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BioMed Central
Page 1 of 17
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Trials
Open Access
Study protocol
Protocol for the combined immunosuppression & radiotherapy in
thyroid eye disease (CIRTED) trial: A multi-centre, double-masked,
factorial randomised controlled trial
Rathie Rajendram
1
, Richard WJ Lee*
2,3
, Mike J Potts
3
, Geoff E Rose
1
,
Rajni Jain
4
, Jane M Olver
4
, Fion Bremner
5
, Steven Hurel
6
, Anne Cook
7
,
Rao Gattamaneni
8
, Marjorie Tomlinson
9
, Nicholas Plowman
10
,
Catey Bunce
1
, Sandra P Hollinghurst
11
, Laura Kingston
12
, Sue Jackson
12
,
Andrew D Dick
2,3
, Nichola Rumsey
12
, Olivia C Morris
1
, Colin M Dayan
13
and JimmyMUddin
1
Address:
1
Moorfields Eye Hospital, City Road, London EC1V 2PD, UK,
2
Department of Clinical Science at South Bristol, University of Bristol, UK,
3
Bristol Eye Hospital, Lower Maudlin Street, Bristol, BS1 2LX, UK,
4
Western Eye Hospital, Marylebone Road, London, NW1 5YE, UK,
5
Department
of Neuroophthalmology, Internal Box 142, The National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N3BG, UK,
6
University College London Hospital, Third Floor East, 250 Euston Road, London, NW1 2PQ, UK,
7
Manchester Royal Eye Hospital, Oxford Road,
Manchester. M13 9WH, UK,
8
Christie Hospital, Wilmslow Road, Manchester, M20 4BX, UK,
9
Bristol Haematology and Oncology Centre, Horfield
Road, Bristol, BS2 8ED, UK,
10
St Bartholomew's Hospital, West Smithfield, London, EC1A 7BE, UK,
11
Academic Unit of Primary Health Care,
Department of Community Based Medicine, University of Bristol, 25 Belgrave Road, Bristol, BS8 2AA, UK,
12
Centre for Appearance Research,
University of the West of England, Fishponds, Bristol, BS16 2JP, UK and
13
Henry Wellcome Laboratories for Integrative Neuroscience and
Endocrinology, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY, UK
Email: Rathie Rajendram - rathie.rajendram@moorfields.nhs.uk; Richard WJ Lee* - richard.lee@bristol.ac.uk;
Mike J Potts - mike.potts@ubht.nhs.uk; GeoffERose-geoff.rose@moorfields.nhs.uk; Rajni Jain - rajnijain@mac.com;
Jane M Olver - janeolver@aol.com; Fion Bremner - fion.bremner@uclh.nhs.uk; Steven Hurel - s.hurel@ucl.ac.uk;
Anne Cook - cookydoc@btinternet.com; Rao Gattamaneni - raogattamaneni@christie.nhs.uk;
Marjorie Tomlinson - marjorie.tomlinson@ubht.nhs.uk; Nicholas Plowman - nick.plowman@bartsandthelondon.nhs.uk;
Catey Bunce - catey.bunce@moorfields.nhs.uk; Sandra P Hollinghurst - s.p.hollinghurst@bristol.ac.uk;
Laura Kingston - Laura2.Kingston@uwe.ac.uk; Sue Jackson - sue@winterbourne.freeserve.co.uk; Andrew D Dick - a.dick@bristol.ac.uk;
Nichola Rumsey - nichola.rumsey@uwe.ac.uk; Olivia C Morris - ocmorris@gmail.com; Colin M Dayan - colin.dayan@bristol.ac.uk;
Jimmy M Uddin - jimmy.uddin@moorfields.nhs.uk
* Corresponding author
Abstract
Background: Medical management of thyroid eye disease remains controversial due to a paucity
of high quality evidence on long-term treatment outcomes. Glucocorticoids are known to be
effective initially but have significant side-effects with long-term use and recrudescence can occur
on cessation. Current evidence is conflicting on the efficacy of radiotherapy and non-steroid
systemic immunosuppression, and the majority of previous studies have been retrospective,
uncontrolled, small or poorly designed.
The Combined Immunosuppression and Radiotherapy in Thyroid Eye Disease (CIRTED) trial was
designed to investigate the efficacy of radiotherapy and azathioprine in combination with a standard
course of oral prednisolone in patients with active thyroid eye disease.
Published: 31 January 2008
Trials 2008, 9:6 doi:10.1186/1745-6215-9-6
Received: 30 October 2007
Accepted: 31 January 2008
This article is available from: http://www.trialsjournal.com/content/9/1/6
© 2008 Rajendram et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0
),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Trials 2008, 9:6 http://www.trialsjournal.com/content/9/1/6
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Methods/design: Patients with active thyroid eye disease will be randomised to receive (i)
azathioprine or oral placebo and (ii) radiotherapy or sham-radiotherapy in this multi-centre,
factorial randomised control trial. The primary outcome is improvement in disease severity
(assessed using a composite binary measure) at 12 months and secondary end-points include quality
of life scores and health economic measures.
Discussion: The CIRTED trial is the first study to evaluate the role of radiotherapy and
azathioprine as part of a long-term, combination immunosuppressive treatment regime for Thyroid
Eye Disease. It will provide evidence for the role of radiotherapy and prolonged
immunosuppression in the management of this condition, as well as pilot data on their use in
combination. We have paid particular attention in the trial design to establishing (a) robust placebo
controls and masking protocols which are effective and safe for both radiotherapy and the systemic
administration of an antiproliferative drug; (b) constructing effective inclusion and exclusion criteria
to select for active disease; and (c) selecting pragmatic outcome measures.
Trial registration: Current controlled trials ISRCTN22471573
Background
Thyroid eye disease (TED) can be a visually disabling and
cosmetically disfiguring condition which significantly
impairs health-related quality of life [1-3]. A wide variety
of immunosuppressive therapies have been used to target
the early active inflammatory phase of the disease, includ-
ing glucocorticoids (GC's), radiotherapy, antiproliferative
agents, T-cell inhibitors and, more recently, biologics. The
goal of these interventions is to suppress the autoimmune
inflammatory phase of the disease, thereby altering the
course of the disease and reducing the severity of residual
changes in the extraocular muscles, orbital fat and other
periocular soft tissues which result in permanent visual
and cosmetic dysfunction [1,4,5].
GC's have been used to treat TED for over forty years, and
several studies have demonstrated their efficacy with an
overall response rate of 63–77% [1]. However, GC treat-
ment is typically discontinued after 3 to 5 months [6-9]
because of the side-effects associated with their long-term
use, and subsequent disease recrudescence is a common
problem [10]. This recurrence may be prevented by the
concomitant use of ciclosporin [11] (which continues
after GC treatment stops), and combinations of
ciclosporin and prednisolone also achieve a better initial
treatment response than either agent alone [6]. However,
the routine use of such second-line immunosuppressive
drugs in the management of TED has been limited by fears
about their potential toxicity, and glucocorticoid mono-
therapy remains the mainstay of conventional treatment.
Radiotherapy is also well established in the treatment of
TED [12,13], and its efficacy was affirmed in 1993 by the
results of a prospective double-blind randomised control
trial (RCT) which reported that orbital radiotherapy was
as effective as oral prednisolone[7]. However, the same
authors subsequently found that radiotherapy was no bet-
ter than placebo (except in a subgroup of patients with
motility impairment) [14], and a recent trial from the
Mayo Clinic in the USA also could not demonstrate a ben-
eficial therapeutic effect [15]. As a result, many clinicians,
particularly in North America, have abandoned its use.
The Mayo study has been widely criticised [16]and Euro-
pean groups argue that the balance of evidence remains in
favour of radiotherapy [17]. In support of this, the most
recent randomised control trial (in patients with relatively
mild disease) found that radiotherapy was better than pla-
cebo when outcome was assessed by clinical measures
[18]. However, this was not associated with quality-of-life
or health economic gain, and the role of radiotherapy as
monotherapy for TED remains the subject of heated
debate [19-28].
Older RCTs have shown that radiotherapy is more effec-
tive in combination with steroids than when either agent
is used alone [29,30]. However, this distinction between
monotherapy and combination therapy is rarely high-
lighted, and the confusion which has resulted from the
inconsistent recent evidence has caused many ophthal-
mologists to discontinue using radiotherapy as part of a
combined treatment regime. Consequently there is a
pressing need for a definitive study to investigate radio-
therapy's role in combination with steroids.
The data supporting the use of ciclosporin combined with
steroids [6,11], and radiotherapy combined with steroids
[30,31] are not surprising given current knowledge about
the benefits of combination therapies in other autoim-
mune ocular and systemic conditions [32,33]. Manipula-
tion of an autoimmune response is more effective when
more than one mechanism of immunosuppression is
used, and this can be especially so early in the disease
[32]. Combined drug treatments can also be continued
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long-term, preventing the disease reactivation which is
commonly seen at the end of typical short-term low dose
steroid monotherapy regimes, and enabling the duration
of an individual's treatment to be tailored to the length of
the active phase of their disease.
Azathioprine is a low-cost second-line immunosuppres-
sive agent which is widely used in the management of
other autoimmune conditions. It is better tolerated than
ciclosporin [34] and does not cause the renal toxicity and
cardiovascular side-effects [35] (including hypertension
and hypercholesterolaemia) associated with ciclosporin.
However, it can cause bone marrow suppression [36] and
hepatotoxicity [37]. This risk has been greatly reduced
with the advent of a laboratory assay for the enzyme thi-
opurine methyltransferase (TPMT), which regulates a key
step in azathioprine metabolism. Now individuals with
low TPMT activity, who would otherwise be at particular
risk of azathioprine toxicity, can be identified and their
treatment modified or withheld [38]. Hence, azathioprine
has safety, tolerability and cost advantages over
ciclosporin.
Retrospective data suggests that azathioprine, when used
in combination with oral prednisolone and radiotherapy,
can significantly reduce the long-term severity of TED and
the need for rehabilitative surgery [39,40]. However, the
use of azathioprine for TED remains highly controversial;
in part because it has previously been proven ineffective as
monotherapy [41]. As with radiotherapy, there is no clear
evidence base and clinical practice consequently varies
widely.
The current trial is designed to investigate whether (i)
radiotherapy and (ii) azathioprine are effective when used
in combination with steroids for the treatment of active TED.
It will also provide pilot data on the possible benefits of
triple therapy (steroids, azathioprine and radiotherapy).
Particular attention in the trial design has been given to
(a) establishing robust placebo controls and masking pro-
tocols which are effective and safe for both radiotherapy
and the systemic administration of an antiproliferative
drug; (b) constructing effective inclusion and exclusion
criteria to select for active disease; and (c) selecting prag-
matic outcome measures. Health economic and carefully
designed quality of life/disfigurement analyses also
accompany the trial.
Methods/design
Trial design
Factorial design, double-masked, randomised controlled
trial. Study recruits receive either azathioprine or placebo
plus either radiotherapy or sham-radiotherapy, in combina-
tion with a standard oral prednisolone regime (Figure 1).
Trial DesignFigure 1
Trial Design.
ACTIVE TED
RADIOTHERAPY
+ AZATHIOPRINE
RADIOTHERAPY
+ ORAL PLACEBO
SHAM - RADIOTHERAPY
+ ORAL PLACEBO
ALL PATIENTS RECEIVE A STANDARD
STEROID REGIME
R
A
N
D
O
M
I
Z
E
SHAM - RADIOTHERAPY
+ AZATHIOPRINE
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Objectives
Primary
To test the hypotheses that in patients being treated with
prednisolone for active TED:
1. Radiotherapy (compared with placebo) induces early
remission and reduces long-term disease severity.
2. Azathioprine (compared with placebo) reduces long-
term disease severity.
Secondary
1. To test the hypotheses that in patients being treated
with prednisolone for active TED, radiotherapy and aza-
thioprine improve health-related quality of life, and are
cost-effective.
2. To validate the use of the GO-QoL (a new TED specific
quality of life score) in the UK population.
3. To improve understanding of the extent and type of
psychosocial distress experienced by TED patients.
4. To conduct an economic evaluation of the cost of TED
and its treatment to patients, the National Health Service
(NHS) and Society.
5. To report the safety and tolerability of radiotherapy and
azathioprine in the study cohort.
Eligibility
Inclusion criteria
• Clinical Activity Score (Table 1) ≥ 4 (worst eye) OR ≥ 2
(worst eye) with a history of proptosis or motility restric-
tion of less than 6 months duration.
• Past or present history of abnormal Thyroid Gland Func-
tion OR a clinical diagnosis of TED made and confirmed
by ≥ 2 muscle involvement on Computed Tomography
(CT) or Magnetic Resonance Imaging (MRI) scan.
Definitions
• Proptosis: Either subjective unilateral proptosis con-
firmed by asymmetry in exophthalmometry of ≥ 2 mm or
subjective bilateral proptosis.
• Motility restriction: Intermittent, inconstant or constant
diplopia [42].
Exclusion criteria
• Age < 20 or > 75 yrs
• Dysthyroid optic neuropathy
• No proptosis or motility restriction (see above for defi-
nitions)
• Use of radioiodine within the last 3 months
• Previous orbital irradiation
• Pre-existing glaucoma with a characteristic optic disc
appearance and associated visual field defect
• Pre-existing Diabetes Mellitus (not simply steroid
induced disease from recent therapy)
• Previous adverse event associated with, or contraindica-
tion to, either prednisolone or azathioprine
• Within 6/12 of pregnancy, women planning pregnancy
• Lactation
• Haemoglobin Concentration > 1 g/dl below the local
laboratory's reference range
• Platelet Count < 130 × 10
9
/L
• White Cell Count below the local laboratory's reference
range
Table 1: Clinical Activity Score
PAIN Pain on eye movement in the last 4 weeks
Pain or oppressive feeling on or behind globe in the last 4 weeks
REDNESS Conjunctival redness
Eyelid redness
SWELLING Chemosis
Swollen caruncle
Eyelid oedema
* Increasing proptosis of ≥ 2 mm during a period of 1–3 months
IMPAIRED FUNCTION * Decrease in eye movement in any direction of ≥ 8° during a period of 1–3 months
* Decrease in visual acuity of ≥ 1 line on the Snellen chart (using a pinhole) during a period of 1–3 months
1 point for each feature present.
*Criteria only counted at follow-up visits.
Maximum Clinical Activity Score is 7 at enrolment visit and 10 at follow-up visits.
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• Lymphocyte Count < 0.8 × 10
9
/L
• Abnormal Thiopurine Methyltransferase (TPMT) activ-
ity
• Abnormal renal function (estimated Glomerular Filtra-
tion Rate (eGFR) < 60 ml/min/1.73 m
2
)
• Abnormal liver function, specifically: bilirubin, alanine
aminotransferase or alkaline phosphatase concentrations
> 1.5× above the local laboratory's reference range
• Malignant or pre-malignant (dysplastic) condition
within the past 5 years
• Previous tuberculosis
• Shingles within the past 3/12
• HIV/AIDS
• Concurrent use of other immunosuppressive agents or
allopurinol
• Live vaccines within the past 3 months
All. patients referred to the Trial Centres with TED are
screened, and those meeting the eligibility criteria are
invited to enrol. The study is conducted according to ICH-
GCP (International Conference on Harmonisation for
Good Clinical Practice in clinical research), as set out in
the European Union Clinical Trials Directive (2001) and
associated UK Regulations (2004), which adhere to the
principles of the Helsinki Declaration. At the first trial visit
informed written consent is obtained and baseline charac-
teristics measured, including completion of a quality of
life questionnaire. Recruits then receive a standard course
of high dose tapering prednisolone (Table 2 &3). If they
either have a < 6 month history of TED (defined as time
since first symptom) or report improvement in any item of
the Clinical Activity Score (CAS) 2 weeks after starting the
trial prednisolone regime, they are considered to have
'active' disease and are randomised at the second trial visit
(Table 4).
Interventions
Radiotherapy
A dose of 20 Gy is administered to the retrobulbar orbit in
12 fractions over 2 to 3 weeks. The protocols used for
treatment planning, verification, field arrangement and
patient immobilisation vary according to the usual prac-
tice of each Trial Radiotherapy Centre.
In Bristol (Bristol Oncology Centre), patients are marked
up on the treatment machine (a 6-MV linear accelerator)
and immobilised with tape across their forehead. Isodose
plans are not produced as a routine, but verification is car-
ried out with Electronic Portal Imaging Devices (EPIDs)
on days 1 and 2. Lasers are used to orientate the patient
and radiation is delivered to 4 cm × 4 cm lateral opposed
fields, using asymmetric jaws to eliminate divergence
towards the contra-lateral lens.
In London (St Bartholomew's Hospital) and Manchester
(Christie Hospital), all patients have an orbital CT scan
prior to treatment as well as a dosimetric plan. Patients are
immobilised with a full head shell, which is individually
made for each trial subject, and radiation is delivered to 5
cm × 5 cm lateral opposed fields using a 6-MV linear accel-
erator. Thermoluminescence dosimetry (TLD) is then
used for both eyes during the first treatment to check the
lens dose.
Azathioprine
Treatment dose varies between 100 mg and 200 mg daily
(dispensed as 50 mg tablets), depending on body weight
(Table 5).
Masking
Trial participants, the clinical investigators responsible for
patient assessments, and data analysts are masked to treat-
ment allocation. Masking success is evaluated at the end
of the study with a questionnaire asking participants and
Table 2: Prednisolone Treatment
Time after enrolment Prednisolone dose (mg/day)
1–3 days 80
4–7 days 60
1–2 weeks 40
3–6 weeks 30
7–10 weeks 20
11–14 weeks 15
15–18 weeks 10
19–20 weeks 7.5
21–22 weeks 5
23–24 week 2.5
Table 3: Other Standardised Trial Treatments
Bisphosphonates Risedronate sodium or alendronic acid
Proton pump inhibitors Lansoprazole or omeprazole
Lubricants Saline minims when required (no non-steroidal anti-inflammatory drops)
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investigators to state whether they think they know which
treatments they received, and if so why.
Placebo treatments
Sham – radiotherapy
In Bristol, treatment is planned as for active therapy,
which does not involve radiation. However, in London
and Manchester, patients having active treatment are
exposed to radiation during both their CT scan and dosi-
metric planning. To avoid this in the sham-treatment
group, sham-CT scans and a generic dosimetric plan with
zero downloaded monitor units (ie no radiation expo-
sure) are used.
Radiotherapy machines make a loud buzzing noise when
switched on and this is the only indicator patients have
that they are receiving treatment. In order to mimic this
for patients allocated to receive sham-radiotherapy,
bespoke noise-emitting devices (NEDs) which make a
similar sound to that which accompanies normal treat-
ment have been constructed, and are positioned above the
gantry of the machines in Bristol, London and Manches-
ter. The NEDs are activated from the radiotherapy suite's
control room for the same duration of time that treatment
would usually be administered. Hence, patients allocated
to the sham-radiotherapy arm of the study have the same
planning and treatment experience, but receive no radia-
tion at all.
Placebo azathioprine tablets
These are made for the trial by St Thomas' Hospital Phar-
macy Manufacturing Unit in accordance with Good Man-
ufacturing Practice and exactly match the appearance of
the active azathioprine tablets, which are removed from
their blister-packs and re-packaged in the same bottles as
the placebos. Both active and placebo drugs are then
labelled as trial-specific Investigational Medicinal Prod-
ucts (IMPs) and distributed to the trial centres.
Placebo azathioprine tablets are also dispensed according
to body weight, so patients in the placebo group take the
same number of tablets per day as they would if receiving
active treatment. (Table 5).
Additional measures to maintain masking
Sham-radiotherapy
The trial radiographers are by necessity aware of each
patient's treatment allocation. Their contact with trial
recruits is therefore the time at which patients are at great-
est risk of being un-masked. In order to minimise this risk,
the number of radiographers involved in the administra-
tion of radiotherapy to trial subjects has been limited as
much as possible. These individuals have all received spe-
cific training about the study and are very aware of the
importance of maintaining masking, which they achieve
by acting out their well-practiced treatment set-up and
delivery protocols in a standard fashion to all patients
regardless of whether they receive sham or active therapy.
The clinical oncologists who consult with patients before
and during treatment are not informed of treatment allo-
cation, and the contents of patients' hospital records are
specially adapted to keep this information concealed until
they complete the study.
The radiotherapy departments involved in the trial have
also examined their local facilities to ensure that other
Table 4: Trial timeline
Week -2 0 1–3 4 5–7 13 20 24 28 36 44 48
Orthoptic assessment ✓✓ ✓ ✓ ✓ ✓ ✓
Clinical assessment ✓✓ ✓ ✓ ✓ ✓ ✓
Blood tests ✓✓✓✓ ✓✓✓✓✓✓✓
Quality of life questionnaires ✓✓ ✓
Prednisolone start stop
Azathioprine/Placebo start
Radiotherapy/Sham-radiotherapy ✓
Week -2 = enrolment; Week 0 = randomisation
Table 5: Azathioprine & Placebo doses
BODY MASS (KG) AZATHIOPRINE STARTING
DOSE (PER DAY)
NUMBER OF AZATHIOPRINE 50
MG TABLETS (PER DAY)
NUMBER OF CORRESPONDING
PLACEBO TABLETS (PER DAY)
< 50 100 mg 2 2
50 – 79 150 mg 3 3
≥ 80 200 mg 4 4
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potential indicators of treatment allocation, such as the
activation of warning lights outside radiotherapy suites
when radiotherapy machines are being used, are identi-
fied and addressed (for example, taking care to sit patients
and relatives out of sight of the warning lights).
Placebo azathioprine tablets
All trial recruits, whether allocated to the azathioprine or
placebo arms of the trial, will have regular blood tests to
monitor for the potential adverse effects of azathioprine.
These results are monitored by an un-masked trial co-
ordinator, who arranges for trial subjects to be recalled if
abnormalities are revealed and adjusts their treatment in
accordance with a standard algorithm (Figure 2).
In order to maintain masking about 5% of the placebo
treated group are also being randomly recalled for identi-
cal drug 'dose' adjustment, and repeat blood tests. The un-
masked trial co-ordinator is never in direct contact with
trial recruits, and the instructions issued to the clinical
investigators to recall patients and adjust their treatment
is standard, regardless of whether they are receiving active
or placebo tablets. Hence, safety is ensured for patients on
azathioprine, and treatment allocation is not revealed to
the trial subjects or investigators.
If the un-masked trial co-ordinator has a query about a
blood test result which is not adequately addressed by the
standard treatment algorithm (Figure 2), they can reveal a
patient's treatment allocation and ask for advice from one
of the clinical investigators at another Trial Centre. This
clause provides a safety net should an unforeseen clinical
scenario arise, and should not introduce bias as the
patient and the clinical investigator responsible for their
assessment remains masked.
Allocation of trial interventions
Patients who are eligible to continue in the study at the
second trial visit (after confirmation of active disease by
response to steroids or short disease duration – see above)
Azathioprine Dose Adjustment/Blood Test AlgorithmFigure 2
Azathioprine Dose Adjustment/Blood Test Algorithm.
Full Blood Count every week for 4 weeks and then every 8 weeks
Liver Function Tests (LFT) at week 4 and then every 8 weeks
Alanine Transferase
(ALT)
If >275IU/L at any point stop
azathioprine & exit trial
If ALT ≥ 120 IU/L (ie
≥3x the upper limit of
normal) repeat LFT in
2 weeks
DECREASED OR
SAME
Continue treatment at
same dose.
Repeat LFT in 8 weeks
If repeat ALT < 120 IU/L
Continue same dose
If repeat ALT ≥
120 IU/L
go back to #
If 2
nd
time discuss with
unmasked investigator
INCREASED
Reduce azathioprine
daily dosage by 50mg
Repeat LFT in 2 weeks
DECREASED
OR SAME
Continue
treatment at
reduced dose
Repeat LFT in
8 weeks
INCREASED
Speak to
investigator
as patient
must EXIT
TRIAL
Bilirubin
If bilirubin > 40µmol/L
Speak to investigator as
patient must EXIT
TRIAL
Alkaline phosphtatase
(ALP)
If >630IU/L at any point stop
azathioprine & exit trial
If ALP ≥ 360 IU/L
(ie ≥3x the upper
limit of normal)
repeat LFT in 2
weeks
DECREASED OR
SAME
Continue treatment
at same dose
Repeat LFT in 6 – 8
weeks
If repeat ALP < 360
IU/L continue same
dose
If repeat ALP ≥
360
IU/L go back to †
If 2
nd
time discuss
with unmasked
investigator
INCREASED
Reduce daily
dosage of
azathioprine by
50mg
Repeat LFT in 2
weeks
DECREASED
OR SAME
Continue
treatment at
reduced dose
Repeat LFT
in 8 weeks
INCREASED
Speak to
investigator
as patient
must EXIT
TRIAL
Full Blood Count
Contact investigator if:
• Lymphocytes <0.5 X 10
9
/L
†
#
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are allocated to treatment groups by minimisation. This is
a dynamic process which reduces the imbalance between
trial arms with respect to a range of predefined prognostic
variables, and a randomisation schedule is therefore not
drawn up in advance. Instead, a form categorising each
study recruit according to the minimisation criteria set out
in Table 6 is returned to the randomisation service at
Moorfields Eye Hospital on enrolment, giving them time
to determine the patient's treatment allocation should
they be eligible to proceed in the study. The trial pharma-
cists at each Trial Centre then phone the randomisation
service on receipt of a trial IMP prescription at the
patient's second visit, and are notified whether they are to
dispense azathioprine or placebo. This is confirmed by
email, which also states the patient's radiotherapy group
– a copy of which is sent to the Trial Radiotherapy Centre
radiographers and the un-masked trial co-ordinator.
Further measures to reduce bias
Standard Patient Assessments
An 'atlas' of standard photographs is being used for refer-
ence in clinical assessments to reduce inter-observer dif-
ferences in the measurement of disease activity and
severity [43].
Management of other factors which have the potential to
influence TED
Endocrine Management
The protocol for endocrine treatment is outlined in Figure
3. This will be administered in liaison with the patient's
endocrinologist, or if the patient is not under the care of
an endocrinologist when enrolled, by the trial investiga-
tors. The trial endocrinologist (CMD) will mediate if a
patient's endocrinologist does not adhere to the trial pro-
tocol, and all protocol deviations will be reported at the
end of the study.
Smoking
All trial subjects are advised to stop smoking and changes
in smoking habits are recorded.
Follow-up
The timing and content of trial assessments are illustrated
in Table 4.
In addition to completing quality of life questionnaires, a
subset of patients will also be selected to participate in a
semi-structured interview to explore their individual con-
cerns, strengths and difficulties in social functioning, cop-
ing strategies, levels of perceived support and the personal
financial consequences of their disease. Interviews will be
tape recorded and subsequently transcribed, after which
the tapes will be erased (transcriptions will also be
destroyed at the end of the study).
At the second study visit all patients are issued with a trial
diary (see Additional file 1). This records a wide variety of
information relevant to their treatment costs, including
use of primary and secondary healthcare, prescriptions,
travel costs, over-the-counter medications, cosmetics and
loss of earnings.
Outcome measures
Primary
1. Binary composite outcome score:
Treatment success and failure will be defined at study
completion (1 year) using a system of major and minor
criteria modified from others [8,14,18] (Figure 4).
2. Ophthalmopathy index [44]:
Treatment response at study completion (1 year) will also
be quantified using the Ophthalmopathy Index (OI) as a
continuous measure of disease severity.
Co-primary
1. Clinical activity score [45,46]:
Table 6: Minimisation Criteria
Minimisation criteria Categories
Smoker at time of TED diagnosis Yes/No
Previous Steroid use* Yes/No
Gender Male/Female
Disease severity TES < 22/TES ≥ 22
Study Centre MEH/BEH/WEH/UCLH/MREH
Disease duration < 6 months/≥ 6 months
Age < 60 years old/≥ 60 years old
Disease activity CAS 2–3/4–5/6–7
Thyroid status on enrolment Hypothyroid/Euthyroid/Hyperthyroid
* Defined as ≥ 20 mg of prednisolone for ≥ 1 month in the previous 6 months
TES: Total Eye Score; MEH: Moorfields Eye Hospital; BEH: Bristol Eye Hospital; WEH: Western Eye Hospital; UCLH: University College London
Hospital; MREH: Manchester Royal Eye Hospital; CAS: Clinical Activity Score.
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Short-term response to treatment (3 months) will be eval-
uated using the Clinical Activity Score (CAS, Table 1) as a
continuous measure of disease activity.
Secondary
1. Clinical measures:
Total eye score (TES) [6].
2. Psychosocial measures [see Additional file 2]:
- Hospital Anxiety and Depression Scale (HADS) score
[47]
- Derriford Appearance Scale-Short Form score [48,49]
- Graves' Ophthalmopathy Quality of Life (GO-QoL)
score [50,51]
- WHOQoL-Brief Quality of Life Assessment Score [52]
- Open-ended responses to interview questions
3. Health economic measures [see Additional file 1]:
The cost of TED and its treatment will be measured from
the perspective of the NHS, the patient and society.
Adverse events
Adverse events will be documented and serious adverse
events will be reported to the trial sponsor and to the
Medicines and Healthcare Products Regulatory Agency
(MHRA). Specific enquiries regarding known side-effects
of the active interventions in the trial (as documented
below) will be made at each visit and documented. Clini-
cal examination will include monitoring for adverse
events.
Prednisolone – gastric irritation/ulceration, weight gain,
sleep disturbance, mood
disturbance, increased susceptibility to infection, increase
in blood pressure, steroid induced diabetes.
Azathioprine – malaise, nausea, vomiting, diarrhoea, rash,
myalgia, hair loss, increased susceptibility to infection.
Regular blood tests will be carried out on all patients to
monitor for bone marrow suppression and liver impair-
ment.
Endocrine Treatment ProtocolFigure 3
Endocrine Treatment Protocol.
TSH, FreeT4 and Free T3 in reference range
No, Free T4 low
Or TSH > 4mu/l
Begin or increase dose of
thyroxine by 50ug/day
Recheck TSH, FreeT4,
Free T3 in 6 weeks
No, but TSH not raised
And Free T4/Free T3 in
reference range
Yes
No, TSH suppressed
AND Free T3 or Free T4
raised
•If on no treatment begin carbimazole
40mg/day
•If on thyroxine reduce by 25–50 ug/day
•If on carbimazole & thyroxine reduce
thyroxine by 25ug/day
•If on carbimazole alone ensure dose
is/increase dose to 40mg/day
Recheck TSH, FreeT4,
FreeT3 in 6 weeks
Recheck TSH, FreeT4,
Free T3 in 3 months
•If on thyroxine or not on treatment – no
change to endocrine treatment
•If on carbimazole alone ensure dose is
40mg/day and add thyroxine 100ug/day
TSH – thyroid stimulating hormone
T4 - thyroxine
T3 - tri-iodothyronine
Trials 2008, 9:6 http://www.trialsjournal.com/content/9/1/6
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Radiotherapy – localized redness of skin, cataracts, radia-
tion retinopathy.
As this is a double-masked trial all adverse events will be
documented and reviewed by the data monitoring com-
mittee who may be unmasked to treatment allocation.
Trial size
Number of patients
A two group continuity corrected chi-squared test with a
0.050 two-sided significance level will have 80% power to
detect the difference between a success rate in the placebo
arm of 60% and success rate in the treated arm of 87%
(odds ratio of 4.462) when the sample size in each group
is 48. It is therefore necessary for there to be 96 subjects
with complete final data sets to be equally distributed to
the 4 treatment groups.
The power for continuous outcome measures is more
favourable and a total sample size of 100 patients will
yield 92% power to detect a difference of 2.7 in the OI
with two-sided 5% alpha, assuming a standard deviation
of 3.3.
CAS is not considered as important as the primary out-
comes in terms of influencing future clinical practice.
However it is of greater interest and importance than the
secondary outcome variables, and as such it has been
selected as a coprimary endpoint and the power of the
trial to detect a clinically important difference is presented
here. Assuming a standard deviation of between 1.2 and
2.0, a total sample of 100 patients will yield between 71%
and 99% power to detect a difference of 1 point with 5%
two-sided alpha.
The above power calculations are based on comparisons
'at the margins' of the factorial design (ie, comparing all
azathioprine treated patients with placebo treated
patients, and all radiotherapy treated patients with sham-
radiotherapy treated patients). There will be low power
for comparisons between individual cells of the factorial
design (eg azathioprine and sham-radiotherapy vs. pla-
cebo and radiotherapy), although these analyses will still
be conducted to generate pilot data on the comparative
efficacy of the 4 combination regimes under investigation.
Binary Composite Primary Outcome MeasureFigure 4
Binary Composite Primary Outcome Measure.
Major Criteria
An improvement of ≥ 1 grade in Gorman diplopia score
An improvement of >
8
o
of eye movement in any direction
A reduction of ≥ 2 mm in proptosis
Minor Criteria
A reduction of ≥ 2 mm in lid aperture
An improvement of ≥ 1 grade in soft tissue involvement
.
An improvement in best-corrected visual acuity of ≥ 1 line on the Snellen chart.
Subjective improvement
Response to Treatment
Very good: ≥ 2 major criteria
Good: 1 major criterion
Fair: ≥ 2 minor criteria
No Change: 1 minor criterion
Worse: Deterioration in at least 1 major or 2 minor criteria.
Response Rate
Number of patients with a fair, good or very good response to treatment versus the number of patients who have no
change or are worse (expressed as a percentage).
Binary Composite Primary Outcome Measure
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Compliance and loss to follow-up
We predict that 33% of eligible patients will choose not to
take part in the study [14], 11% will be excluded because
of TPMT inactivity [53], 10% of the azathioprine treated
group will be intolerant of therapy or suffer an adverse
event necessitating withdrawal from the trial [54], and 5%
will drop-out for other reasons.
Statistical analyses
Data analysis will proceed according to CONSORT guide-
lines for randomised controlled trials. The first stage of the
analysis will be to use descriptive statistics to describe the
group of individuals recruited to the trial in relation to
those eligible, and to investigate comparability of the trial
arms at baseline. The primary intention-to-treat analyses
will comprise comparisons between radiotherapy versus
sham-radiotherapy, and azathioprine versus placebo, for
each of the two primary outcomes at 12 months follow
up. The comparisons will be made using appropriate (that
is, logistic or linear) multivariable regression models,
adjusting for minimisation variables, the factorial design,
and the value of the outcome variable at baseline. Full
attention will be paid to the estimates and the confidence
intervals for these comparisons as well as the p-values.
Secondary analyses will then be conducted using regres-
sion models with further adjustment for any prognostic
factors that exhibit marked imbalance at baseline. Patients
who have no outcome data for the primary analyses will
have data imputed using last observation carried forward.
Patients who have become non-compliant for any reason
will still be invited to produce outcome data such that
they can be included in the intention to treat analyses. The
assumptions required for the regression models will be
investigated using appropriate diagnostic plots, and
actions such as transformation of continuous outcome
variables taken as necessary.
The co-primary outcome CAS at 3 months follow up, and
all secondary outcomes, will be analysed in the same way,
using appropriate (linear or logistic) regression models
depending on the nature of the outcome measure. Bonfer-
roni corrections for multiple testing will be considered for
the secondary outcomes.
Other secondary analyses will involve: (a) investigation of
any interaction between the two interventions for each of
the two primary outcomes; (b) pre-planned sub-group
analyses to ascertain any differential effects of the inter-
ventions according to steroid use versus no steroid use in
the six months prior to enrolment. These secondary anal-
yses are readily performed as extensions to the multivari-
able regression models described above, by simply
introducing the appropriate interaction terms. However,
the precision of the estimates of interaction is very likely
to be too poor, and high p-values will most likely reflect
low power and so cannot be taken as evidence for no
interactions.
Economic evaluation
Costs will be related to the percentage of patients respond-
ing to treatment. Incremental cost effectiveness ratios will
be formed, which will estimate the extra cost per extra
patient responding to (i) radiotherapy; and (ii) azathio-
prine 12 months after randomisation. A secondary analy-
sis will estimate the cost-of-illness of TED from a societal
perspective.
Trial organisation
Trial Centres and Investigators are listed in Table 7. Addi-
tional trial centres may be added if recruitment is slower
than anticipated.
Table 7: Trial Centres & Principal Investigators
Trial sponsor University of Bristol
Trial Centres and Principal Investigators
Bristol Eye Hospital and University of Bristol Richard Lee and Colin Dayan
Moorfields Eye Hospital Jimmy Uddin
University College Hospital Fion Bremner, Steve Hurel
Western Eye Hospital Jane Olver, Rajni Jain
Manchester Royal Eye Hospital Anne Cook
Radiotherapy Centres
Bristol Oncology Centre Marjorie Tomlinson
St Bartholomew's Hospital Nicholas Plowman
The Christie Hospital Rao Gattamaneni
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Trial Steering Committee
The Trial Steering Committee will monitor and supervise
the trial and comment on any proposed major protocol
amendments (Table 8).
Data Monitoring Committee
The data monitoring committee (DMC) includes an inde-
pendent ophthalmologist with experience of thyroid eye
disease and an independent statistician (Table 8).
No formal interim analysis is planned. The trial statisti-
cian will report to an independent DMC which will mon-
itor the trial in all its respects. It will review data from the
trial every 12 months, consider the findings from other
relevant studies and if considered appropriate may con-
duct a masked interim analysis. The trial will only be ter-
minated as a result of this analysis if the p value is smaller
than 0.0001 and the DMC decides that this is the best
course of action to take.
Study co-ordination
This study will be centrally co-ordinated by Moorfields
Eye Hospital Clinical Trials Unit (CTU). As well as provid-
ing the telephone randomisation service the CTU will be
responsible for data management.
Trial documentation and data collection
The trial centres are provided with a Protocol, Standard
Operating Procedures [see Additional file 3] (including
standardised colour plates for patient assessments [43]),
Source Documentation and Case Report Forms [see Addi-
tional file 4]. Adverse event forms are completed at each
participant's visit. Serious adverse events will be reported
to the University of Bristol (the Trial Sponsor) and to the
Medicines and Healthcare products Regulatory Agency
(MHRA).
Ethics and competent authority review
Applications to UK Main and Local Research Ethics Com-
mittee (REC) have received favourable opinions and a
Clinical Trials Authorisation has been issued by the
MHRA.
Publication policy
The results of this trial will be submitted for publication
in peer-reviewed medical journals regardless of whether
the outcome is in favour of the trial interventions. Author-
ship agreements have been signed by the investigators
prior to the start of the study.
Proposed trial time-table
Trial start
January 2006
Projected trial end
December 2011
Trial duration
6 Years
Duration of each patient's participation
12 months
Discussion
This randomised controlled trial of azathioprine and radi-
otherapy (with prednisolone) will be the first to evaluate
the role of these interventions as part of a long-term com-
bined immunosuppressive treatment regime for TED. We
Table 8: Trial management
Core trial management committee
Richard Lee Chief Investigator (Ophthalmology), University of Bristol and Bristol Eye Hospital, UK
Colin Dayan Chief Investigator (Endocrinology), University of Bristol and Bristol Royal Infirmary, UK
Jimmy Uddin Principal investigator (Ophthalmology), Moorfields Eye Hospital. London, UK
Rathie Rajendram Co-investigator (Ophthalmology), Moorfields Eye Hospital, London, UK
Catey Bunce Medical statistician, Moorfields Eye Hospital, London, UK
Trial Steering Committee
Maarten P Mourits Professor of Ophthalmology, Academic Medical Centre, Amsterdam, NL
John Lazarus Professor of Endocrinology, University of Wales, Cardiff, UK
John Sparrow Consultant Ophthalmologist, Bristol Eye Hospital, UK
Data Monitoring Committee
John Forrester Professor of Ophthalmology, University of Aberdeen and Aberdeen Royal Infirmary, UK
Gillian Adams Consultant Ophthalmologist, Moorfields Eye Hospital, London, UK
Roberto Melotti Senior statistician, North Bristol NHS Trust, Bristol, UK
Trials 2008, 9:6 http://www.trialsjournal.com/content/9/1/6
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hope to help resolve the debate which has arisen from
recent monotherapy studies [16,55], and seek not only to
establish whether the addition of azathioprine or radio-
therapy confers benefit in patients treated with glucocorti-
coids, but also to test the principle of combination
therapies in TED.
The use of a factorial design enables us to evaluate two
interventions in a single study and is the most valid means
of establishing whether the combination of two or more
therapies achieves incremental benefits [56]. It also makes
efficient use of patients, which is especially important
because of the limited numbers of potential recruits with
active TED [56,57]. However, in using a factorial design
we are assuming (but will have insufficient power to test)
that there is no interaction between trial interventions, as
if a significant biological or statistical interaction between
radiotherapy and azathioprine treatment exists, our calcu-
lation of their independent effects will be incorrect. The
validity of the study design therefore rests on the judge-
ment of the trial investigators and statistical advisors that
the potential for an interaction between our interventions
to have a 'clinically significant' effect on the interpretation
of the trial data is very low (ie ≤ 5%). We believe this to be
a reasonable assertion and consider that the risk of gener-
ating uninterpretable data is outweighed by the benefits
of using a factorial design to assess combination treat-
ments for an uncommon condition. Our small sample
size will also limit our sensitivity to small differences in
treatment efficacy, which is a compromise we accept as
integral to the conduct of a pragmatic study.
In addition to the restricted number of trial subjects, there
are many factors in the natural history and clinical evalu-
ation of TED which pose challenges to the objective and
scientific comparison of treatment outcomes. For exam-
ple, the control of systemic thyroid dysfunction reduces
disease severity, but delay in TED treatment until a 2
month period of euthyroidism has been maintained (as
has been advocated by other investigators [7,9,14,18]) in
order to prevent this confounding interpretation of treat-
ment efficacy, potentially misses the opportunity to
obtain maximal benefit from immunosuppression in the
earliest, most active phase of the disease. A patient's smok-
ing status, previous exposure to steroids and disease sever-
ity can also independently influence their response to
treatment. Furthermore, measures of disease activity and
severity are notoriously subjective [58,59], and although
some outcome measures have been used more often than
others in previous studies, there is no single standardised
and robustly validated scoring system to use in the assess-
ment of treatment efficacy.
We have sought to address the potential influence of mul-
tiple confounding factors through the use of a minimisa-
tion strategy to ensure their even distribution across trial
arms (Table 6). The absence of validated outcomes is
more problematic, particularly with regard to measures of
disease severity, which need to incorporate a range of
parameters to quantify both cosmetic deformity and vis-
ual dysfunction. The available continuous scoring systems
[6,44] can be relatively insensitive to clinically significant
treatment differences and depend on large sample sizes.
Consequently, recent studies have tended to use binary
composite outcome measures, weighted to detect
improvement in a selected disease components, such as
oculomotility [8,42,43,46]. However, no two studies have
used the same criteria to define treatment success, and we
have combined elements of each in order to generate our
scoring system (Figure 4). There is greater consensus on
the measurement of clinical activity and the CAS is an
accepted standard which has been widely used in recent
studies [8,14,15,18,60,61], however it remains limited by
its subjectivity [58,59] and inability to predict response to
steroids [45].
In order to ameliorate the problem of subjectivity in clin-
ical assessments with consequent inter-observer variabil-
ity we are using Dickinson et al.'s [43] reference atlas of
colour plates and our standard operating procedures for
patient examinations are based on those advocated by the
European Group on Graves Ophthalmopathy
(EUGOGO). In addition, we are seeking to lay the foun-
dations for fully objective measurement of disease activity
and severity through an ancillary Magnetic Resonance
Imaging (MRI) study which is being conducted alongside
the trial.
We have gone to great lengths to establish placebo con-
trols for the trial interventions, in particular with sham-
radiotherapy and decoy dose changes for patients allo-
cated to receive placebo tablets. However, there is a risk
that the common side-effects of azathioprine, such as
lethargy and nausea, will unmask investigators and
patients to their treatment allocation. This may be off-set
by the overlap between the side-effect profiles of azathio-
prine and prednisolone and the success of our masking
procedures will ultimately be evaluated by questionnaire
when each patient completes the trial.
Referral patterns to the study centres dictate that it is
impractical to restrict trial entry to patients who have not
been previously exposed to steroids. Hence, all potential
recruits who have sufficiently active disease to be eligible
for trial entry will be enrolled regardless of their prior ster-
oid exposure, and the potential this has to bias their sub-
sequent immunoresponsiveness is accounted for in the
minimisation criteria. In addition, the practicalities of
day-case admission for intravenous (IV) prednisolone
treatment have prevented the trial centres from adopting
Trials 2008, 9:6 http://www.trialsjournal.com/content/9/1/6
Page 14 of 17
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this as their usual practice, despite recent evidence in
favour of IV administration [62], and we are consequently
using oral prednisolone in the trial.
In summary, the CIRTED trial [63] seeks to utilise a high-
quality, pragmatic trial design to evaluate combination
immunotherapies for the treatment of TED and enhance
the evidence base available to inform treatment decisions
for both patients and health care professionals.
Abbreviations
CAS: Clinical Activity Score; CT: Computed Tomography;
CTU: Clinical Trials Unit; DMC: Data Monitoring Com-
mittee; EUGOGO: European Group on Graves Ophthal-
mopathy; GC: Glucocorticoids; GO-QoL: Graves
Ophthalmopathy Quality of Life; HADS: Hospital Anxiety
and Depression Scale; IMP: Investigational Medicinal
Product; MHRA: Medicines and Healthcare products Reg-
ulatory Agency; MRI: Magnetic Resonance Imaging; NED:
Noise-emitting device; NHS: National Health Service; OI:
Ophthalmopathy Index; RCT: Randomised Control Trial;
REC: Research Ethics Committee; TED: Thyroid Eye Dis-
ease; TES: Total Eye Score; TLD: Thermoluminescence
Dosimetry; TPMT: Thiopurine Methyltransferase
Competing interests
The author(s) declare that they have no competing inter-
ests.
Authors' contributions
RR: Participated in development of the trial protocol.
Coordinated the trial's set-up at Moorfields Eye Hospital
and facilitated the set-up of the other study sites in Lon-
don. Prepared the trial's standard operating procedures,
study documentation and publicity. Drafted the manu-
script.
RWJL: Conceived and designed the trial. Secured trial
funding and coordinated its multi-centre management.
Led the trial's set-up at Bristol Eye Hospital. Prepared the
trial's standard operating procedures, study documenta-
tion and publicity. Drafted the manuscript.
MJP: Participated in development of the trial protocol.
GER: Contributed to trial design and participated in devel-
opment of the trial protocol.
RJ and JMO: Led the trial's set-up and coordination at the
Western Eye Hospital, London.
FB, SH: Led the trial's set-up and coordination at Univer-
sity College London Hospitals.
AC: Led the trial's set-up and coordination at Manchester
Royal Eye Hospital.
RG: Led the set-up of trial radiotherapy at the Christie
Hospital, Manchester.
MT: Responsible for trial radiotherapy at Bristol Oncology
Centre.
NP: Led the trial's radiotherapy set-up at St Bartholomew's
Hospital, London.
CB: Participated in development of the trial protocol. Set-
up the trial's randomisation procedure. Coordinates sta-
tistical analyses.
SPH: Designed and coordinates the trial's health eco-
nomic evaluation.
ADD: Helped to secure trial funding and facilitated its set-
up at Bristol Eye Hospital.
NR, SJ and LK: Designed, implement and analyse the
trial's psychosocial assessments.
OCM: Leads coordination at Moorfields Eye Hospital.
CMD: Conceived and designed the trial. Secured trial
funding and coordinated its multi-centre management.
Designed and coordinates the trial's endocrine manage-
ment protocol. Drafted the manuscript.
JMU: Conceived and designed the trial. Secured trial fund-
ing and led its set-up at Moorfields Eye Hospital. Helped
to draft the manuscript.
All authors read and approved the final manuscript.
Additional material
Additional file 1
Patient Diary: Resource use, Personal Costs and Health Record. A diary
for patients to keep their appointments in and to document travel and
other related expenses.
Click here for file
[http://www.biomedcentral.com/content/supplementary/1745-
6215-9-6-S1.pdf]
Additional file 2
Quality of Life Questionnaires. Questionnaire to assess the patent's qual-
ity of life. This material uses the WHOQOL-UK and the assistance of the
University of Bath and the World Health Organisation is acknowledged.
Click here for file
[http://www.biomedcentral.com/content/supplementary/1745-
6215-9-6-S2.pdf]
Trials 2008, 9:6 http://www.trialsjournal.com/content/9/1/6
Page 15 of 17
(page number not for citation purposes)
Acknowledgements
We wish to thank:
▪ Dr Alan Montgomery (Department of Community Based Medicine, Uni-
versity of Bristol) and Rosemary Greenwood (Research and Development
Support Unit, United Bristol Healthcare Trust) for their statistical support
and advice on trial design.
▪ The clinical research teams at Bristol Eye Hospital (Annie Hinchcliffe and
Cherry Daly), the Western Eye Hospital (Maryam Zamani and Avril Char-
nock), University College Hospital London (Helen Armstrong) and Man-
chester Royal Eye Hospital (Sophie Perry), for establishing and managing
each trial centre.
▪ Nicola Harris (Moorfields Eye Hospital Research and Development
department) for co-ordinating the trial's administration across study sites
and Suzanne Cabral (Moorfields Eye Hospital Research and Development
department) for facilitating the trial's multi-centre set up.
▪ Emma Dawson (Moorfields Eye Hospital) and Sarah Schofield (Bristol Eye
Hospital) for their work on the development of the orthoptic assessment
protocols.
▪ Dr Sally Goodman for her contribution to setting up the trial radiotherapy
protocols at Bristol Oncology Centre
▪ The Radiotherapy teams in Bristol Oncology Centre (Sue Yarrow and Sue
Cowley), St Bartholomew's Hospital, London (Christine Usher, Christine
Bradley, Margaret Sharp) and the Christie Hospital, Manchester (Libby
Mills)
This trial was funded by the following charitable bodies:
▪ The National Eye Research Centre
▪ Moorfields Eye Hospital Special Trustees
▪ Medical Research Committee of the Charitable Trusts for the United
Bristol Hospitals
The following author receives funding related to the trial:
▪ RR receives a half-time salary from Moorfields Eye Hospital Special Trus-
tees for her participation in the trial.
▪ RL receives funding from the National Eye Research Centre
The following authors receive funding unrelated to the trial:
▪ CD receives funding from- Diabetes Vaccine Development Centre, Jules
Thorn Trust, Diabetes UK, Diabetes Research and Wellness Foundation.
▪ RL receives funding from the James Tudor Foundation and the Charles
Hayward Foundation
The funding bodies did not have a role in study design or the collection of
data. They also did not have a role in the writing of the manuscript or the
decision to submit the manuscript for publication.
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Additional file 3
Standard Operating Procedures. Standard operating procedures for the
combined immunosuppression & radiotherapy in thyroid eye disease
(CIRTED) trial. This material is a modification of the Standard Operat-
ing Procedures advocated by the European Group on Graves Ophthalmop-
athy (EUGOGO), and utilises Dickinson & Perros's reference atlas of
colour plates [43].
Click here for file
[http://www.biomedcentral.com/content/supplementary/1745-
6215-9-6-S3.pdf]
Additional file 4
Case Report Form. Case report form used in the combined immunosup-
pression & radiotherapy in thyroid eye disease (CIRTED) trial.
Click here for file
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