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…
ID
Source
Brief title
Condition
- Autoimmune disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Patients will be assessed for disease activity using the CDAI (Clinical disease
activity index), DAS 28 (CRP/ESR), Health Assessment Questionnaire (HAQ), Short
Form 36 and FACIT Fatigue questionnaire as described below.
Primary Endpoint Efficacy Analysis
Treatment response assessed using the Clinical Disease Activity Index (CDAI) at
16 weeks. Section 4.11, defines treatment response/failure criteria.
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 primary response.
The primary analysis will focus on whether there is a superiority of
Tocilizumab over Rituximab in histologically defined *B cell poor* patients.
Secondary outcome
Secondary Endpoint Efficacy Analysis
1. For the B-cell rich synovial pathotypes, we aim to show non-inferiority of
Rituximab compared to Tocilizumab.
2. Germinal Centre pathotypes will constitute an exploratory component to the
trial as insufficient power will be generated to show a significant difference
in clinical response between each treatment.
3. Area under the curve (AUC) of mean improvement in DAS28 over time between 0,
16 and 48 weeks.
4. Percentage of patients with low disease activity (DAS28 < 3.2) at 12, 24,
36, 48, 96 weeks
5. Percentage of patients in remission (DAS28 < 2.6) at 16, 48 and 96 weeks
6. Percentage of patients with ACR 20, 50 and 70 response rates at 16, 48 and
96 weeks
7. Percentage of patients with a low clinical disease activity index score
(CDAI)
8. Mean % change in DAS28 between baseline and 16, 48 and 96 weeks
9. Mean % change in clinical disease activity index score (CDAI) between
baseline and 16, 48 and 96 weeks
10. Mean change in HAQ score between baseline and 16, 48 and 96 weeks
11. Change in Fatigue score between baseline and 16, 48 and 96 weeks
12. Serious adverse events over 12 months; the rate of serious adverse events
in the 16 week period following a switch from one technology to the other will
be compared
13. Mean change in erosive score by the van der Heijde/Sharp scoring system at
24 and 48 weeks.
14. Reduction in US 2D grey scale and power Doppler signal at 16, 48 and 96
weeks.
6.3 Exploratory end point
1. The effect of synovial immuno-histology on drug response rates and disease
outcome.
Background summary
Rheumatoid arthritis (RA) is one of the most important chronic inflammatory
disorders in the UK. The diagnosis of RA leads to considerable morbidity and an
increased mortality1, 2. According to the National Audit Office (2009 -
http://www.nao.org.uk/) there are 26,000 new cases of RA each year with 582,000
prevalent cases in England. 45% of these people are of working age and within 1
year of diagnosis 30% are unemployed. RA is characterized by a symmetrical,
erosive polyarthritis, resulting from chronic synovitis, and the presence of
circulating autoantibodies such as rheumatoid factor (RF) and anti-cyclic
citrullinated peptide (ACPA), strongly suggesting an autoimmune pathogenesis.
Although biological therapies have revolutionized the treatment of RA, a
sizable group of patients (30-40%) are *resistant*3, 4.
Recently there has been a greater understanding of the importance of B cells in
driving the inflammatory processes involved in RA. B cells may drive synovial
inflammation by production of autoantibodies, acting as effective
antigen-presenting cells and may promote synovial inflammation by producing
pro-inflammatory cytokines5. Thus, depletion of B cells could interfere with
important mechanisms involved in the perpetuation of the inflammatory response
in RA. Rituximab is a chimeric monoclonal antibody directed against the CD20
antigen expressed by B cells, has been approved by the US Food and Drug
Administration and by the European Medicines Agency in Europe for the treatment
of patients with RA who have had an inadequate response (ir) or were intolerant
to tumour necrosis factor alpha (TNF) inhibitors. Current evidence on the
efficacy of Rituximab relates primarily to rheumatoid factor positive patients,
although even within this population clinical responses are heterogeneous with
only 60% achieving an ACR20 response at 6 months6, 7. Recent synovial-based
studies suggest that the heterogeneous clinical response may in part be
explained by variable B cell depletion within the synovial tissue rather than
simply in the peripheral blood8-10. A growing body of evidence would suggest
that a more rational approach to Rituximab therapy and a stratified approach to
patients may be required11-13. Despite this, NICE guidelines have recommended
that all patients with inadequate response to anti-TNF therapy should receive
Rituximab (NICE, http://www.nice.org.uk/CG79). A *blind* implementation of
these guidelines will result in many patients, unlikely to respond, receiving a
B Cell depleting agent with the associated risks with none of the potential
benefits. A tailored approach to this intervention with patient stratification
is required to better identify both responders and non-responders. In this
proposed study we will test the hypothesis that the presence or absence of B
cells and B cell-associated signatures within the joint will enrich for
response/non-response to the B cell depleting agent Rituximab. We also
hypothesize that in patients with a B-cell poor synovial biopsy, alternative
biologics such as the IL-6 receptor blocker Tocilizumab will be more effective.
This study is considered a type A clinical study according to MHRA risk.
Study 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. In addition, we will examine if clinical response is
associated with inhibition of B cell-linked pathways within the synovium and
dependent on local B cell lineage depletion and whether survival of
auto-reactive B cells within *protected* synovial niches are responsible for
B-cell joint re-population and disease resistance-relapse?
Study design
This is a multi-site, multi-country, open-label randomised controlled clinical
trial. Patients recruited to this study will undergo a synovial biopsy prior to
randomisation. Possible synovial biopsy sites are the knee, elbow, shoulder,
wrist, ankle, MCP, PIP, and MTP joints.
Patients will subsequently be stratified in to 3 groups (B Cell Poor, B Cell
Rich, Germinal Centres (GC) Rich) according to the following B-cell score prior
to therapeutic intervention. All participating site staff will be blinded to
the pathotype (B Cell Poor, B Cell Rich, Germinal Centre). This result will be
recorded centrally prior to randomisation of the patient.
Intervention
Rituximab:
Rituximab is a genetically engineered chimeric mouse/human monoclonal antibody
representing a glycosylated immunoglobulin with human IgG1 constant regions and
murine light-chain and heavy-chain variable region sequences.
OR Tocilizumab:
Tocilizumab humanised IgG1 monoclonal antibody against the human interleukin-6
(IL-6) receptor produced in Chinese hamster ovary (CHO) cells by recombinant
DNA technology
Biopsy:
Patients will receive a synovial biopsy between 1 to 3 weeks prior to their
baseline visit.
Study burden and risks
In this study patients will be randomised to receive either Rituximab or
Tocilizumab. No placebo arm has been included, as withholding an approved
potentially beneficial therapy would not be comparable with good standards of
clinical practice. Tocilizumab has been approved for the use in patients with
moderate to severe RA Thus, there will be no greater risk from administered
pharmacotherapy during this study than would be expected in routine clinical
care.
All patients will have arthroscopic synovial biopsies which would not
necessarily be considered routine clinical care and thus the main risks to
patients enrolled would be associated with this interventional procedure. The
procedure itself has excellent safety and tolerability and can be applied to
both large and small joints in most patients. Arthroscopic biopsies, whilst
being technically more complicated and requiring theatre time, have been
extensively validated with respect to tissue quality in therapeutic
intervention studies.
Walden Street 5
London E1 2EF
NL
Walden Street 5
London E1 2EF
NL
Listed location countries
Age
Inclusion criteria
Patients will be recruited with active RA:
1. Patients who have failed anti-TNF therapy (inadequate responders * ir). Note: this includes patients that have failed anti-TNF therapy because of reactions.
2. Who are eligible for Rituximab/TCZ therapy according the Dutch guidelines*
3. Patients should be receiving a stable dose Methotrexate for at least 4 weeks prior to biopsy visit.
4. 2010 ACR / EULAR Rheumatoid Arthritis classification criteria for a diagnosis of Rheumatoid Arthritis.
5. Over 18 years of age
Exclusion criteria
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 effective contraception during the study and for at least 12 months after stopping study treatment.
3. History of or current primary inflammatory joint disease or primary autoimmune disease other than RA.
4. Prior exposure to Rituximab or Tocilizumab for the 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 biopsy visit (Visit 2).
7. Oral prednisolone more than 10mg per day or equivalent * 4 weeks prior to biopsy
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-002535-28-NL |
| ClinicalTrials.gov | NCT??volgt |
| CCMO | NL56487.058.16 |