Stratification of biologic therapies for rheumatoid arthritis by pathobiology
| ISRCTN | ISRCTN10618686 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN10618686 |
| EudraCT/CTIS number | 2014-003529-16 |
| Secondary identifying numbers | 18178 |
- Submission date
- 05/11/2015
- Registration date
- 05/11/2015
- Last edited
- 12/08/2022
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Musculoskeletal Diseases
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 antiTNFa 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 2015 to January 2021 (updated 11/12/2020, previously: December 2020)
Who is funding the study?
1. Medical Research Council (UK)
2. Arthritis Research UK
Who is the main contact?
Jo Peel
Contact information
Public
EMR Clinical Trials Manager
Centre for Experimental Medicine & Rheumatology
William Harvey Research Institute
Barts and The London School of Medicine & Dentistry
2nd Floor, John Vane Science Centre
Queen Mary University of London
Charterhouse Square
London
EC1M 6BQ
United Kingdom
Study information
| Study design | Three-arm randomised parallel trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised parallel trial |
| Study setting(s) | Other |
| 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 | Stratification of Biologic Therapies for Rheumatoid Arthritis by Pathobiology (STRAP): A randomised, open-labelled biopsy driven stratification trial in DMARD inadequate responder patients randomised to etanercept, tocilizumab or rituximab |
| Study acronym | STRAP |
| Study hypothesis | In patients failing DMARD therapy, with a B cell poor synovial pathotype, Rituximab is inferior to Tocilizumab and Etanercept therapy. |
| Ethics approval(s) | Wales Research Ethics Committee, 16/12/2014, ref: 314/WA/1209 |
| Condition | Rheumatoid arthritis |
| Intervention | Participants are randomly allocated to one of three groups: Group 1: Participants receive 50mg etanercept administered subcutaneously once weekly for the study duration. Group 2: Participants receive 1000mg rituximab by iv infusion on days 1 and 15. This cycle is repeated every 24 weeks. Group 3: Participants receive 162 mg tocilizumab administered subcutaneously once weekly for the study duration. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | 1. Etanercept 2. Rituximab 3. Tocilizumab |
| Primary outcome measure | Treatment efficacy is determined by calculating the number of patients with an ACR 20 response at 16 weeks. |
| Secondary outcome measures | Not provided at time of registration |
| Overall study start date | 15/06/2015 |
| Overall study end date | 09/01/2021 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | Planned Sample Size: 207; UK Sample Size: 207 |
| Total final enrolment | 187 |
| Participant inclusion criteria | Current inclusion criteria as of 08/09/2017: 1. 2010 ACR / EULAR Rheumatoid Arthritis classification criteria for a diagnosis of RA * 2. Patient with DMARD failure eligible for anti-TNF-α therapy as per 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 and over 6. Patients must be capable of giving informed consent and the consent must be obtained prior to any screening 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. ** Current NICE guidelines available at the following link: http://www.nice.org.uk/guidance/ta375. Previous inclusion criteria: 1. 2010 ACR / EULAR Rheumatoid Arthritis classification criteria for a diagnosis of RA 2. Patient with DMARD failure eligible for antiTNFa therapy as per UK NICE guidelines (those who have both of the following): 2.1. Active RA as measured by DAS28>5.1 2.2. Have undergone trials of two DMARDs, including MTX (unless contraindicated). A trial of a DMARD is defined as being normally of 6 months, with 2 months at standard dose, unless significant toxicity has limited the dose or duration of treatment. 3. Over 18 years of age 4. Patients must be capable of giving informed consent and the consent must be obtained prior to any screening procedures |
| Participant exclusion criteria | Current exclusion criteria as of 08/09/2017: 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 26. For patients potentially eligible for MRI any of the following conditions: Pacemakers and/or other non-removable metal objects, diagnosis of claustrophobia or a history of anxiety or claustrophobia during previous MRI scanning, abnormal creatinine/protein ratio at screening that precludes administration of MRI contrast medium (e.g. gadolinium) in accordance with local guidelines , previous allergic reactions to MRI contrast medium (e.g. gadolinium) The PI reserves the right to exclude patients at their 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. Previous exclusion criteria: 1. Women who are pregnant or breastfeeding 2. Women of childbearing potential or males whose partners are women of childbearing potential, unwilling to use effective contraception during the study (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 inflammatory joint disease or autoimmune disease other than RA (if secondary to RA, then the patient is still eligible) 4. Prior exposure to Rituximab, any antiTNF, Tocilizumab, or any 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. Intraarticular or parenteral corticosteroids ≤ 4 weeks prior to baseline synovial biopsy 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 |
| Recruitment start date | 15/06/2015 |
| Recruitment end date | 31/05/2019 |
Locations
Countries of recruitment
- England
- Scotland
- United Kingdom
- Wales
Study participating centres
London
E1 4DG
United Kingdom
Heath Park Way
Cardiff
CF14 4XW
United Kingdom
Mindelsohn Way
Birmingham
B15 2TH
United Kingdom
235 Euston Road
Bloomsbury
London
NW1 2BU
United Kingdom
Freeman Road
High Heaton
Newcastle upon Tyne
NE7 7DN
United Kingdom
84 Castle Street
Glasgow
G4 0SF
United Kingdom
Windmill Road
Oxford
OX3 7LD
United Kingdom
Southampton
SO16 6YD
United Kingdom
Chapeltown Road
Leeds
LS7 4SA
United Kingdom
Oxford Road
Manchester
M13 9WL
United Kingdom
Southend
SS2 6GD
United Kingdom
Nethermayne
Basildon
SS16 5NL
United Kingdom
London
SE1 9RT
United Kingdom
Homerton Row
Hackney
Homerton
E9 6SR
United Kingdom
Hills Road
Cambridge
Cambridge
CB2 0QQ
United Kingdom
Pond Street
Hampstead
London
NW3 2QG
United Kingdom
Denmark Hill
London
SE5 9RS
United Kingdom
Wolverhampton Road
Heath Town
Wolverhampton
WV10 0QP
United Kingdom
Brunswick Road
Cannock
WS11 5XY
United Kingdom
Edinburgh
EH4 2XU
United Kingdom
Sponsor information
University/education
Mile End Road
London
E1 4NS
England
United Kingdom
"ROR" |
https://ror.org/026zzn846 |
|---|
Funders
Funder type
Research council
Government organisation / National government
- Alternative name(s)
- Medical Research Council (United Kingdom), UK Medical Research Council, MRC
- Location
- United Kingdom
Private sector organisation / Other non-profit organizations
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 30/06/2022 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Stored in non-publicly available repository |
| Publication and dissemination plan | Not provided at time of registration |
| IPD sharing plan | 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. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Basic results | 16/12/2021 | 10/02/2022 | No | No | |
| Protocol (other) | 28/02/2022 | 12/08/2022 | No | No | |
| HRA research summary | 28/06/2023 | No | No |
Editorial Notes
12/08/2022: Protocol file uploaded.
10/02/2022: The results of this trial posted to EudraCT have been added.
13/12/2021: The intention to publish date was changed from 21/12/2021 to 30/06/2022.
11/12/2020: The following changes were made to the trial record:
1. The overall end date was changed from 21/12/2020 to 09/01/2021.
2. The plain English summary was updated to reflect these changes.
24/07/2019: The total final enrolment was added.
02/04/2019: The condition has been changed from "Topic: Musculoskeletal disorders; Subtopic: Musculoskeletal (all Subtopics); Disease: Musculoskeletal" to "Rheumatoid arthritis" following a request from the NIHR.
04/02/2019: IPD sharing statement added.
12/12/2018: The following changes were made to the trial record:
1. The recruitment end date was changed from 30/11/2018 to 31/05/2019.
2. The overall trial end date was changed from 30/11/2019 to 21/12/2020.
3. The intention to publish date was added.
4. Western General Hospital was added as a trial participating centre.
12/09/2017: Sponsor has been updated from "Barts Health NHS Trust,Peri-operative medicine research group, Adult Critical Care Research Office, Level 4, The Royal London Hospital " to "Queen Mary University of London, Mile End Rd, London E1 4NS". Funder name has been corrected to Arthritis Research UK. Plain English summary has been updated. "Centre for Experimental Cancer Medicine" has been removed as a trial participating centre.
08/09/2017: Overall trial end date has been changed from 15/06/2018 to 30/11/2019. Laura White's contact information has been updated. Recruitment end date has been changed from 15/06/2018 to 30/11/2018. Inclusion and exclusion criteria has been updated. Trial participating centres have been added. Trial link has been added. Sponsor has been updated from "Barts Health NHS Trust" to "Queen Mary University of London". ARUK has been added as an additional funder.
15/03/2016: Verified study information with principal investigator.
