This study has been transitioned to CTIS with ID 2024-518965-85-00 check the CTIS register for the current data. The primary objective of this study is to investigate the potential differential effects of RTX and OBI on the composition of lymph…
ID
Source
Brief title
Condition
- Autoimmune disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The proportion of patients with depletion of total CD19+ and other B lineage
cells in the peripheral blood (quantitative using ImmunoSeq analysis) and lymph
nodes, defined as a decrease of >2 points on a 4-point semi-quantitative scale.
These will be separate co-primary endpoints. We will statistically test the
difference in the proportions of patients with depletion by these criteria in
RTX- versus OBI-treated patients.
Secondary outcome
Correlation between CD19+ lymphocyte (and other B lineage cells) depletion in
peripheral blood/tissues and clinical response. Depletion
(defined as a decrease of >2 points on a 4-point semi-quantitative scale of
CD19+ cells in the lymph node) will be related to clinical response
(defined as a >4 point improvement in cSLEDAI or any improvement in BILAG-2004
score) in a 2x2 chi-square test for all 20 patients.
Further secondary and exploratory outcomes are changes in B lineage cells and
associated (pathogenic) T cell subsets in lymph nodes and skin of SLE patients
in comparison to the changes in the peripheral blood compartment, analyses to
investigate whether change in B lineage cells and associated (pathogenic) T
cell subsets in tissues is associated with clinical outcomes and/or known
serological biomarkers such as antidsDNA and complement components C3 and C4.
Background summary
Systemic lupus erythematosus (SLE)is an immune-mediated inflammatory disease
(IMIDs) of which the cellular and molecular alterations of the immune system
driving the diseases still remains largely unknown. Accordingly, it remains
difficult to predict the indvidual patient*s response to treatment. Moreover,
the patient*s response to treatment remains heterogeneous and difficult to
predict, despite the development of a variety of novel and powerful drugs
(including the so-called biologicals). Therefore, there is a clear need for the
identification and validation of cellular and molecular biomarkers which can
provide useful clinical information for diagnosis, classification, prognosis
and treatment, as well as the development of new therapeutic strategies.
Biomarkers can be found and analyzed in different body compartments, of which
the peripheral blood is most easily accessible. However, previous studies in RA
and other IMIDs showed that adaptive immune responses in other tissues such as
lymph nodes also play an important role. Investigating other immune
compartments of the body such as the lymph nodes could result in new insights.
To study the early pathogenesis of inflammatory conditions, in 2008 our
department initiated core-needle inguinal lymph node biopsy sampling. Since
then we performed more than 100 lymph node biopsy procedures. We showed that
the procedure is well-tolerated and that, other than a small hematoma which
does not require therapy in most of the cases, no complications were reported.
In the current study, we aim to investigate the effects of rituximab and
obinutuzumab (both anti-CD20 therapy) in SLE by studying the immune alterations
taking place in lymph nodes in comparison to peripheral blood. In this way we
will be able to compare the effects of rituximab and obinutuzumab and assess
potential differential immune alterations in the lymph nodes (secondary
lymphoid organ) and the peripheral blood (systemic).
Hypotheses:
• OBI depletes CD20+ cells from the tissues more effectively than RTX
• Clinical treatment results in SLE are related to depletion of CD20+ cells
from the tissues
• CD20+ depleting therapy results in significant changes in B lineage cells and
associated (pathogenic) T cell subsets in the tissue of SLE patients, which may
be different from the changes observed in the peripheral blood
Study objective
This study has been transitioned to CTIS with ID 2024-518965-85-00 check the CTIS register for the current data.
The primary objective of this study is to investigate the potential
differential effects of RTX and OBI on the composition of lymph nodes and other
target organs (i.e. skin and/or kidney) as well as (subsets of) immune cells in
the peripheral blood. Furthermore, we aim to identify immunological alterations
in lymphoid tissue and inflamed skin and/or kidney tissues of SLE patients and
to correlate these alterations with disease stage/phenotype, prognosis, and
treatment response. We thereby aim to identify and validate novel biomarkers
that can be used for personalized medicine in SLE.
Study design
Patients will receive either RTX 2x1000mg + 100mg methylprednisolone or OBI
2x1000mg + 100mg methylprednisolone (two-week interval) in a non-blinded
clinical trial. Researchers in the lab handling patient samples and performing
analyses will be blinded for the treatment.
Intervention
RTX 2x1000mg vs. OBI 2x1000mg + 100mg methylprednisolone (two-week interval)
Study burden and risks
The patient will receive an infusion of RTX or OBI twice (with an interval of 2
weeks). In addition, a needle biopsy will be taken from an inguinal lymph node
twice and in total blood will be taken 4 times (max 94ml). If there is also SLE
activity in the skin or kidney, we want to examine these tissues as well.
However, these last 2 tissues are optional and the kidney biopsy is only done
if clinically indicated (once). The research will increase the insight into the
pathogenetic processes that play a role in the onset and persistence of SLE and
the effect of anti-CD20 therapy on this. This insight may lead to the
identification and validation of new biomarkers that bring "personalized
medicine" in SLE a step closer. In addition, new insights into the pathogenesis
can lead to the development of new therapies or therapeutic strategies. In this
study, obinutuzumab and rituximab are compared to see if either provides better
B cell depletion in the tissues. In view of the relatively small risk of
complications, we consider this study justified.
Meibergdreef 9
Amsterdam 1105 AZ
NL
Meibergdreef 9
Amsterdam 1105 AZ
NL
Listed location countries
Age
Inclusion criteria
SLE patients who:
1. fulfill ACR 1997 and/or SLICC and/or ACR/ EULAR 2019 criteria,
2. have a SLEDAI-2K score >=6.
3. are aged between 18-75
4. are clinically determined to have severity of disease and refractoriness
that supports the off-label use of anti-CD20 therapy
Exclusion criteria
- Patients who are not able to give informed consent. - Pregnancy - Severe
renal impairment (eGFR <30ml/min/1.73m2 according to CKD-EPI formula) - Present
or previous treatment with any cell depleting therapies, including anti-B-cell
therapy, belimumab or other investigational agents (e.g., abetimus sodium, anti
CD40L antibody, BG9588/ IDEC 131) in the last 3 years. Investigational agent
applies to any drug not approved for sale in the country in which it is being
used. - Intravenous cyclophosphamide 90 days prior to anti-CD20 therapy - Any
non-biologic investigational agent (investigational agent applies to any drug
not approved for sale in the country in which it is being used) 30 Days Prior
to anti-CD20 therapy (or 5 half-lives, whichever is greater) - Live vaccines
within 30 days prior to baseline or concurrently with anti-CD20 therapy -
Presence of any other disease for which study subjects need chronic or
intermittent immunosuppressive therapy (e.g. prednisolon for COPD). - History
of infection: • Currently on any suppressive therapy for a chronic infection
(such as tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus,
herpes zoster and atypical mycobacteria) • Hospitalization for treatment of
infection within 60 days of Day 0. • Use of parenteral (IV or IM) antibiotics
(anti-bacterial, antiviral, anti-fungal, or anti-parasitic agents) within 60
days of Day 0 - History of malignancies neoplasm within the last 5 years except
basal cell or squamous cell carcinoma of the skin treated with local resection
only or carcinoma in situ of the uterine cervix treated locally and with no
evidence of metastatic disease for 3 years - Have any intercurrent significant
medical or psychiatric illness that the investigator considers would make the
candidate unsuitable for the study, including evidence of serious suicide risk
including any history of suicidal behaviour in the last 6 months and/or any
suicidal ideation in the last 2 months or who in the investigator's judgment,
poses a significant suicide risk - Have a history of a primary
immunodeficiency, including significant IgG deficiency (IgG level < 400 mg/dL)
or IgA deficiency (IgA level < 10 mg/dL) - Have current drug or alcohol abuse
or dependence, or a history of drug or alcohol abuse or dependence within 365
days prior to Day 0 - Have a historically positive HIV test or test positive at
screening for HIV - Hepatitis status: • Serologic evidence of current or past
Hepatitis B (HB) infection based on the results of testing for HBsAg and HBcAb
as follows: patients positive for HBsAg or HBcAb are excluded • Positive test
for Hepatitis C antibody - Have a history of an anaphylactic reaction to
parenteral administration of contrast agents, human or murine proteins or
monoclonal antibodies - Have any other clinically significant abnormal
laboratory value in the opinion of the investigator
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 |
|---|---|
| EU-CTR | CTIS2024-518965-85-00 |
| EudraCT | EUCTR2022-004335-12-NL |
| CCMO | NL83820.018.23 |