsequent
symptoms and disability, using a daily diary, with advice to plan and pace
activity in order to avoid exacerbations. Strategies include developing
awareness of early warning of exacerbations; limiting demands; regular
planned rest and relaxation, and alternating of different sorts of
activities. The aim is to achieve optimal adaptation to the illness.13 A/ME
have helped to design the APT manual and have endorsed this version of
pacing, which is based on what is published and what patients and clinicians
have reported as helpful (see appendices 4,6 & 11).
UMC (the control treatment) will include symptomatic pharmacotherapy (see
appendix 5), with no specific advice regarding activity and rest management
beyond that normally given by the clinician; there will be no specific
therapist involvement. In particular there will be no diary monitoring with
consequent advice. Subjects randomised to UMC will be placed on a waiting
list for the therapy of their choice, to start after their last follow-up
interview, in order to improve recruitment and ensure adequate care. The
nature of UMC actually given by individual clinicians will be recorded (see
appendix 5).
3.4 What are the proposed practical arrangements for allocating participants
to trial groups?
The Clinical Trial Unit (CTU) trial statistician will prepare subject
numbers for each centre by permuted block randomisation, using a
computerised randomisation system, so that equal allocation is achieved
every N subjects recruited in each centre. N will be unknown to trial
centres and will vary throughout the trial to prevent allocation
predictions. Local centre doctors (including centre leaders) will assess
consecutive clinic new patients, as usual, and pass on details of willing
potentially eligible patients to the centre research nurse (RN) for trial
screening. Reasons for non-participation at this stage, and demographic
details, will be recorded. Once an eligible subject has given informed
consent, and completed the baseline assessment by the centre RN, the RN will
contact the centre leader, who will contact the CTU web-site for an
automatically given trial identification number and treatment allocation,
with the trial co-ordinator (TC) being automatically informed at the same
time. The centre leader will immediately inform the subject of his/her
treatment group in person or by phone, and also inform the appropriate
therapist or clinician (for UMC). We will not stratify our sample by
anything beyond centres since there is no replicated evidence that any
factor influences treatment response (section 2.3; predictors of outcome)
and stratification by all possible factors would be elaborate and reduce
recruitment. Potential predictors are common enough to be well distributed
by chance alone in the 600 subjects to be studied.
3.5 What are the proposed methods for protecting against other biases?
Assessment bias at outcome will be minimised by use of self-rated primary
outcomes. The secondary measures include an exercise test and we will
therefore endeavour to keep the outcome assessor conducting these (Research
nurse: RN) blind to treatment group.
Bias by non-participation will be measured by recording measures from
potential subjects who did not meet criteria for the trial and from those
who refuse consent. Therapists will receive training and some supervision
together in order to minimise inter-centre differences.
Therapist compliance with treatments will be monitored in two ways. (1) All
therapists will receive weekly local supervision and monthly central group
supervision. All therapy sessions will be audiotaped. Some tapes will be
used by trainers/supervisors to provide feedback to therapists on competence
and treatment fidelity. Any significant deviations from the manual will be
noted. (2) One taped session per subject will be randomly chosen and
assessed blindly and independently by two assessors to assess adherence to
manual defined therapy.
Subject non-compliance with treatment will be measured both by recording
attendance and by therapist ratings of adherence to therapy using a visual
analogue scale.
Generalisability will be measured by comparing between different centres and
disciplines.
3.6 What are the planned inclusion/exclusion criteria?
Inclusion criteria: Subjects will be required to meet operationalised Oxford
criteria for CFS.2 This means 6 months or more of medically unexplained,
severe, disabling fatigue affecting physical and mental functions.2 We will
operationalise CFS in terms of fatigue severity and disability as follows: a
Chalder fatigue score23 of four or more and an SF36 physical function
score24 of less than 75 (see section 3.9). We chose these broad criteria in
order to enhance generalisability and recruitment. The more narrowly defined
CDC criteria are about to be revised and then superseded by an empirically
derived definition (PDW is a member of this CDC led group). Those subjects
who also meet the criteria for “fibromyalgia” (chronic widespread pain) will
be identified but included,25 because CFS and “fibromyalgia” commonly
coexist.26 Subjects will be of either gender. There will be no upper age
limit, but all subjects will be aged at least 18 years old, since younger
patients usually require a different family oriented approach.27 Subjects
will be discouraged from starting over the counter medicines or alternative
treatments, but if they do, they will be encouraged to report their use to
the centre research nurse, so that their use can be compared between centres
and treatment groups.
Exclusion criteria: The RN will use a standardised psychiatric interview,28
under supervision by the centre psychiatrist, to exclude those who are at
significant risk of self-harm and those with a chronic somatisation
disorder, as well as determine the psychiatric exclusions listed in the
Oxford diagnostic criteria for CFS.2 All potential subjects will be screened
for important medical exclusions, by history and physical examination.1,2,4
Appropriate investigations4 will be undertaken by either the referring
doctor or the centre consultants (checked by the RN). Other exclusions will
be: subjects who do not speak or read English adequately (because of the
self-report questionnaires); subjects unable to either attend hospital
reliably or to do therapies; those less than 18 years old (see inclusions);
those who have previously been treated within a fatigue clinic with CBT, GET
or APT.
3.7 What is the proposed duration of treatment period?
All subjects will have their first 4 sessions once weekly, and will then be
seen fortnightly for 10 further sessions, making 14 sessions in total over
23 weeks. Clinical experience suggests that this initially intense therapy
works best. The same amount of time spent with the therapist will control
for non-specific therapeutic effects.
3.8 What is the proposed frequency and duration of follow up?
Subjects will be seen at 10 weeks (between the 7th and 8th treatment
sessions), 24 and 52 weeks after treatment starts.
3.9 What are the proposed outcome measures?
Primary efficacy measures:
Since we are interested in changes in both symptoms and disability we have
chosen to make both fatigue and physical function primary outcomes. This is
because it is possible that a specific treatment may relieve symptoms
without reducing disability, or vice versa. Both these measures will be
self-rated. The 11 item Chalder fatigue questionnaire measures the severity
of symptomatic fatigue,23 and has been the most frequently used measure of
fatigue in most previous trials of these interventions. We will use the
0,0,1,1 item scores to allow a categorical threshold measure of “abnormal”
fatigue with a score of 4 having been previously shown to indicate abnormal
fatigue.23 A Likert scoring (0,1,2,3) will also be used, as a secondary
outcome measure, to better measure response to treatment. The SF-36 physical
function sub-seal24 measures physical function, and has often been used as
an important outcome measure in trials of CBT and GET. We will count a score
of 75 (out of a maximum of 100) or more as indicating normal function, this
score being one standard deviation below the mean score (90) for the UK
working age population.29
Secondary measures:
Efficacy: 1. The self-rated Clinical Global Impression (CGI) change score
(range 1-7) provides a self-rated global measure of change, and has been
used in previous trials.30 2. Daytime physical movement (an objective
measure of activity) will be measured over 48 hours with an Actiwatch
attached to the ankle. 3. The Hospital Anxiety and Depression scale will
measure change in anxiety and depression.31 4. The 36 item short-form health
survey (SF-36) measures not only physical but also social and role
functioning.24 5. The EuroQOL (EQ-5D) visual analogue scale provides a
simple global measure of quality of life.32 6. The Client Service Receipt
Inventory (CSRI), adapted for use in CFS,33 will measure hours of
employment/study, wages and benefits received, allowing another more
objective measure of function. 7. An operationalised Likert scale (from much
better to much worse) of the nine CDC symptoms of CFS.1
Adverse effects: Apart from finding out why subjects who prematurely stop
their therapy did so (see section 2.6), we will also administer the CGI, the
SF-36 physical functional scale and the operationalised nine CDC symptoms of
CFS1 at all interviews, in order to monitor for significant set-backs.
Possibly predictive variables (measured at baseline): 1. The Queen’s College
three minute step test (which measures heart rate response to exercise and
estimates VO2max).34 2. Body mass index, which has been shown to predict
poor functional response to GET.35 3. Pervasive inactivity (measured by
actigraphy) has predicted poor response to CBT.15 4. Hospital Anxiety and
Depression sub-scale scores for depression and anxiety have been shown to
predict poor outcome with treatment.36 5. Current membership of a self-help
group, shown to predict poor outcome with CBT.36 5. The CSRI will measure
disability benefits received,33 again shown to predict poor outcome with
CBT.15,36 6. We will ask subjects their preferential treatment. 7. We will
also examine whether CDC or “ME” criteria define response, because of many
patients and some clinicians belief that pacing is better than CBT and GET
in these patients.1,4
Process variables (measured during therapy and at follow-up): Changes in
fitness,34 physical activity (by actigraphy), the belief that
exercise/activity is harmful, the belief that symptoms indicate harm, the
belief that control of activity is beneficial, and an enhanced sense of
control of the illness will all be measured. We will also measure the
strength of the therapeutic alliance.37
Economic: The number of hours per week of voluntary and paid work or study
will be calculated. Service utilisation and costs of treatment will be
calculated. The CSRI will collect service utilisation data, wages and
benefits received.
3.10 How will the outcomes be measured at follow-up?
All subjects will be re-assessed in clinic. Self-rated measures will be
posted to the subject prior to the visit and checked for completion by the
RN. Although all our primary and secondary outcomes are either self-rated or
objective, we will endeavour to keep the RNs blind to treatment group in
order to minimise interview bias. Subjects who drop out of treatment will be
assessed as soon as possible, rather than waiting for the normal follow-up.
Those who cannot attend clinic will be offered home assessments (or failing
this assessment by telephone or by post). Those subjects who have dropped
out of the study will be telephoned to offer an opportunity to learn why,
and will be sent questionnaires by post for the two primary outcomes, if
willing to receive them.
3.11 Will health service research issues be measured at follow-up?
We will be measuring health and other service utilisation for all subjects,
and the associated costs (best national estimates of long-run marginal
opportunity costs). Lost productivity and caregiver costs will also be
measured.
3.12 What is the proposed sample size and what is the justification for the
assumptions underlying the power calculations?
Assumptions: At one year we assume that 60% will improve with CBT, 50% with
GET, 25% with APT and 10% with UMC. The existing evidence suggests that at
one year follow up, 50 to 63% of subjects with CFS had a positive outcome,
by intention to treat, in the three RCTs of rehabilitative CBT,15,17,18 with
69% improved after an educational rehabilitation that closely resembled
CBT.22 This compares to 18 to 63% improved in the two RCTs of GET,19,20 and
47% improvement in a clinical audit of GET.38 For usual medical care 6% to
17% improved by one year in two RCTs.15,22 There are no previous RCTs of APT
to guide us,” but we estimate that APT will be at least as effective as the
control treatments of relaxation and flexibility used in previous RCTs, with
26% to 27% improved on primary outcomes.18,19 We propose that a clinically
important difference would be between 2 and 3 times the improvement rate of
UMC.
Power analyses: Our planned intention to treat analyses will compare APT
against UMC, and both CBT and GET against APT. Assuming ? = 5 % and a power
of 90 %, we require a minimum of 135 subjects in the UMC and APT groups, 80
subjects in the GET group and 40 in the CBT group.39 However these last two
numbers are insufficient to study predictors, process, or
cost-effectiveness. We will not be able to get a precise estimate of the
difference between CBT and GET, though our estimates will be useful in
planning future trials. As an example, to detect a difference in response
rates of 50% and 60%, with 90% power, would require 520 subject per group;
numbers beyond a realistic two-arm trial. Therefore, we will study equal
numbers of 135 subjects in each of the four arms, which gives us greater
than 90% power to study differences in efficacy between APT and both CBT and
GET. We will adjust our numbers for dropouts, at the same time as designing
the trial and its management to minimise dropouts. Dropout rates were 12 and
33% in the two studies of GET and 3,10, and 40% in the three studies of
rehabilitative CBT.12,14 On the basis of our own previous trials, we
estimate a dropout rate of 10%. We therefore require approximately 150
subjects in each treatment group, or 600 subjects in all. Calculation of the
sample size required to detect economic differences between treatment groups
requires data of cost per change in outcome, which is not currently
available. Since costs are not expected to vary significantly between or
within groups, the treatment determined number of 150 per arm is likely to
find significant differences in cost-effectiveness.
3.13 What is the planned recruitment rate?
All centres will recruit at a rate of a minimum of 33 subjects per year. All
centres see a minimum of 100 new patients with undiagnosed chronic fatigue
per year. We estimate that 50 patients will meet eligibility criteria, and a
conservative estimate is that two thirds will agree to enter the trial. Only
seven and 15% of eligible subjects refused to participate in the previous
GET trials15,16 and three, 10 and 26% of those eligible refused CBT.12,14 We
are therefore confidant that recruitment, at an overall rate of 200 subjects
per year is feasible and will achieve 600 participants over three years. We
will however closely monitor recruitment, especially in the first six
months, and the trial management committee, after advice from the TSC, will
consider replacing those centres that either do not recruit sufficient
subjects, or fail to provide quality data.
3.14 Are there likely to be any problems with compliance?
Non-compliance was less than 10% in our own 3 RCTs, although higher in
others trials. Since our estimates of efficacy were based on all these
studies, which incorporated non-compliance, our numbers of subjects should
be adequate, especially as non-compliance will not differentially affect
predictors and process.
Compliance with both the treatments and the study will be maximized by the
collaboration and support of AfME, and by the inclusion of APT, which is
recommended by most patient charities, in the trial. The acceptability of
and compliance with the UMC will be maximized by being placed on a waiting
list for the therapy of their choice.
3.15 What is the likely rate of loss to follow-up?
We estimate 10% on the basis of data summarized in section 3.12. We will
contact lost subjects to gather as much outcome data as possible,
particularly the two primary outcome measures, which could be recovered by
phone, fax, or post.
3.16 How many centres will be involved? Six
3.17 Are there any planned subgroup analyses?
Not beyond the inter-centre comparisons of the two primary outcomes.
3.18 What are the proposed type of analyses
Efficacy: We will analyse all outcomes by intention to treat. We will
perform pair-wise comparisons of the proportions with a positive primary
outcome in the APT and UMC groups, and in the APT and combined GET and CBT
groups, using chi-squared tests. We will perform chi-squared tests for trend
across the UMC, APT and GET groups, and across the UMC, APT and CBT groups.
Any inter-centre or baseline significant inter-group differences will be
controlled for using logistic regression. Secondary end-points for efficacy
will compare changes from baseline to 12 months on both the 33-point Chalder
fatigue scale and 100-point SF36 physical function scores using analysis of
covariance. Other secondary outcome measures will be compared by t tests or
Kruskall Wallis tests, depending on the distribution.
Adverse effects: The drop-out rates and the prevalence of both specific and
any adverse effects will be compared by Chi square test.
Predictions and process of treatment: Associations between post-treatment
outcomes and both predictor and process variables (including demographic,
illness duration, and other putative clinical indicators) will be examined
using multiple linear and logistic regression modelling techniques,
including a limited examination of first order interactions. We anticipate
that the sample size will be sufficient to identify important general
predictors from a random-split, training set of two thirds (?400), with
partial validation in the remainder, used as a test set. Shrinkage
techniques (to allow for over-optimism in variable selection) will be
applied in the development of a prognostic model to be applied to patients
outside the trial. Economic evaluations: The incremental
cost-effectiveness/utility ratios will be derived and confidence intervals
reported. Considering the difficulties of a ratio measure and the common
finding of non-normality in the distribution of the criterion variable, we
will employ bootstrapping methods. Cost-effectiveness acceptability curves
will be fitted and net benefits calculated. Sensitivity analyses will also
be carried out.
3.19 What is the proposed frequency of analyses?
We will do one post-trial analysis, because we are interested in process,
predictors and cost-effectiveness, which will require the fall number of
subjects. The Data Monitoring and Ethics committee may wish to collate blind
adverse outcome data during the trial to ensure that no specific therapy is
causing undue adverse effects.
3.20 Has any pilot study been carried out using this design?
We ourselves completed three out of seven of the RCTs of CBT and GET. The
therapies and measures to be used are essentially the same as used in these
successful trials. Because APT is less well tested, we will pilot this
treatment in the first six months of the trial.
3.21 Will there be NHS cost implications for this trial?
Yes; the costs of the extra therapists and the service support costs.
3.21 Over what period is funding requested? Five years
4. Trial management
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.
The six centre leaders, and co-leaders where appropriate, will oversee
recruitment, inform subjects and therapist of their randomisation, and will
help screen subjects. They will also be responsible for recruitment,
training, and day-to-day supervision of the local therapists, centre RN and
database/clerical officer. The PI (PW) will chair the trial management
committee (TMC, composed of applicants, collaborators, and TC), which will
initially meet every 2 months for the first year and then as necessary.
4.2 What will be the responsibilities of the applicants?
Drs. Peter White (PW), Michael Sharpe (MS) and Trudie Chalder (TC) will be
centre leaders. PW will be the co-trainer and co-supervisor of GET (with Ms
Lucy Darbishire) and will supervise the trial coordinator. MS and TC will
oversee training and supervision of CBT (with Mr Vincent Deary). TC will
oversee training and co-supervise APT (with Dr Diane Cox). PW, MS, and TC
will oversee treatment adherence.
4.4 What will be the responsibilities of the staff employed on the grant?
The Trial co-ordinator (TrCo) will be responsible for checking the quality
of the central trial database, and will send local research nurses (RNs)
query forms as necessary. The TrCo will monitor trial recruitment against
targets and regularly communicate these data to centre leaders and the PL
Along with the applicants, he/she will train and help to supervise the local
centre RNs and database/clerical officers. The TrCo will write a regular
trial newsletter for subjects and trial staff. The TrCo will service the
meetings of the TMC, TSC and DMEC. He/she will be primarily responsible for
analysis and writing up, with appropriate support.
The local centre 0.6 WTE Research Nurses (RNs) will screen all potential and
participating subjects, consenting the eligible subjects, and execute
baseline and outcome assessments, endeavouring to remain blind to trial arm,
providing preliminary summary analyses of actigraphy data analysed locally.
They will send birthday and Christmas (or New Year) cards to all their
centre subjects for the duration of the project
The local centre 0.5 WTE database entry clerical officer will enter the hard
copy data on the CTU designed database at a local level, sending the data
regularly and electronically to the CTU. They will also be responsible for
communication by phone and letter with potential and actual trial subjects,
with an ansaphone available out of hours.
The three 0.5 WTE therapists at each centre, funded by the NHS, will receive
training in both London and their centres in the first 6 months, then treat
the subjects locally, monitor their subjects’ treatment adherence and
attendance, audiotaping every session, and attend the appropriate London
centres monthly for supervision. In order to encourage manual adherence and
treatment enthusiasm, the therapies will be provided by separate staff (CBT
by a CB therapist, GET by a physiotherapist, and APT by an occupational
therapist). Ms Lucy Darbishire (GKT), Dr Diane Cox (St Martin’s College,
Lancaster) and Mr Vincent Deary (South London and the Maudsley Trust) will
help to train and supervise GET, APT and CBT respectively, on a part-time
basis. Dr Paul McCrone (GKT) will analyse the health economic data.
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 Wessely 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.
4.6 Trial Steering committee
Chairman: Professor Tom Craig, (GKT). Independent members: Professor Anne
Farmer (Institute of Psychiatry); Dr Meirion Llewelyn (University of Wales);
Mrs. Frankie Campling (ex-sufferer and CFS counsellor). Applicants: PW, MS
and TC, and the trial co-ordinator.
5 Financial details of the trial
5.1 Financial summary
The total cost to the MRC is: £1,921.883
Research staff costs: One London based trial co-ordinator (grade AR4) for 5
years: £234,258. Two non-London (Oxford & Edinburgh) based 0.6 WTE RNs
(grade G) for 4.25 years: £164,440. Two non-London based 0.5 WTE database
entry/clerical officers (CG5) 4.25 years: £102,186. Two London (RFH & GKT)
based 0.6 WTE RNs (grade G) for 4.25 years: £183,302. Two London based 0.5
WTE database entry/clerical officers (CG5) for 4.25 years: £114,568. One
London (two Barts/London centres) based WTE RN (grade G) for 4.25 years:
£152,753. One London based WTE database entry/clerical officer (CG5) for
4.25 years: £120,729. One London based economist: 165 days over 5 years:
£21,869. Total: £1,097,266
Overheads: 46 per cent of research salaries: Total: £504,742
Equipment: 12 “Actiwatch Plus” activity sensors (Cambridge Neurotechnology),
6 “Sleepwatch” analysis packages, 6 reader/interface base stations, 11
computers, printers and software, 36 Polar heart rate monitors and
transmitter belts, 6 digital metronomes, twelve-inch steps and stop-watches
for fitness testing, 18 audio machines, 3,150 audiotapes. Total: £36,360
Staff Travel: Inter alia: Travel and/or accommodation (5 nights maximum)
expenses of therapists and research staff for training and/or supervision,
centre leaders for TMC meetings. Total: £64,880
Consumables: Inter alia: CTU randomisation and database design and
maintenance (78 days @ £385): £30,030. Therapist training/supervision
consultancy: £45,240. Travel expenses for treatment of subjects: £10 per
session for 450 subjects (14 visits): £63,000. Research travel expenses for
subjects (£20 x 4 x 600): £48,000. A/ME consultancy costs: £4,312 (14 days).
Total: £218,635
Costs to the NHS: £1.179.909
Costs of therapists: We have approached our NHS providers for these costs.
We need 7 WTE therapists in the 6 centres: 2.5 WTE of CBT, 2 WTE
physiotherapists, and 2.5 WTE OTs. Considering different costs in and out of
London, this amounts to £241,424 p.a. over 4.5 years (including 6 months
training), a total of £1,086,359. Service costs amount to £93,550.
Total: £1,179,909.
Year 2003/4 2004/5 2005/6 2006/7 2007/8
Total
----------------------------------------------------------------------------
----
Research 398,205 415,622 423,268 429,429 255,359 1,921,883
Treatment 241,424 241,424 241,424 241,424 120,663 1,086,359
Service 24,600 19,700 19,700 19,700
9,850 93,550
----------------------------------------------------------------------------
----
TOTAL 664,229 676,746 684,392 690,553 385,872
3,101,792
5.2 Justification for support requested
The trial coordinator will be an experienced post-doctorate science graduate
with research, administrative, statistical and computer experience. This
experience is necessary for the multiple tasks required.
The six 0.6 WTE local research nurses (RNs) need to be trained in the use of
the assessments and trial research methodology, and be able to use a
computer in order to summarise actigraphy data. We have chosen nurses in
order to be able to adopt a consistent and caring approach to subjects
through the trial, helping to reduce dropouts, especially in the UMC arm.
Each RN will complete 400 assessments in total, 100 a year, on top of
screening other potential subjects. The initial assessment and consenting
will take 3 hours, the later ones taking 1.5 hours. Face-to-face interviews
are necessary for the SCDD and fitness/activity measures. Some assessments
will be done at a subject’s home.
The six 0.5 WTE local data entry/clerical officers will code and enter the
trial data onto the CTU designed database at a local level, sending the data
to the CTU by email. They will be responsible for keeping hard copies of
data and consent forms, as well as being a contact point for staff and
subjects.
NHS funded therapists need to be appropriately trained and experienced in
treating patients independently as well as under supervision. When not
treating trial patients they may be treating non-participants and will be
required after the trial to provide treatments for the UMC group. Because of
the relatively small number of subjects, they will be employed half time on
the trial.
Equipment & Consumables: All research staff need computers for analysis and
communication. We have previously found that travel expenses for subjects
significantly enhances recruitment. Double expenses for research interviews
allow subjects to return the Actiwatches. Co-training with specific
therapists will enhance the quality of therapy. CTU expenses will enhance
the quality of the data.
Travel: Centre leaders will attend the TMC every 2 months and then less
often for 5 years. Therapists and their supervisors will attend London for
10 days initial training and then monthly supervision; to ensure optimal
manual based therapy.
Economics: 165 days will be required over 5 years for training RNs and
analysis.
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.
Appendices
1. Participating centres. 2. CBT manual. 3. GET manual. 4. APT manual. 5.
UMC guidance. 6. Manual explaining the essential elements of the therapies
and how they are differentiated. 7. Knowledge of other current CFS trials.
8. Names and addresses of proposed members of the TSC. 9. Names and
addresses of proposed members of the DMEC. 10. Proposed patient information
sheet. 11. Letter of support from AfME. 12. Letters of agreement to be
applicants or collaborators (lodged with MRC). 13. Letters confirming NHS
provider support for the project (lodged with MRC).
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