A placebo controlled study of the effect of EXTended treatment with Rituximab on resistant Rheumatoid Arthritis: Clinical and radiological outcomes

ISRCTN	ISRCTN23348591
DOI	https://doi.org/10.1186/ISRCTN23348591
Secondary identifying numbers	RR06/7719

Submission date: 02/01/2008
Registration date: 27/03/2008
Last edited: 29/06/2016

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Musculoskeletal Diseases

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Not provided at time of registration

Contact information

Prof Paul Emery
Scientific

Chapel Allerton Hospital
AUMD 2nd Floor
Chapeltown Road
Leeds
LS7 4SA
United Kingdom

Phone	+44 (0)113 392 4884
Email	p.emery@leeds.ac.uk

Study information

Study design	Single-centre study consisting of parts: Part 1: Open-label study. Part 2: Double-blind, partially randomised, placebo-controlled study.
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Not specified
Study type	Treatment
Participant information sheet	Not available in web format, please use the contact details below to request a patient information sheet
Scientific title	A placebo controlled study of the effect of EXTended treatment with Rituximab on resistant Rheumatoid Arthritis: Clinical and radiological outcomes
Study acronym	EXTRRA
Study objectives	Extending the standard dosing regimen of rituximab (3 doses rather than 2), will lead to better clinical outcomes in patients as measured by radiographic changes, B cell depletion and patient report.
Ethics approval(s)	Approved by the West Glasgow Research Ethics Committee on 4 September 2007 (ref: 07/S0703/68)
Health condition(s) or problem(s) studied	Rheumatoid arthritis
Intervention	Part 1 open-label study (first two doses of IMP): 2 doses x 1 g rituximab infusion (with methylpred pre-infusion) plus methotrexate as standard treatment dictates. Part 2 double-blind, placebo-controlled study (third dose: IMP or placebo): After the second rituximab infusion in Part 1 open-label study, the level of B-cell remaining in each patient will be measured. Those who have none remaining will be automatically assigned to the placebo arm. Those who still have remaining B-cells (non-depletors) will be randomly assigned to either placebo or 1 g rituximab. The clinicians will be blind to this information. Both IMP and placebo groups will receive methotrexate as standard treatment dictates, but no methylpred pre-infusion will be given.
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Not Specified
Drug / device / biological / vaccine name(s)	Rituximab
Primary outcome measure	Proportion of patients with B cells receiving three doses of rituximab vs proportion of patients with B cells who receive standard dose (two doses) rituximab who achieve ACR20 response at Week 28.
Secondary outcome measures	Disease Activity Measures: 1. Proportion of patients with ACR50 response at 6 months 2. Proportion of patients with ACR70 response at 6 months 3. Change in DAS28-ESR from baseline to 6 months 4. EUropean League Against Rheumatism (EULAR) response rates at 6 months 5. Change in ACR core set from baseline to 6 months 6. Change in 36-item Short Form health survey (SF-36) from baseline to 6 months 7. Proportion of patients achieving DAS28-ESR remission at 6 months 8. Proportion of patients achieving DAS28-ESR low disease state at 6 months Disability measures: 1. Change in Health Assessment Questionnaire (HAQ) score from baseline at weeks 12, 28, 40 and 52 Quality of Life: 1. Change in the Rheumatoid Arthritis Quality of Life (RA-QoL) score from baseline at weeks 12, 28, 40 and 52 Radiological: 1. Change in modified Sharp Radiographic Score for X-rays of dominant hand from baseline at 12 months, measuring total score, erosion score and joint space narrowing score 2. Change in ultrasound score for synovitis in dominant hand, assessed on grey scale and power Doppler, from baseline at weeks 28, 40 and 52 3. Change in MRI score (high field and peripheral) for synovitis, bone oedema and erosions in dominant hand from baseline at weeks 12, 28, and 40 Immunological: 1. Proportion of patients with PPC depletion (measured at week 2, 4 and 6) and correlation of this with response and relapse (measured at 6, 9 and 12 months) 2. Change in serological status (rheumatoid factor positivity or not) from baseline at 6 months
Overall study start date	04/09/2007
Completion date	04/09/2010

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Upper age limit	80 Years
Sex	Both
Target number of participants	60
Key inclusion criteria	1. Able and willing to give written informed consent and comply with the requirements of the study protocol 2. Patients with rheumatoid arthritis for at least 6 months, diagnosed according to the revised 1987 American College of Rheumatology (ACR) criteria for the classification of rheumatoid arthritis 3. Patients who have experienced an inadequate response to previous or current treatment with etanercept, infliximab or adalimumab because of toxicity or inadequate efficiency (etanercept for >3 months at 25 mg twice weekly, at least 4 infusions of infliximab at >=3 mg/kg or adalimumab for >=3 months at 40 mg every other week) or be unsuitable for treatment with anti-TNF therapy because of contra-indication 4. Patients who have been washed out from etanercept, infliximab or adalimumab or ¡Ý4 weeks prior to treatment with rituximab 5. All Disease Modifying Anti-Rheumatic Drugs (DMARDs) other than methotrexate should be withdrawn at least 4 weeks prior to rituximab therapy (see above for anti-TNF therapy) 6. 28-item Disease Activity Score (DAS28) >3.2 7. Age 18-80 years 8. Corticosteroids (<=10 mg/day prednisolone or equivalent) permitted if stable for at least 4 weeks prior to screening and NSAIDs permitted if stable for at least 2 weeks prior to screening. 9. Patients of reproductive potential (males and females) using a reliable means of contraception (e.g., contraceptive pill, IntraUterine Device [IUD], physical barrier) 10. If female and of childbearing potential, a negative urine pregnancy test within two weeks prior to therapy 11. Presence of erosive joint disease of at least 1 joint on x-ray (except if Distal InterPhalangeal [DIP] joint of the hand)
Key exclusion criteria	1. Bone/joint surgery within 8 weeks prior to therapy or joint surgery planned within 24 weeks of therapy 2. Rheumatic autoimmune disease other than RA or significant systemic involvement secondary to RA 3. History of, or current, inflammatory joint disease other than RA or other systemic rheumatic disorder Excluded previous/concomitant medications: 1. Concurrent treatment with any DMARD (apart from methotrexate) or any anti-TNF therapy or other biologic agent 2. Treatment with any investigational agent within 4 weeks of screening or 5 half lives of the investigational drug 3. Previous treatment with any cell depleting therapy therapies including investigational agents (e.g., CAMPATH®, anti-CD4, anti-CD5, anti-CD3, antiCD19) 4. Intra-articular or parenteral steroids within 4 weeks prior to therapy except for joints undergoing arthroscopy and/or Magnetic Resonance Imaging (MRI) where IA steroids are not permitted within 12 weeks prior to therapy 5. Receipt of a live vaccine within 4 weeks prior to randomisation Exclusions for General Safety: 1. History of severe allergic or anaphylactic reactions to humanised or murine monoclonal antibodies (e.g., infliximab or adalimumab) 2. Evidence of significant uncontrolled concomitant diseases such as cardiovascular disease, nervous system, pulmonary, renal, hepatic, endocrine or gastrointestinal disorders 3. Known active bacterial, viral, fungal mycobacterial infection (including tuberculosis, or atypical mycobacterial disease but excluding fungal infection of the nailbeds) or any episode of infection requiring hospitalisation or treatment with intravenous (iv) antibiotics within 4 weeks of therapy or oral antibiotics within 2 weeks of therapy 4. History of, or currently active, primary or secondary immunodeficiency 5. History of solid organ malignancy in the past 5 years (excluding basal cell or squamous cell carcinomas of the skin which have been excised and cured) 6. Pregnant women or breastfeeding mothers 7. History of alcohol, drug or chemical abuse within 6 months prior to screening 8. Neuropathies or neurovasculopathies which might interfere with pain evaluation 9. Intolerance or contraindications to oral (po) or iv steroids Laboratory exclusion criteria (at screening): 1. Serum creatinine >140 mmol/l 2. ASpartate aminoTransferase (AST) or ALanine aminoTransferase (ALT) >2.5 times upper limit of normal 3. Platelet count <100 4. Haemoglobin <8.5 5. Neutrophils <1.5x10.3/µl 6. Positive tests for hepatitis B surface antigen or hepatitis C antibody 7. Levels of IgG and/or IgM below 5.65 and 0.55 mg/mL respectively
Date of first enrolment	04/09/2007
Date of final enrolment	04/09/2010

Locations

Countries of recruitment

England
United Kingdom

Study participating centre

Chapel Allerton Hospital

Leeds
LS7 4SA
United Kingdom

Sponsor information

University of Leeds (UK)
University/education

Quality Assurance Department
LGI-Old Site
Great George Street entrance
A/B Corridor
Leeds
LS 1 3EX
United Kingdom

Phone	+44 (0)113 392 6473
Email	t.j.kurdziel@leeds.ac.uk
Website	http://www.leedsth.nhs.uk/sites/research_and_development
"ROR"	https://ror.org/024mrxd33

Funders

Funder type

Industry

Roche Pharmaceuticals (Switzerland)

No information available

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
Publication and dissemination plan	Not provided at time of registration
IPD sharing plan

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	results:	01/06/2015		Yes	No

Editorial Notes

29/06/2016: Publication reference added