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Abstract
Background: Interstitial lung disease (ILD) frequently complicates systemic autoimmune disorders resulting in
considerable morbidity and mortality. The connective tissue diseases (CTDs) most frequently resulting in ILD include:
systemic sclerosis, idiopathic inflammatory myositis (including dermatomyositis, polymyositis and anti-synthetase
syndrome) and mixed connective tissue disease. Despite the development, over the last two decades, of a range of
biological therapies which have resulted in significant improvements in the treatment of the systemic manifestations of
CTD, the management of CTD-associated ILD has changed little. At present there are no approved therapies for CTD-ILD.
Following trials in scleroderma-ILD, cyclophosphamide is the accepted standard of care for individuals with severe or
progressive CTD-related ILD. Observational studies have suggested that the anti-CD20 monoclonal antibody, rituximab,
is an effective rescue therapy in the treatment of refractory CTD-ILD. However, before now, there have been
no randomised controlled trials assessing the efficacy of rituximab in this treatment population.
Methods/design: RECITAL is a UK, multicentre, prospective, randomised, double-blind, double-dummy, controlled
trial funded by the Efficacy and Mechanism Evaluation Programme of the Medical Research Council and National
Institute for Health Research. The trial will compare rituximab 1 g given intravenously, twice at an interval of 2 weeks,
with intravenously administered cyclophosphamide given monthly at a dose of 600 mg/m2 body surface area in
individuals with ILD due to systemic sclerosis, idiopathic inflammatory myositis (including anti-synthetase syndrome) or
mixed connective tissue disease. A total of 116 individuals will be randomised 1:1 to each of the two treatment arms,
with stratification based on underlying CTD, and will be followed for a total of 48 weeks from first dose. The primary
endpoint for the study will be change in forced vital capacity (FVC) at 24 weeks. Key secondary endpoints include: safety,
change in FVC at 48 weeks as well as survival, change in oxygen requirements, total 48-week corticosteroid exposure
and utilisation of health care resources.
(Continued on next page)
* Correspondence: t.maher@imperial.ac.uk
1
NIHR Biomedical Research Unit, Royal Brompton Hospital, Sydney Street,
London SW3 6NP, UK
6
Fibrosis Research Group, National Heart and Lung Institute, Imperial College
London, Sir Alexander Fleming Building, Imperial College, London SW7 2AZ, UK
Full list of author information is available at the end of the article
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Saunders et al. Trials (2017) 18:275 Page 2 of 11
utilisation of health care resources and fewer hospital Table 1 Outline of planned treatment interventions by visit
visits. There are currently no available biomarkers for Rituximab group Cyclophosphamide group
assessing response to therapy or risk of disease pro- Day 0 IV active rituximab 1000 mg IV 600 mg mg/m2 body
gression in CTD-ILD. By closely studying patients in surface area
each treatment arm and undertaking exploratory bio- Day 14 IV active rituximab 1000 mg Placebo
marker analysis it is hoped that we might identify Week 4 Placebo IV 600 mg mg/m2 body
potential disease- and therapy-specific biomarkers for surface area
future development and use in clinical practice. Week 8 Placebo IV 600 mg mg/m2 body
Against the potential benefits must be balanced the surface area
risks of treatment. As noted, rituximab is a well- Week 12 Placebo IV 600 mg mg/m2 body
established therapy for a range of indications and, as surface area
such, its safety profile is well known. Potential risks of Week 16 Placebo IV 600 mg mg/m2 body
therapy include; infusion reactions, infection, arthralgia surface area
and hypercholesterolaemia. Very rarely, long-term hypo- Week 20 Placebo IV 600 mg mg/m2 body
gammaglobulinaemia and neutropaenia have been surface area
reported. These side effects can be balanced against IV intravenously administered
Fig. 1 Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) figure. BP blood pressure, ECG electrocardiogram, 6MWT 6-min
walk test, QoL quality of life, mRSS modified Rodnan Skin Score
total of six doses. If clinically required, individual doses Both cyclophosphamide and rituximab as well as the
may be delayed by up to 10 days. If longer delay is re- placebo will have identical appearances (clear, colourless
quired the planned dose should be omitted and the next liquid) and will be drawn up in identical volumes so as
scheduled dose given. Body surface area will be calcu- to avoid unblinding of the study drug.
lated with baseline measurements using the Mosteller
method with dose modification for any subjects with a Non-Investigational Medicinal Product (nIMP) drugs
Body Mass Index (BMI) >30 Kg/m2: The following nIMPS will be used in this study and
administered to both groups when they receive cyclo-
phosphamide/rituximab/placebo. All nIMPS are open
BSA m2 ¼ square root of ðheight ðcmÞ x weight ðkgÞ=3600Þ
label and generic forms can be used:
Rituximab will be administered by intravenous infu- 1. Mesna will be administered to patients in both
sion at a dose of 1000 mg. The dose will be repeated at groups at day 0 and monthly until week 20. Mesna
14 days. This second dose may be delayed by up to 200 mg will be given by intravenous infusion in
10 days. If it is not given within this time it should be 100 ml 0.9% sodium chloride over 30 min
omitted. immediately prior to cyclophosphamide/rituximab/
Placebo infusions will be administered in order to placebo. Additionally, Mesna 400 mg will be
maintain the blind and all patients will receive seven administered per os at 2 h and 400 mg at 6 h
infusions in total. post cyclophosphamide/rituximab/placebo infusion
Saunders et al. Trials (2017) 18:275 Page 5 of 11
(with ±60 min maximum difference, time will be instruments used will be the SF-36 and the EuroQol 5
recorded). On days of clinic visits (including the screen- dimensions health survey (EQ5D), the SGRQ, K-BILD
ing visit), patients must refrain from strenuous activity and the Scleroderma Health Assessment Questionnaire.
for at least 12 h prior to pulmonary function testing.
Smoking will be discouraged throughout the study day Health economics
(clinic visit) and will not be permitted in the 30-min The RECITAL study will provide reliable data about the
period prior to spirometry. Patients should also avoid efficacy and safety of rituximab compared to standard
cold temperatures, environmental smoke, dust, or areas therapy. As rituximab is considerably more expensive
with strong odours (e.g. perfumes). Washout of bron- than cyclophosphamide, the issue of cost-effectiveness
chodilator therapies (beta-agonist or anticholinergic and affordability will arise if we show that it is more ef-
drugs) should be undertaken before spirometry: 24 h for fective than standard treatments. In a study of this size
long-acting and 8 h for short-acting bronchodilators. it may be difficult to perform standard cost-effectiveness
analyses (e.g. cost per quality-adjusted life year (QALY)),
Assessment of safety but we can estimate cost-effectiveness using surrogate
The checking for the occurrence of adverse events (AEs) clinical outcomes and also reliably estimate costs for
and clinical endpoints will begin from randomisation and care in the two treatment groups including costs of
will continue for the individual patient until they complete drug, tests and investigations, health care visits (hospital,
their follow-up at 48 weeks. At each study visit the investi- GP, clinic). We will also have a range of patient-based
gator or designee will make an assessment of safety and outcomes using validated questionnaires. Working with
will specifically review the clinical history and investiga- the health economic team at the University of East
tion findings with regard to the occurrence of adverse or Anglia, the health economic analysis will deliver a high-
serious adverse events (SAEs). Details of adverse and quality analysis using standard techniques to inform our
clinical events will be captured on the trial eCRF. understanding of the cost-effectiveness of the new
treatment.
Research blood samples
All biological samples for future research will be col- Discontinuation or withdrawal of study subjects
lected and handled according to a study-specific proced- The study drug will be discontinued if, in the opinion
ure, stored anonymously and labelled using a unique of the local investigator/caring physician, an individual
study number to permit accurate linkage to clinical data. participant’s disease has progressed despite receiving
Samples will be initially processed and stored at study study therapy. The decision regarding progression will
sites in accordance with the study-specific procedure for rest with the local physician, but indicators of disease
handling RECITAL biological samples, to facilitate trans- progression will include: worsening symptoms, progres-
fer to the Royal Brompton Hospital (RBH) Biological sion of radiological changes and reduction in FVC of
Research Unit (BRU) Royal Brompton Hospital (RBH), >10% or DLco of >15% from baseline or reduction in
Sydney Street, London, SW3 6NP. resting oxygen saturations from baseline. Individuals
The storage of samples and use in future unspecified with progressive disease will be unblinded from the
research will be performed in accordance with the study and, if felt appropriate by their caring physician,
Human Tissue Act 2004, and the RBH policy for ‘the ac- may be offered the alternative treatment regimen on an
quisition, storage and use of human biological specimens open-label basis (i.e. patients receiving rituximab will
for research’. Stored samples may be used to assess be offered cyclophosphamide and those receiving cyclo-
future biomarkers for the risk of developing lung fibrosis phosphamide will be considered for rituximab). Simi-
and the prognosis of this condition. larly, in the case of individuals discontinuing treatment
because of AEs the option will be open to the local car-
Routine safety blood tests ing physician to initiate open-label treatment with the
Routine safety blood tests including full blood count, alternate treatment regimen.
urea and electrolytes and liver function tests will be Subjects discontinuing the study drug will be in-
undertaken in the clinical laboratories at local sites vited to continue with planned monitoring and end-
according to local policies and procedures. of-study visits. Complete protocol required data will,
whenever possible, be collected for all individuals who
Quality of life assessment are randomised into the study whether or not they
Quality of life will be assessed by self-administered ques- receive their assigned treatment or discontinue the
tionnaires. These will be completed at baseline and study prematurely. Subjects discontinuing study treat-
repeated at the first follow-up visit for primary endpoint ment will be asked to return for the primary endpoint
at 24 weeks and final follow-up visit at 48 weeks. The (week 24) and final (week 48) follow-up visits. Apart
Saunders et al. Trials (2017) 18:275 Page 8 of 11
from the treatment week-12 visit they will not be re- of the clinical trial protocol and will comply with
quired to attend any further treatment phase visits regulatory requirements. Local personnel will be
once treatment is discontinued. trained on the InForm system. Access will be re-
stricted to site personnel, trial managers, trial moni-
Permanent discontinuation of IMP tors and the data management team. Personnel will
Permanent discontinuation of study medication should have individual logon and passwords. It will be the
occur in the following circumstances: investigator’s responsibility to ensure the accuracy of
all data entered and recorded in the eCRFs. Trial
Consent withdrawn monitors will check the accuracy of the eCRF data
Pregnancy against source documents.
New diagnosis of tuberculosis, infective hepatitis It is anticipated that the majority of source data
or HIV (medical progress notes and letters, tests and investi-
gations) will be filed in the individual patients’ med-
Possible temporary discontinuation of IMP ical records. Any deviation from source data being
In the following cases withdrawal of study drug is highly present in the medical notes will be identified and
recommended: documented. The eCRF and source documents must
be available at all times for review by the sponsor’s
Episode of severe infection requiring prolonged clinical trial monitor, auditors and for inspection by
antibiotic treatment (>14 days) or hospitalisation the Medicines Health Regulatory Agency. The accur-
New diagnosis of bladder cancer acy of eCRF data will be verified by review of the
New occurrence of neurological symptoms source documents and details will be provided in the
suggesting a diagnosis of progressive multifocal Trial Monitoring Report.
leukoencephalopathy (PML)
Statistical analysis
However, in special circumstances and after review of
Before starting the data analysis, the level and pattern
the clinical data, consultation with the appropriate spe-
of the missing data in the baseline variables and out-
cialist (urologist, neurologist) and members of the multi-
comes, and any treatment group crossovers, will be
disciplinary team, an appropriate risk benefit assessment
established by forming appropriate tables. The likely
and consultation with the patient, the investigator may
causes of any missingness and crossovers will be in-
decide not to withdraw the subject. In each case, as this
vestigated. This information will be used to determine
is an intention-to-treat trial, patients will be invited to
whether the level and type of missing data and the
continue attending study visits to allow for full collection
crossover rate have the potential to introduce bias
of study data.
into the analysis results for the proposed statistical
methods, or substantially reduce the precision of esti-
Serious adverse event (SAE) reporting and adverse event
mates related to treatment effects.
(AE) reporting
AEs and SAEs will be identified according to standard
criteria and will be recorded in the eCRF and reported Primary efficacy analysis
to the sponsor. Given the nature of participants’ under-
lying disease and also the known profile of the drugs Analysis of the primary outcome will be by
under investigation, a number of expected AEs and SAEs intention-to-treat. The data will be analysed
have been defined. Expected adverse reactions are listed according to the initial randomisation groups
as the known side effects of the IMP reported in the with no changes made in respect of subsequent
Summary of Product Characteristics (SmPCs) of cyclo- withdrawals or crossovers
phosphamide, rituximab and sodium chloride. Events The hypothesis to be tested is that rituximab is
that are expected and related to underlying disease will superior to cyclophosphamide. The study will be
include study endpoints and disease progression or considered positive if statistical significance at the
worsening of pre-existing respiratory or rheumatological level of 0.05 (two-tailed) is achieved
symptoms. To test the hypothesis above and estimate the
difference in FVC at week 24 and its 95%
Data management and data checking confidence interval, a three-level hierarchical
Data will be collected on an eCRF system. The In- (mixed/multilevel) model will be used: let
Form system will be used to develop the eCRF and FVCiw represent the FVC (in millilitres) for
will be designed in accordance with the requirements patient i at week w and t (i) represent the
Saunders et al. Trials (2017) 18:275 Page 9 of 11
Interim analyses
Intercept term: represents the estimate FVC on No formal interim analysis is planned. A regular review
week 0 (the start of the treatment, first visit after of safety data will be conducted to monitor the safety of
randomisation). This term will comprise an patients in the trial. A Data Monitoring Committee
individual-level random effect which will be drawn (DMC) will follow number of deaths, early discontinu-
from a distribution parameterised using the associated ation due to AEs and SAEs in an unblinded fashion. A
centre-level random effect. Hence, the unexplained planned DMC meeting will be held to review all avail-
variation in the FVC scores will be split in to three able data after the 12th randomised patient has
components corresponding to the three levels of the completed the week-24 visit and twice yearly.
model, i.e. the variation attributable to the centre
(between-centre variation) and the individual End of study
(between-individual variation), as well as the residual The primary endpoint for the trial is at 24 weeks, with a
variation (within-individual variation). CTD diagnosis final study visit timed at 48 weeks to determine longer-
stratum (categorical) used for randomisation will be term efficacy and to ensure that all significant AEs are
added as a covariate. Other baseline covariates might detected. The trial will formally end when the final
be added if further analysis reveals a substantial subject completes their week-48 visit.
imbalance
Change over time term: this represents a coefficient Ethics and dissemination
which captures the changes in FVC over time The study conduct will comply with all relevant laws of
(measured in weeks) and an interaction term between the EU and all relevant laws and statutes of the UK includ-
time and treatment. This interaction term will capture ing, but not limited to, the Human Rights Act 1998, the
the difference in change of FVC between the two Data Protection Act 1998, the Medicines Act 1968, the
treatment groups per week. The magnitude at Medicines for Human Use (Clinical Trial) Regulations
24 weeks and its 95% confidence interval will be 2004, and with all relevant guidance relating to medicines
calculated to answer the research question. and clinical studies from time to time in force including,
but not limited to, the ICH GCP, the World Medical
Linear change is assumed over time with different Association Declaration of Helsinki entitled ‘Ethical Prin-
slopes (the interaction term represents the difference in ciples for Medical Research Involving Human Patients’
the slope); however, alternatives will be considered if the (2008 Version), the NHS Research Governance Frame-
rate of change is not constant over the 24-week period. work for Health and Social Care (Version 2, April 2005).
Alternatives are to include quadratic and square root The study was approved on 18 October 2013 by the UK
terms. This will be assessed before the unblinding. Medicines and Healthcare Regulatory Agency in compli-
Residual error term: it is assumed that the residual ance with the European Clinical Trials Directive and the
errors have a normal distribution. Medicines for Human Use (Clinical Trials) Regulations
2004 and its subsequent amendments. The study was pro-
Secondary efficacy analysis vided with ethical approval by the NRES Committee
London Westminster (Ref no.: 13/LO/0968) on 20 August
Analysis of secondary efficacy outcomes will also be 2013. The approved patient information sheet and consent
by intention-to-treat form are available in Additional files 3 and 4.
Change in continuous physiological variables Data from the study will be published in abstract form
between baseline and 48 weeks will be assessed by at international meetings and will be submitted for pub-
similar multilevel modelling as described for the lication in a peer-reviewed journal and will be reported
primary outcome to the study funder.
Categorical change in physiological variables will be
measured using chi-squared tests under the null Discussion
hypothesis of no difference between the treatment ILD is an important cause of morbidity and mortality in
groups patients with CTD. This trial should better define the
Saunders et al. Trials (2017) 18:275 Page 10 of 11
optimal management of patients with severe CTD-ILD. Availability of data and materials
Current therapy is limited by side effects and the risk of Not applicable, as data not yet available.
Acknowledgements
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in
Members of the DMC: Andrew Wilson, Clive Kelly and Ashley Jones.
published maps and institutional affiliations.
Members of the TSC: Tim Harrison, Bridget Griffiths, Kim Fliglestone,
Nik Hirani, Rachel Hoyles, Ira Jakupovic, Alexandra Marler, Daphne Babalis,
Author details
Vicky Tsipouri, Deborah Ashby, Helen Parfrey and Toby Maher. 1
NIHR Biomedical Research Unit, Royal Brompton Hospital, Sydney Street,
We are grateful to the late Mrs. Anne Mawdsley for her input into protocol
London SW3 6NP, UK. 2Princess Alexandra Hospital, Brisbane, QLD, Australia.
design and to Ed Waddingham and Matyas Szigeti for their input into the 3
Imperial Clinical Trials Unit, School of Public Health, Imperial College
statistical analysis plan. Rick Fordham has provided input into the design of
London, St. Mary’s Campus, Norfolk Place, London W2 1PG, UK. 4Norwich
the economic evaluation component of the study.
Medical School, University of East Anglia, Norfolk and Norwich University
The funder has no role in the trial design, collection, management, analysis
Hospital, Norwich, UK. 5Respiratory Medicine Division, Department of
or interpretation of data, writing of reports or submission for publication.
Medicine, University of Cambridge School of Clinical Medicine,
Additional infrastructure support for the study is being provided by the
Addenbrooke’s Hospital, CUHNHSFT and Papworth Hospital NHS Foundation
Royal Brompton NIHR-funded Biomedical Research Unit. The views and
Trust, Cambridge, UK. 6Fibrosis Research Group, National Heart and Lung
opinions expressed therein are those of the authors and do not necessarily
Institute, Imperial College London, Sir Alexander Fleming Building, Imperial
reflect those of the NIHR.
College, London SW7 2AZ, UK. 7Centre for Rheumatology and Connective
Tissue Diseases, Royal Free Campus, University College London, London NW3
Funding 2PF, UK.
The RECITAL study is funded in full by the Efficacy and Mechanism
Evaluation Programme of the Medical Research Council and National Received: 15 June 2016 Accepted: 25 May 2017
Institute for Health Research (Ref: 11/116/03). Funding approval was
obtained following external peer reviews. Dr. Toby Maher is supported
by an NIHR Clinician Scientist Fellowship (NIHR Ref: CS-2013-13-017). References
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