Condition category
Musculoskeletal Diseases
Date applied
15/05/2019
Date assigned
17/05/2019
Last edited
17/05/2019
Prospective/Retrospective
Retrospectively registered
Overall trial status
Ongoing
Recruitment status
No longer recruiting

Plain English Summary

Background and study aims
Rheumatoid arthritis (RA) is a long-term disease causing pain, swelling (inflammation) and stiffness in the joints. It is part of a group of diseases called autoimmune diseases, where the immune system starts to attack healthy joints. In healthy people, the body produces different types of immune cells. One of these is the B-cell, which produces antibodies to fight infection. In people with RA, these do not behave properly and produce antibodies which attack a person’s own body even if there is no infection. There are 26,000 new cases of RA each year, which costs the NHS around £560 million annually. Often the first line of treatment involves the use of disease-modifying anti-rheumatic drugs (DMARDs), which work by slowing down the progress of the disease by suppressing the immune system. In about 40% of cases however, patients do not show any real signs of improvement (DMARD failures). In recent years, drug treatments for RA have improved dramatically. So-called “biologic treatments” such as the drug tocilizumab, are made from proteins and work by blocking the activity of the chemicals or cells which trigger the inflammation of the joints. Another important treatment used in RA is a group of drugs known as anti-TNF (anti-tumour necrosis factor), such as etanercept and rituximab, which work directly on the immune system to reduce the number of B-cells, stopping them from producing antibodies which will attack the healthy cells. Currently, patients are treated with tocilizumab, etanercept or rituximab on a trial and error basis. The aim of this study is to predict which treatment will work best for patients, this is known as stratified or personalised medicines.

Who can participate?
Adults with RA who have DMARD failure and are eligible for antiTNF therapy.

What does the study involve?
Participants have a minimally invasive synovial biopsy of an inflamed joint and are then randomly allocated to one of three groups, who are each treated with a different drug. Those in the first group receive a 50mg subcutaneous injection (injection under the skin) of etanercept once a week. Those in the second group receive a 1000mg intravenous infusion (a drip into a vein) of rituximab day 1 and 15 of the study this treatment is repeated every 24 weeks. Those in the third group receive a 162mg subcutaneous injection of tocilizumab once a week. Participants come in for monthly visits for 1 year. The main outcome of the trial is the number of participants in each treatment group who show more than a 20% improvement (ACR20) in their symptoms 16 weeks into the study.

What are the possible benefits and risks of participating?
Benefits include regular reviews and if treatment is not effective it will be switched at 4months rather than at 6 months. There is a small risk of complications associated with the biopsy and patients receiving Rituximab as part of the trial might not be guaranteed to continue to receive it. This is because treatment with Rituximab typically requires you to have been treated with another biological drug first in standard care.

Where is the study run from?
Centre for Experimental Medicine and Rheumatology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London (UK)

When is the study starting and how long is it expected to run for?
June 2018 to December 2020

Who is funding the study?
Medical Research Council

Who is the main contact?
Jo Peel
j.peel@qmul.ac.uk

Trial website

http://www.matura-mrc.whri.qmul.ac.uk/

Contact information

Type

Public

Primary contact

Ms Jo Peel

ORCID ID

Contact details

Centre for Experimental Medicine & Rheumatology
2nd Floor
John Vane Science Centre
Queen Mary University of London
Charterhouse Square
London
EC1M 6BQ
United Kingdom
+44 (0)20 7882 3497
j.peel@qmul.ac.uk

Additional identifiers

EudraCT number

2017-004079-30

ClinicalTrials.gov number

Nil known

Protocol/serial number

STRAP-EU

Study information

Scientific title

Stratification of biologic Therapies for RA by Pathobiology: a randomised, open-labelled biopsy-driven stratification trial in DMARD inadequate responder patients randomised to Etanercept, Tocilizumab or Rituximab

Acronym

STRAP-EU

Study hypothesis

In patients failing DMARD therapy, with a B cell poor synovial pathotype, Rituximab is inferior to Tocilizumab and Etanercept therapy.

Ethics approval

1. Approved 01/02/2018, Ethics Committee Hospital-Faculty Saint-Luc (Avenue Hippocrate 55.14 -Tour Harvey, niveau O - 1200 Bruxelles; 027645514; commission.ethique-saint-luc@uclouvain.be), ref: 2017/21NOV/526.
2. Approved 06/07/2018, AOU Inter-company Ethics Committee "Major of Carita" (C.so Mazzini n.18 - 28100 Novara; 03213733081; segreteria.scientifica@comitatoeticonovara.it), ref: CE 32/18.
3. Approved 24/08/2018, Ethics Committee for Clinical Research (CEIC) (Lisbon) (Joao Eurico Cabral da Fonseca Centro Hospitalar de Lisboa Norte, EPE - Hospital de Santa Maria Servico de Reumatologia, Avenida Prof. Egas Moniz, Piso 7, 1649-035, Lisbon), ref: LC/LC/OF/2018/9325/20180526.
4. Approved 29/06/2018, Research Ethics Committee with medicines at the Hospital Clínic de Barcelona (Villarroel, 170 – 08036 Barcelona (España); 93 227 54 00), ref: 10/2018.
5. Approved 13/03/2019, Univ. Policlinico Foundation A. Gemelli Ethics Committee (Fondazione Policlinico Unlversitario Agostino Gemelli IRCCS Universita Cattolica del Sacro Cuore, Largo Agostino Gemelli 8, 00168 Roma; +39 06 3015 6124 -5556; comitato.etico@policlinicogemelli.it), ref: 0011631/19.
6. Approved 24/07/2018, Independent Ethics Committee University Hospital of Cagliari (Azienda Ospedallero Unlversltarla di Cagliari
P.O. San Giovanni di Dio: via Ospedale 54 - 09124 Cagliarl Segreteria Tecnlco Scientlflca; 0706092547), ref: PG/2018/9999.

Study design

Three-arm randomised parallel trial

Primary study design

Interventional

Secondary study design

Randomised parallel trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Rheumatoid arthritis

Intervention

1. Rituximab
Rituximab (MabThera® 500mg concentrate for infusion, Roche Products Ltd) is available as 50ml single-use vials containing 500mg Rituximab for infusion (10mg/ml). Patients randomised to receive rituximab therapy will be given treatment on days 1 and 15, which is one infusion cycle. A patient initially randomised to Rituximab and deemed a responder at 16 weeks will be retreated at 24 weeks. All treatment infusions will be prepared, administered and monitored according to the guidance included in the SmPC. Patients with inadequate response at week 16 to Rituximab will be switched to Etanercept at that visit or the following visit.

2. Tocilizumab
Tocilizumab (RoActemra SC® 162mg solution for injection in a pre-filled syringe, Roche Products Ltd) subcutaneous (SC) formulation is a sterile, yellowish, preservative-free liquid solution of approximately pH 6.0 for SC injection. It is supplied at a concentration of 180 mg/mL in syringe/autoinjector (AI) forms with a nominal amount of 162 mg of Tocilizumab in 0.9 mL of arginine, methionine, and histidine buffered solution. Tocilizumab will be prescribed as per license. The recommended dose of Tocilizumab for adult patients with RA is 162mg administered as a weekly subcutaneous injection and it will be self-administered by patients. Patients will be treated with tocilizumab for up to 48 weeks unless they switch treatment during the trial. Patients with inadequate response at week 16 to Tocilizumab will be switched to Etanercept at that visit or the following visit.

3. Etanercept
Etanercept (Enbrel® 50mg solution for injection in pre-filled pen, Pfizer) is available in pre-filled pens containing 50mg of Etanercept in a clear, and colourless or pale yellow solution. Etanercept will be prescribed as per license. The recommended dose of Etanercept for adult patients with RA is 50 mg (given as a subcutaneous injection) once a week and it will be self-administered by patients. Patients will be treated with etanercept for up to 48 weeks unless they switch treatment during the trial. Patients who have an inadequate response at 16 weeks to Etanercept will be switched to Rituximab at that visit or the following visit.

Secondary failures (i.e. after week 16) to first biologic:
Patients showing initial clinical response by 16 weeks will be subsequently classified as a secondary failure at subsequent study visits, if their ACR response is less than 20% at any subsequent follow up visit. Such patients should switch treatment either at that visit or the following visit.

The total treatment period is 48 weeks and a 30 day safety follow-up will be performed 30 days after the patients last trial visit.

Randomisation
Patients will be stratified according to synovial histopathology (2 strata based on B cells, or a third strata where result is unknown) and methotrexate use (yes/no), and randomised using ratio 1:1:1 to three treatments.

Intervention type

Drug

Phase

Not Applicable

Drug names

1. Etanercept
2. Rituximab
3. Tocilizumab

Primary outcome measure

Treatment response will be assessed using the ACR20 response at 16 weeks

Secondary outcome measures

1. For the B-cell rich synovial pathotypes, we aim to compare treatment effects (with 95% confidence intervals) of Rituximab to Tocilizumab and Etanercept (treated together for analysis).
2. The interaction between treatments and B-cell status (rich and poor) will be tested using the likelihood ratio test between nested logistic regression models. The model will use all the sample and will be adjusted for MTX.
3. Patients who fail to respond during the first 16 weeks and cross-over treatment will also provide evidence regarding the efficacy of the two treatments and the predictive significance of B-cells in synovial biopsies. The post cross-over results will be combined with the pre-cross-over results in a secondary analysis stratified by pre/post cross-over.

Overall trial start date

01/09/2017

Overall trial end date

31/12/2020

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

Patients will be recruited with active RA:
1. 2010 ACR / EULAR Rheumatoid Arthritis classification criteria for a diagnosis of RA
2. DMARD failure eligible for anti-TNF-α therapy as per UK NICE guidelines
3. Minimum of 3 swollen joints – the joint selected for biopsy and a minimum of 2 from 28 joint count set, as assessed at biopsy visit
4. Selected joint for biopsy must be minimum grade 2 synovial thickening, as assessed at the biopsy visit
5. 18 years of age and over
6. Capable of giving informed consent and the consent must be obtained prior to any screening procedures

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

207 patients (this recruitment target combines both STRAP-EU (EudraCT number: 2017-004079-30) and the UK STRAP trial (EudraCT number: 2014-003529-16). Target for STRAP-EU trial: maximum of 60 patients.

Participant exclusion criteria

Patients will be excluded if they have any contraindication to Etanercept, Rituximab or Tocilizumab therapy:
1. Pregnant or breastfeeding
2. Women of child-bearing potential or males whose partners are women of child-bearing potential, unwilling to use an effective method of contraception (recommend double contraception) throughout the trial and beyond the end of trial treatment for the duration as defined in the relevant SmPC; 12 months for Rituximab, at least 3 weeks for Etanercept, and at least 3 months for Tocilizumab.
3. History of or current primary inflammatory joint disease or primary rheumatological autoimmune disease other than RA (if secondary to RA, then the patient is still eligible).
4. Prior exposure to Rituximab, any anti-TNF, Tocilizumab, or any other biologic for treatment of RA
5. Treatment with any investigational agent ≤ 4 weeks prior to baseline or < 5 half-lives of the investigational drug (whichever is the longer)
6. Intra-articular or parenteral corticosteroids ≤ 4 weeks prior to the screening visit.
7. Oral prednisolone more than 10mg/d or equivalent ≤ 4 weeks prior to baseline synovial biopsy.
8. Active infection
9. Known HIV, active Hepatitis B/C infection. Hepatitis B screening test must be performed at or in the preceding 3 months of the screening visit.
10. Septic arthritis of a native joint within the last 12 months
11. Septic arthritis of a prosthetic joint within 12 months or indefinitely if the joint remains in situ
12. Latent TB infection unless they have completed adequate antibiotic prophylaxis
13. Malignancy (other than basal cell carcinoma) within the last 10 years
14. New York Heart Association (NYHA) grade III or IV congestive heart failure
15. Demyelinating disease
16. Known allergy to latex, Rituximab, Tocilizumab or Etanercept
17. Any other contra-indication to the study medications as detailed in the applicable SmPC including low IgG levels, at physician’s discretion
18. Receipt of live vaccine <4 weeks prior to first IMP infusion or dose
19. Major surgery in 3 months prior to first IMP infusion or dose
20. Presence of a transplanted organ (with the exception of a corneal transplant >3 months prior to screening).
21. Known recent substance abuse (drug or alcohol).
22. Poor tolerability of venepuncture or lack of adequate venous access for required blood sampling during the study period
23. Patients unable to tolerate synovial biopsy or in whom this is contraindicated including patients on anticoagulants. Oral antiplatelet agents are permitted.
24. Currently recruited to another clinical trial.
25. Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that would impart, in the judgment of the investigator, excess risk associated with study participation or study drug administration, or which, in the judgment of the investigator, would make the patient inappropriate for entry into this study

Recruitment start date

21/06/2018

Recruitment end date

31/05/2019

Locations

Countries of recruitment

Belgium, Italy, Portugal, Spain

Trial participating centre

Cliniques Universitaires Saint-Luc
10 Avenue Hippocrate
Brussels
1200
Belgium

Trial participating centre

AOU Maggiore della Carita de Novara
Corso Mazzini 18
Novara
28100
Italy

Trial participating centre

CENTRO HOSPITALAR LISBOA NORTE, E.P.E. – HOSPITAL DE SANTA MARIA
Avenida Prof. Egas Moniz
Lisbon
1649-035
Portugal

Trial participating centre

Hospital Clinic de Barcelona
Calle Villarroel, 170
Barcelona
08036
Spain

Trial participating centre

Fondazione Policlinico Universitario A. Gemelli
Largo Francesco Vito, n.1
Rome
00168
Italy

Trial participating centre

Azienda Ospedaliero Universitaria (AOU) di Cagliari
via Ospedale, 54
Cagliari
09124
Italy

Sponsor information

Organisation

Queen Mary University of London

Sponsor details

Joint Research Management Office
5 Walden Street
London
E1 2EF
United Kingdom
020 7882 7275
Research.Governance@qmul.ac.uk

Sponsor type

University/education

Website

http://www.jrmo.org.uk/

Funders

Funder type

Research council

Funder name

Medical Research Council

Alternative name(s)

MRC

Funding Body Type

government organisation

Funding Body Subtype

National government

Location

United Kingdom

Results and Publications

Publication and dissemination plan

Planned publication in a high-impact peer-reviewed journal.

IPD sharing statement: the anonymised raw data will be stored in a non-publically available repository called TranSMART (once the paper has been published). More information can be found here: http://www.matura.whri.qmul.ac.uk/TranSMART.php.

Intention to publish date

01/06/2021

Participant level data

Stored in repository

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

17/05/2019: Trial's existence confirmed by the Ethics Committee Hospital-Faculty Saint-Luc.