- To evaluate the safety and efficacy of anti-IgE therapy with respect to:Clinical disease activity (DAS44), laboratory parameters and adverse events. - To evaluate whether disease activity correlates with immunological parameters, including…
ID
Source
Brief title
Condition
- Autoimmune disorders
- Joint disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1. Clinical parameters for disease activity are measured by the DAS44 (Disease
Activity Score on 44 joints) assessment. Responses are classified as follows:
- Complete response is defined as a DAS44 improvement of > 1.2 and DAS<2.4
- Moderate response is defined as DAS44 improvement of 1.2 and DAS >2.4:
OR
DAS 44 improvement of >0.6 en <=1.2 and DAS <=3.7:
- Non-response is defined as DAS44 improvement of >0.6 en <=1.2 improvement
and DAS >3.7
OR improvement of <=0.6
2. Immunological parameters in peripheral blood and synovium after treatment
with anti-IgE antibodies (omalizumab) are:
- proportion of peripheral blood basophils, mast cells in synovium
- functional presence of IgE-ACPA,
- IgE , FcERI expression on basophils, mast cells, B cells and DC
- synovial infiltration of B cells, plasmacells, mast cells and (IgE-)ACPA
presence in synovial fluid
3. Safety and toxicity parameters are evaluated according to WHO Common
Toxicity Criteria
Secondary outcome
not applicable
Background summary
The discovery of antibodies against cyclic citrullinated proteins (ACPA) was a
breakthrough. These antibodies are highly specific for RA and the occurrence of
ACPA is observed several years before the onset of the disease.
Moreover, recent evidence was raised for a pathogenic role of ACPA: Fc*RI+
cells from ACPA+ RA patients can be directly activated by citrullinated
antigens, using an ex vivo human model. These data show the ability of
citrullinated proteins to crosslink IgE-ACPA specifically via Fc*RI and support
a functional role of IgE-ACPA in ACPA+ RA patients.
Humanized anti-IgE antibodies have been developed for clinical use in asthma:
rhuMAb-E25 or omalizumab has been successfully used for the treatment of
allergic asthma. The mechanisms of action of human anti-IgE are diverse (12).
First, it neutralizes IgE by binding to the constant region 3 of the heavy
chain at a site that prevents IgE to bind to its receptors. Secondly, anti-IgE
forms trimers and tetramers that sweep away antigens. Thirdly, by reducing free
IgE by >99%, anti-IgE also markedly reduces the density of FcepsilonRI on mast
cells, basophils and DCs. In conclusion, if IgE-ACPA are involved in disease
progression in RA, this humanized blocking IgE antibody has great potential to
benefit IgE-ACPA positive RA patients.
Study objective
- To evaluate the safety and efficacy of anti-IgE therapy with respect to:
Clinical disease activity (DAS44), laboratory parameters and adverse events.
- To evaluate whether disease activity correlates with immunological
parameters, including immunopathology and IgE-ACPA-autoantibodies.
ADDENDUM:
1. To provide treatment with anti-IgE therapy to Rheumatoid Arthritis (RA)
patients who participated in the original protocol of the TIGER study P10.161.
2. To assess the safety and tolerability of long term treatment with anti-IgE
therapy in a clinical setting.
Study design
A randomized placebo-controlled double blinded single-center, phase IIa study
investigating anti-IgE therapy (omalizumab) in IgE-ACPA positive rheumatoid
arthritis patients.
ADDENDUM:
This is an open label extension study in IgE-ACPA positive RA patients who
participated in the TIGER trial P10.161. After completion of visit 7 in the
original study, patients who in the investigators clinical judgement would
benefit from the anti-IgE treatment will be offered enrolment in this extension
study.
Intervention
This investigation is a placebo-controlled randomized double blinded
single-center phase IIa study, administering subcutaneously every four weeks
300 mg of monoclonal anti-IgE antibody or placebo in patients with IgE-ACPA
positive RA during 6 months.
ADDENDUM:
During the open label extension study with IgE-ACPA positive RA, patients will
be administered subcutaneously every four weeks 300 mg of monoclonal anti-IgE
antibody during extra 12 months.
Treatment with omalizumab comprises the following :
At day 168 (Month 6), day 196 (M 7), day 224 (M 8), day 252 (M 9), day 280 (M
10), day 308 (M 11), day 336 (M 12), day 336 (M 13) M 14 M 15 M 16 M 17 M 18
patients receive a subcutaneous injection with 300 mg omalizumab during short
stay at the clinic.
Study burden and risks
Risk for adverse events caused by omalizumab:
headache, nausea, unwelness, allergic reaction
Other risks:
Pain or hematome by venous punction or sucutaneous administering of medicine
Pain caused by arthroscopy
Discomfort caused by investigation procedures :
extra blood withdrawal during treatment with omalizumab /placebo.
Albinusdreef 2
Leiden 2333 ZA
NL
Albinusdreef 2
Leiden 2333 ZA
NL
Listed location countries
Age
Inclusion criteria
1. Patients with refractory active rheumatoid arthritis (RA). Refractory disease is defined as persistent or relapsed disease activity despite conventional treatment, i.e. combination of disease modifying antirheumatic drugs including maximal tolerable doses of methotrexate. Active disease is defined as a DAS44 (Disease Activity Score of 44 joints) score of more than 3.6
2. Presence of IgE-ACPA
3. Age above 18 years
4. WHO performance status 0, 1 or 2
5. Informed consent according to rules and regulations of Leiden University Medical Center.
Addendum: Rheumatoid arthritis patients included in placebo controlled TIGER study during 6 months according to the inclusion and exclusion criteria (see original protocol P10.161) can be included in the open label extension protocol, regardless their previous treatment (omalizumab or placebo).
Exclusion criteria
1. History of allergic or anaphylactic reaction to any therapeutic agent or known hypersensitivity to any component of anti-IgE monoclonal antibodies or to murine proteins.
2. No previous therapy with corticosteroids or a biological agent during the last 3 months.
3 No previous therapy with rituximab, leflunomide
4. Life expectation of less than 6 months
5. History of severe CNS disturbances and psychiatric problems
6. Severe uncontrolled infections including parasitosis
7. Irreversible major organ dysfunction, defined by any of the following criteria:
- creatinine clearance < 40 ml/min.
- left ventricular ejection fraction < 40%;
- pericardial effusion with haemodynamic consequences.
- resting arterial oxygen tension (PaO2) < 8 kPa (<60 mmHg) and / or resting arterial carbon dioxide tension (PaCO2) > 6.7 kPa (>50 mmHg).
- sustained 3-fold increase in serum transaminase or bilirubin.
8. HIV positivity
9. Positive pregnancy test or unwillingness to use adequate contraception for the duration of the study
10. History of cancer, including solid tumors, hematological malignancies and carcinoma in situ (except for basal cell and squamous cell carcinoma of the skin that have been treated and cured).
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 | EUCTR2009-017306-36-NL |
| CCMO | NL33504.058.10 |
| Other | NTR TC=2434 |