Stratification of biologic Therapies for Rheumatoid Arthritis by Pathobiology

• Register: EUCTR
• Last refreshed on: 22 April 2024
• Main ID: EUCTR2017-004079-30-PT
• Date of registration: 29/06/2018
• Prospective Registration: Yes
• Primary sponsor: Joint Research & Development Office (QMUL)
• Public title: Stratification of biologic Therapies for Rheumatoid Arthritis by Pathobiology
• Scientific title: Stratification of Biologic Therapies for RA by Pathobiology (STRAP)-EU: A randomised, open-labelled biopsy-driven stratification trial in DMARD inadequate responder patients randomised to Etanercept, Tocilizumab or Rituximab. - STRAP-EU
• Date of first enrolment: 09/08/2018
• Target sample size: 207
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-004079-30
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, Italy, Portugal, Spain

Contacts

• Name: Coordenadora Técnica
• Affiliation: Hospital de Santa Maria

• Name: Coordenadora Técnica
• Affiliation: Hospital de Santa Maria

Key inclusion & exclusion criteria

Inclusion criteria:
Patients will be recruited with active Rheumatoid Arthritis:
1. 2010 ACR / EULAR classification criteria for a diagnosis of Rheumatoid Arthritis *
2. Patients with DMARD failure and eligible for anti-TNF therapy according to UK NICE guidelines **
3. Patients must have a 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 or over
6. Patients must be capable of giving informed consent and the consent must be obtained prior to any screening procedures
7. Willingness and ability to comply with scheduled visits, treatment plans and laboratory tests and other study procedures
* The ACR/EULAR classification for a diagnosis of RA could have been at any time in the patient's disease history; the score does not need to be 6
or more at screening.
**According to the UK National Institute for Health and Care Excellence (NICE) guidelines, the TNF-a inhibitors are recommended as options for
the treatment of adults who have both of the following characteristics:
1) Disease is severe, that is, a disease activity score (DAS28) greater than 5.1
2) Disease has not responded to intensive therapy with a combination of conventional disease modifying antirheumatic drugs (DMARDs).
Current NICE guidelines available at the following link:
http://www.nice.org.uk/guidance/ta375.

Are the trial subjects under 18? no
Number of subjects for this age range: 0
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 10
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 5

Exclusion criteria:
Patients will be excluded if they have any contraindication to Etanercept,
Rituximab or Tocilizumab therapy:
1. Women who are pregnant or breast-feeding
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 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 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 anti-coagulants. Oral anti-platelet
agents are permitted.
24. Patients currently recruited to other clinical trials.
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.

The PI reserves the right to exclude patients at his centre, if they have concerns regarding compliance with the study procedures or any other aspect of the study eligibility not necessarily limited to the above exclusion criteria.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Musculoskeletal Diseases [C05]

Rheumatoid Arthritis
MedDRA version: 20.0 Level: LLT Classification code 10003268 Term: Arthritis rheumatoid System Organ Class: 100000004859

Intervention(s)

Trade Name: MabThera
Product Name: MabThera
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Rituximab
Other descriptive name: Rituximab
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 10-

Trade Name: RoActmera
Product Name: RoActmera
Pharmaceutical Form: Solution for injection
INN or Proposed INN: Tocilizumab
Other descriptive name: TOCILIZUMAB SC
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 162-

Trade Name: Enbrel
Product Name: Enbrel
Pharmaceutical Form: Solution for injection in pre-filled pen
INN or Proposed INN: ETANERCEPT
CAS Number: 185243-69-0
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-

Primary Outcome(s)

Primary end point(s): The primary end point will assess the difference in the ACR 20 response between Rituximab and other treatments (Tocilizumab and Etanercept therapy treated together for analysis) at 16 weeks from baseline in the B-cell poor pathotype sub-group.

Timepoint(s) of evaluation of this end point: 16 weeks

Main Objective: The main aim of this project is to test the hypothesis that the presence or absence of specific synovial cellular and molecular signatures (B cells and B cell-associated signatures), assessed following a synovial tissue biopsy, will enrich for response / non-response to the B cell depleting anti-CD20 monoclonal antibody (mAb) Rituximab.

The primary aim of this project is to show that in patients failing DMARD therapy, with a B cell poor synovial pathotype, Rituximab is inferior to Tocilizumab and Etanercept (treated together for analysis) therapy.

Secondary Objective: In addition to the primary objective previously stated, we will address the following questions:
1) Can a diagnostic synovial biopsy showing a B-cell “rich/poor pathotype” define specific disease responsive/resistant subsets for patient stratification and help rationalize biologic drug choice?
2) Is clinical response associated with inhibition of B cell-linked pathways within the synovium and dependent on local B cell lineage depletion?
3) Is survival of auto-reactive B cells within “protected” synovial niches responsible for B-cell joint re-population and disease resistance-relapse?

For the B-cell-rich synovial pathotypes, we aim to compare the treatment effects of Rituximab to the other two treatment options (Tocilizumab and Etanercept, treated together for analysis). Finally, we aim to examine the interaction between treatments and B-cell status (rich and poor).

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: 48 weeks.

Secondary end point(s): 1. Patients deemed treatment failures at 16 weeks, will be switched to the other therapeutic option. Such patients will be considered a new patient starting at week 0 with treatment response assessed again at 16 weeks for ACR20 response.
2. For the B-cell-rich synovial pathotype sub-group, we aim to compare the treatment effects of Rituximab to the other two treatment options (Tocilizumab and Etanercept, treated together for analysis)
3. To examine the interaction between treatments and B-cell status (rich and poor).

Secondary ID(s)

2017-004079-30-BE

STRAP_ReDA_012206

Source(s) of Monetary Support

Medical Research Council

Arthritis Research UK

Ethics review

Status: Approved
Approval date: 06/08/2018
Contact:

Results

• Results available: Yes
• Date Posted: 16/12/2021
• Date Completed: 23/01/2021
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-004079-30/results