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The William Harvey Research Institute - Barts and The London

Experimental Medicine & Rheumatology

Current clinical studies and trials biobanked at EMR

Pathobiology of Early Arthritis Cohort (PEAC)

[NIHR CRN Portfolio Study ID: 5339]

Status: This study is currently open to recruitment.

The MRC funded Pathobiology of Early Arthritis Cohort (PEAC) was established through the contribution of a consortium of 5 independent, national centres of excellence, patient recruitment continues at Barts the lead site. This project has created an extensively phenotyped cohort of early inflammatory arthritis patients with linked, detailed pathobiological data.

The development of a prospective early arthritis cohort with high quality clinical and imaging data (state-of-the-art 3D/4D ultrasound-US / power-Doppler-PDU imaging) together with a comprehensive collection of biological samples (blood, urine and synovial tissue) is providing a unique resource to search for early predictors of disease evolution as well as to enable early proof of concept/mechanistic studies with stratified entry according to the imaging and immunological profile. This cohort has provided an ideal platform for novel clinical trials. 

PEAC Bio & Data-Resource Metrics

PEAC is a unique deeply phenotyped biomedical repository with current recruitment at 370 early arthritis patients (<than 12 months symptoms duration, DMARD naïve), unparalleled worldwide 2-time point US-guided synovial biopsies (time 0/baseline and 6 months) and matched serum/plasma, DNA, RNA, cryopreserved peripheral blood mononuclear cells (PBMCs) linked to 3-monthly stringent clinical outcome measures including US synovitis & PDU score. Approximately 1800 visits have been performed, with 362 baseline and 287 follow-up synovial biopsies collected so far. Blood samples and urine have been collected for 616 time-points. 

Further information

http://www.peac-mrc.mds.qmul.ac.uk

R4-RA Clinical Trial

“A randomised, open labelled study in anti-TNFa inadequate responders to investigate the mechanisms for Response - Resistance to Rituximab versus Tocilizumab in RA” 

[ISRCTN97443826]
[EudraCT: 2012-002535-28]
[NIHR CRN Portfolio Study ID: 14524]
Status: Not recruiting 

Evidence from PEAC (see above), in which synovial biopsies have been taken from patients with early arthritis, indicate that there are at least three distinct histo-morphological subtypes. These are described as fibroblast (pauci-immune), lymphoid (B-cell rich, with or without germinal centre formation) and Myeloid (rich in monocytes but poor in B cells), which correspond to different transcriptomic signatures.

With these subsets in mind, the overarching hypothesis of this study is whether a diagnostic synovial biopsy showing a “B-cell rich / B- cell poor” pathotype can predict response and define certain disease responsive / resistance subsets for patients stratification and help to rationalize drug choice.

The purpose of this study is to test the hypothesis that the presence or absence of specific synovial and molecular signatures (B-cells and B-cell associated signatures), assessed through obtaining tissue from a synovial biopsy, will enrich for response / non-response to Rituximab, and B-cell depleting anti-CD20 monoclonal antibody.  Patients are eligible if they have failed anti-TNF therapy and will undergo a synovial biopsy baseline and then be randomised to receive Rituximab or Tocilizumab.

This is a multi-site, international clinical trial, 12 UK and 8 EU sites recruited 164 patients between February 2013 and November 2017. Patient follow-up is now complete and the results of this trial, the first biopsy driven RCT in RA, will be published in January 2020.

This study is being funded by the National Institute of Health Research Efficacy and Mechanism Evaluation program (NIHR EME).

R4-RA Bio & Data-Resource Metrics

In R4-RA, following a synovial biopsy, anti-TNF-ir patients are randomised to Rituximab or Tocilizumab. In addition to the US-guided synovial biopsy at baseline R4RA collects a second biopsy at primary end-point in 1/3 of patients as well as matched serum/plasma, DNA, RNA, cryopreserved peripheral blood mononuclear cells (PBMCs) 3 monthly, linked to stringent clinical outcome measures including US synovitis & PDU scores. 164 patients have been recruited and randomised to the R4RA trial, 2427 visits performed, with 164 baseline and 74 follow-up synovial biopsies collected. During the trial blood samples were collected for 1394 time-points, and 790 ultrasounds and 395 X-rays were collected and centrally analysed (analysis ongoing).

Further information

http://www.r4ra-nihr.whri.qmul.ac.uk

STRAP & STRAP-EU Clinical Trials

[ISRCTN: 10618686]
[EudraCT: 2014-003529-16] / [EudraCT: 2017-004079-30]
[NIHR CRN Portfolio Study ID: 18178] 
Status: Closed to recruitment 

“Stratification of Therapy for RA by Pathobiology”

Maximising Therapeutic Utility in Rheumatoid Arthritis (MATURA) is an ambitious research project jointly funded by MRC and Versus Arthritis to identify and test biomarkers predictive of response to therapy in rheumatoid arthritis (RA), thereby allowing the stratification of patients into groups according to the therapies that are most likely to be effective. The project comprises two work-streams: Workstream 1 is managed by Prof Costantino Pitzalis the Centre for Experimental Medicine and Rheumatology, and Workstream 2 is managed at The University of Manchester.

An important component of the Workstream 1 is the STRAP Trial, a randomised control trial which aims to test the utility of synovial histomorphology and B cell number together with specific molecular signatures as potential biomarkers to guide therapeutic decisions in patients failing DMARD therapy to improve on current response rates and identify patients more likely to respond.  Patients are randomised to receive Rituximab, Tocilizumab or Anti-TNF therapy following a baseline synovial biopsy.

This trial closed to recruitment in May 2019, there are 21 UK sites and 6 European centres, and a total of 226 patients were recruited. The results will be available in 2020.

STRAP/STRAP-EU Bio & Data-Resource Metrics

Following a synovial biopsy, DMARD-inadequate (ir) patients are randomised to anti-TNF, Rituximab (RTX) or Tocilizumab (TCZ). In addition to the US-guided synovial biopsy at baseline STRAP collects a second biopsy at primary end-point in 1/3 of patients as well as matched serum/plasma, DNA, RNA, cryopreserved peripheral blood mononuclear cells (PBMCs) 3 monthly, linked to stringent clinical outcome measures including US synovitis & PDU scores.

This trial closed to recruitment in May 2019, there are 21 UK sites and 6 European centres, and a total of 226 patients were recruited. The results will be available in 2020.

Further information

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

Therapist

ISRCTN reference: ISRCTN 18262002
[NIHR CRN Portfolio Study ID: 18893] 

Preliminary data suggest that up-regulation of IL-17 and the ThH17 pathway occurs in patients with rheumatoid arthritis (RA) who have been treated with anti-tumor necrosis factor- alpha (anti-TNFα) therapy but demonstrate an incomplete clinical response. A deeper understanding of this is required in order to determine whether IL-17 or the ThH17 pathway is a valid target for intervention in this population to improve response outcome.

The main aim of this study is to examine the relationship of IL-17 expression within blood and synovium of subjects with RA as relates to clinical response or non-responses to anti-TNF therapy.  Clinical assessments, ultrasound assessments, synovial tissue bio-markers obtained from the ultrasound-guided synovial biopsy and study specific blood sampling are being used to evaluate the pattern of activity shown in the Th17 pathway. Recruitment of 57 patients took place in 10 NHS Trusts, results are now being analysed and will be published in 2019. 

Therapist Bio & Data-Resource Metrics

Biological samples (tissue & fluids) were collected at five timepoints over a 24 week follow-up period and are linked to stringent clinical outcome measures. Recruitment status for this study is 57 patients, with 27 baseline and 20 follow-up synovial tissue biopsies collected.  Blood samples have been collected for 280 time-points and include wholeblood, serum, peripheral blood mononuclear cells (PBMCs), and DNA. In addition, urine was collected at four timepoints. 

Further information

http://www.trp-nocri.whri.qmul.ac.uk 

Investigation of the Role of Microbiota in Arthritic Inflammation in DMARD-naïve Early Arthritis patients (IRMA)

[NIHR CRN Portfolio Study ID: 31852]

Status: This trial is recruiting patients at Barts.

There are many reports that strongly suggest that certain bacteria living in the mouth and in the intestines of RA patients may cause and/or worsen RA. The purpose of the observational IRMA study is to identify RA patients who also have periodontitis (inflammation in their gums caused by bacteria) and compare them to healthy individuals. We will compare the presence of bacteria in the mouth with the RA disease activity and severity and investigate whether the presence of periodontitis and certain bacteria are related to the inflammation in joints and severity of RA disease. The long term goal is to determine if treating periodontitis, caused by certain bacteria, may help to improve the outcomes for patients with RA.

IRMA Bio & Data-Resource Metrics

Biological samples (tissue & fluids) are collected at three timepoints over a 24 week follow-up period and are linked to stringent clinical outcome measures. Recruitment status for this study is currently 12 patients, with 6 baseline synovial tissue biopsies collected.  Blood samples have been collected for 27 time-points and include wholeblood, serum, plasma and peripheral blood mononuclear cells (PBMCs), and DNA. In addition, stool samples and oral samples (saliva, GCF and plaque) are also collected.

Further information

Investigation of the Role of Microbiota in Arthritic Inflammation in DMARD-naïv

Psoriatic Arthritis Pathobiology and its Relationship with Clinical Disease Activity (PSABRE)

This study focus is exploring the relationship between synovial and skin histological, molecular and gene profiles, and the evolution of clinical disease characteristics, in patients with psoriatic arthritis who have failed standard non-biologic therapy and are eligible for biologic treatment. We hypothesise that specific biomarkers exist which predict or correlate to the course of an individual’s disease. This study primarily aims to determine if levels of IL-23 in psoriatic synovium or skin correlate with clinical disease activity. Other cellular and molecular biomarkers will also be explored as secondary objectives. We aim to identify one or a panel of biomarkers that can facilitate patient stratification for disease severity and likely response to treatment. This study recruited patients at Barts.

PSABRE Bio & Data-Resource Metrics

Biological samples (tissue & fluids) are collected at four timepoints over a 48 week follow-up period and are linked to stringent clinical outcome measures. Recruitment status for this study is 29 patients, with 29 baseline and 15 follow-up synovial tissue biopsies collected, along with paired skin biopsies for 18 patients (18 baseline and 11 follow-up skin biopsies).  Blood samples have been collected for 83 time-points and include wholeblood (RNA), serum, plasma, peripheral blood mononuclear cells (PBMCs) and buffy coat (DNA).

Phosphoproteomic profiling of Tofacitinib response in Rheumatoid Arthritis (Phospho-Tof-RA)

Status: The study is currently open to recruitment at Barts Health with a recruitment target of 20 patients.

The aim of the study is to investigate the hypothesis that the cytokine and phosphoproteomic profiles of RA synovial tissue determine response to Janus kinase (JAK) inhibition with tofacitinib and thus whether pre-treatment examination of joint tissue can help select patients most likely to respond to tofacitinib. Patients will then undergo a baseline US-guided synovial biopsy of a clinically active joint and will then commence standard therapy of tofacitinib. This study aims to recruit 20-30 patients.

Phospho-Tof-RA Bio & Data-Resource Metrics

Biological sample collection will include synovial biopsy tissue and blood at three timepoints over a 12 week follow-up period (biopsy tissue to be collected at baseline & week 12 follow-up, blood to be collected at all three timepoints) and will be linked to stringent clinical outcome measures. Blood samples to be collected include serum, plasma, peripheral blood mononuclear cells (PBMCs), RNA and DNA.

 

 

Rituximab in patients with primary Sjögren's syndrome (TRACTISS)

ISRCTN reference: ISRCTN 65360827

A multi-centre, randomised double blind placebo controlled phase III clinical trial of anti-B-cell therapy in patients with primary Sjögren's syndrome with fatigue, oral dryness. The aim of the study is to assess the extent to which rituximab improves symptoms of fatigue and oral dryness in patients with primary Sjögren’s syndrome with a 30% reduction at 48 weeks from baseline in either oral dryness or fatigue measured using Visual Analogue Scales (VAS – Range 0-100mm) will be the primary endpoint. Patients were randomised on a 1:1 basis to receive either rituximab or placebo infusion. Each patient recruited to the study will have an approximate 48 weeks of intervention/follow up examination. Males and female were recruited between 18 and 80 years of age with an AECG diagnosis of Primary Sjögren’s Syndrome.

TRACTISS Bio & Data-Resource Metrics

Biological samples (tissue & fluids) were collected at five timepoints over a 48 week follow-up period and are linked to clinical outcome measures. Recruitment status for this study is 136 patients, with 27 baseline and 17 follow-up salivary gland biopsies collected.  Blood samples have been collected for 680 time-points and include tissue (salivary gland), saliva, serum, peripheral blood mononuclear cells (PBMCs), RNA and DNA. 

Further information

http://www.isrctn.com/ISRCTN65360827 

Optimal management of RA patients who require Biologic Therapy (ORBIT)

[EudraCT: 2009-011268-13]

A multi-centre open label randomised controlled trial comparing rituximab with anti-TNF therapy in biologic naïve patients over 12 months. The primary purpose of the trial is to identify whether rituximab therapy or anti-TNF therapy is more effective in improving the clinical symptoms, signs, physical function and health-related quality of life of ‘biologic-naïve’ patients with active rheumatoid arthritis. 

ORBIT Bio & Data-Resource Metrics

Biological samples (synovial tissue & blood) were collected at three timepoints over a 12 month follow-up period and are linked to clinical outcome measures including DAS28 (primary outcome measure), VAS pain score and HAQ score. Recruitment status for this study is 277 patients, with 18 baseline synovial tissue biopsies collected.  Blood samples have been collected at approximately 830 time-points with plasma, serum, RNA, DNA and peripheral blood mononuclear cells (PBMCs) biobanked at EMR. 

Further information

https://clinicaltrials.gov/ct2/show/NCT01021735

Functional consequences of disease susceptibility in Systemic Lupus Erythematosus (BHSLE)

[REC study No. 07/H0718/49] 

Genetic studies define genetic factors that predispose to disease; however they do not define the mechanism by which the genes affect the disease progress. This study is aimed at exploring the mechanisms by which causal genetic factors influence disease development. DNA and clinical information are used to look for similarities and differences between people with SLE and those unaffected by the disease. These data can be used to identify genetic differences that are more common in SLE patients and then ask how these genetic factors affect the immune system and how they influence the nature and severity of the disease. Current recruitment status for this study is 220 patients.

BHSLE Bio & Data-Resource Metrics

Blood samples have been collected for 220 patients along with clinical data. Sample types collected and biobanked include plasma, DNA and peripheral blood mononuclear cells (PBMCs).

Mechanisms of joint damage and repair in musculoskeletal diseases (Research Biobank - RBB)

[LREC study No. 07/Q0605/29]

The purpose of the study is to understand the mechanisms which lead to joint inflammation, destruction and repair in arthritis. By understanding such mechanisms it is hoped we shall be able to intervene therapeutically both by preventing damage and, when damage has already occurred, by repairing joint tissues. The pathogenetic mechanisms responsible for joint destruction in various form or arthropathies involve inflammation/damage of the various tissue components that constitute a normal joint. These include the lining of the joint (synovium) the articular cartilage, the subchondral bone and the capsule. Direct investigations in these tissues (primary sites of the pathogenetic process) are likely to allow better understanding of the mechanisms underlying joint destruction and potentially lead to better therapies.

Patients undergoing joint arthroplasty who have Rheumatoid arthritis (RA) and/or Osteoarthritis (OA) are currently recruited to this study. Patients are currently recruited at Newham University Hospital (Barts Health NHS Trust).

RBB Bio & Data-Resource Metrics

This study has been on-going since 2008 and to date (up to 1st April 2019) approximately 800 patients have been recruited. Biological samples that have been collected predominantly comprise of synovial tissue and cartilage, with some blood components and synovial fluid also biobanked from some patients.

Research Tissue Bank (RTB)

[IRAS Project ID 181156]

With a current study duration of 10 years (August 2017-2027) the objective of the EMR RTB is to facilitate ongoing sample and data collection to progress research in patient stratification in rheumatic conditions, biomarker research, imaging, genetics, pathology and physiology of the musculoskeletal system as well as in the physiology of joint tissues. This includes generic ethical approval for a range of potential prospective research without a need for individual project-based ethical approval.

Research will take place internally within EMR, and will also facilitate collaborations with academic and industry partners where tissue and/or data will be released following a formal assessment and approval process. The EMR Biobank will facilitate a broad program of research to further the understanding of the physiology and pathology of joint tissues for the development of new treatments and develop strategies and methods to identify disease pathotypes through less invasive methods with potential for a stratified medicine approach.

The tissues donated to the EMR RTB may include: Synovial tissue, Cartilage, Bone, Whole blood and isolated blood cell subsets, Urine, Synovial Fluid, DNA, RNA, Saliva, Skin, Hair. Salivary glands samples (surplus from diagnostic labial or major SG biopsies) Tonsil/lymph node/spleen biopsy/tissue, kidney biopsies and other solid tissue related to disease or Surplus tissue from intervention and/or diagnostic procedures e.g. tonsils (tonsillectomy) bone marrow, peripheral nerves and brain biopsies. Samples from healthy donors can also be donated to the EMR RTB.

RTB Bio & Data-Resource Metrics

Since starting recruitment in August 2017, biological samples have been collected/biobanked (and utilised for research) from 125 recruited patients and 39 healthy donors (up to 1st April 2019). Sample types collected and biobanked include plasma, DNA, RNA, peripheral blood mononuclear cells (PBMCs) and cell-free synovial fluid.

Further information