The primary objective is to study changes in synovial inflammation in serial biopsy samples following the administration of abatacept in patients with active rheumatoid arthritis.The secondary objectives of this study are to (I) assess clinical…
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Source
Brief title
Condition
- Autoimmune disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Changes in synovial inflammation in serial biopsy samples following the
administration of abatacept in patients with active rheumatoid arthritis.
Secondary outcome
clinical response
cellular responses of synovial explants to inflammatory stimuli, and/or
antagonists, before and after treatment with abatacept
synovial biomarkers predictive of the clinical response to abatacept treatment
the changes in phenotypes of peripheral blood mononuclear cells (PBMCs)
Background summary
Rheumatoid arthritis (RA) is a chronic and progressive inflammatory disease
marked by infiltration of synovial tissue by activated lymphocytes, dendritic
cells (DC) and macrophages, and proliferation of stromal fibroblast-like
synoviocytes (FLS). Interactions between activated lymphocytes and other cells
in synovial tissue play an important role in the perpetuation of RA pathology.
Current therapies provide only partial protection against inflammation and
joint destruction, and not to all patients. Therefore, increased knowledge of
the molecular basis of RA and the working mechanism of therapeutic compounds is
necessary for the analysis of their efficacy and rational application in the
clinic. Abatacept, a human recombinant soluble fusion protein, composed of the
extracellular domain of CTLA-4 and a mutated IgG1 Fc fragment, has shown a
remarkable efficacy in clinical trials in patients with RA. Abatacept is
proposed to work by interfering with the interaction of CD28 on T cells with
its ligand CD80 or CD86 on antigen presenting cells.This ligation lowers the
treshhold for T cell receptor activation. However, T-cell function in abatacept
clinical trials has never been studied and there is no direct evidence that the
T cell receptor is actively engaged in RA synovial T cells.
Understanding the mechanism of action of Abatacept in RA will need to consider
not only the potential effects of this compound on classical TCR costimulation
and T cell activation, but also possible direct and indirect effects on B cells
and other cells expressing CD80/86 in the synovial tissue, such as T cells,
monocyte/macrophages, and DCs. We have some preliminary data from a previous
study suggesting that B cells and macrophages (antigen presenting cells
decrease after therapy with abatacept and that the T cells stay unaffected. The
aim of this study is to expand these immunohistochemical data and to study
changes in cytokine production of ex vivo stimulated synovial biopsies after
treatment, in order to identify the mechanism of action of abatacept.
Study objective
The primary objective is to study changes in synovial inflammation in serial
biopsy samples following the administration of abatacept in patients with
active rheumatoid arthritis.
The secondary objectives of this study are to
(I) assess clinical response
(II) assess cellular responses of synovial explants to inflammatory stimuli,
and/or antagonists, before and after treatment with abatacept
(III) identify synovial biomarkers predictive of the clinical response to
abatacept treatment
(IV) investigate the changes in phenotypes of peripheral blood mononuclear
cells (PBMCs)
Study design
Following a screening period of 2-3 weeks, patients will be enrolled into a
prospective open label study for a period of 24 weeks. Synovial biopsies from
an actively inflamed joint (knee, ankle or wrist) will be obtained by
mini-arthroscopy or ultrasound guided biopsy before administration of abatacept
and at week 16 of treatment.
Clinical evaluation of joint pain and swelling will be done at baseline and
repeated after 4, 8, 12, 16 and 24 weeks of treatment. Patients will be seen
for efficacy and safety assessments in accordance with standard guidelines for
clinical practice.
In total there will be 9 study visits: screening, baseline, week 2, week 4,
week 8, week 12, week 16, week 20 and week 24. There will be a ± 3 day
deviation for all return visits. All visits will be fixed with reference to the
baseline visit.
Intervention
ABATACEPT (ORENCIA ) for 24 weeks
mini-artroscopy
Study burden and risks
The treatment of abatacept can cause side effects, although they are usualy
mild.
Mini-artroscopy:
Mostly, the arthroscopy is performed without complaints. However, a small risk
exists of complications, such as joint infection
(< 0,3%) . Carefully cleaning the skin and the use of sterile gloves minimize
the change of getting an infection. The joint can also be stiff a few days
after the arthroscopy. Reactions to local anesthesia can occur but disappear
quickly.
Meibergdreef 9 F4-105
1105 AZ Amsterdam ZO
NL
Meibergdreef 9 F4-105
1105 AZ Amsterdam ZO
NL
Listed location countries
Age
Inclusion criteria
Males and females with a diagnosis of active rheumatoid arthritis (with a DAS28 CRP > 3,2) who have failed MTX therapy, with an inflamed knee, ankle or wrist joint.
Exclusion criteria
Pregnancy, breastfeeding
subjects who are impaire, incapacitated or incapable of completing study related assessments
subjects who meet diagnostic criteria for any other rheumatic disease (e.g. lupus erythematous)
subjects who have previously received treatment with an investigational biologic RA therapy, antie-TNF theray, rituximab, tocilizumab or abatacept
subjects with active vasculitus of a major organ system with the exception of rheumatoid nodules
Subjects with current symptoms of severe, progressive, or uncontrolled renal,
hepatic, hematological, gastrointestinal, pulmonary, cardiac, neurological, or
cerebral disease, or other medical conditions that, in the opinion of the
investigator, might place the subject at unacceptable risk for participation in this
study.
Subjects with a history of cancer within the last five years (other than nonmelanoma
skin cell cancers cured by local resection). Existing non-melanoma
skin cell cancers must be removed prior to dosing.
Subjects who have clinically significant drug or alcohol abuse.
Subjects with any serious bacterial infection within the last 3 months, unless
treated and resolved with antibiotics, or any chronic bacterial infection (such as
chronic pyelonephritis, osteomyelitis and bronchiectasis).
Subjects at risk for tuberculosis (TB). Specifically, subjects with:
a) A history of active TB within the last 3 years even if it was treated
b) A history of active TB greater than 3 years ago unless there is documentation
that the prior anti-TB treatment was appropriate in duration and type
c) Current clinical, radiographic or laboratory evidence of active TB
d) Latent TB which was not successfully treated
Subjects with herpes zoster or cytomegalovirus (CMV) that resolved less than 2
months prior to signing informed consent.
Subjects with evidence (as assessed by the Investigator) of active or latent
bacterial or viral infections at the time of potential enrollment, including subjects
with evidence of Human Immunodeficiency Virus (HIV), Hepatitis B or Hepatitis
C infection detected during screening.
Subject who have received any live vaccines within 3 months of the anticipated
first dose of study medication or who will have need of a live vaccine at any time
following Day 1 of the study
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 | EUCTR2010-021435-14-NL |
| CCMO | NL32939.018.10 |