Primary:To evaluate the efficacy of belimumab and a single cycle of rituximab administered in a combination regimen to adult participants with SLE. Secondary:Other aspects of efficacy. Safety and tolerability. Questionnaires.
ID
Source
Brief title
Condition
- Autoimmune disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Proportion of participants with a state of disease control defined as a SLE
Disease Activity Index (SLEDAI)-2K score *2, achieved without
immunosuppressants and with corticosteroids at a prednisone equivalent dose of
*5 mg/day at Week 52.
Secondary outcome
Major: Clinical remission (SLEDAI-2K score=0) at Week 64.
Others (e.g.): Clinical or complete remission (SLEDAI-2K score=0) by visit and
for *24 weeks. Disease control (SLEDAI-2K score *2) at week 104, by visit. Time
to first (severe) flare. Adverse events. See protocol pages 10-12 for complete
list.
Background summary
SLE is characterized by autoantibodies, including antibodies to double-stranded
DNA (dsDNA), and by abnormal B cell activation and differentiation, indicating
that therapies which deplete or modulate B cells could be beneficial in
treating SLE. Belimumab and rituximab are monoclonal antibodies that achieve
their expected pharmacology through different but complementary mechanisms;
therefore, based on their mechanisms of action, synergistic effects when used
in combination in the treatment of SLE are possible compared to either
treatment alone. Belimumab treatment increases peripheral memory B cells
potentially by mobilization from tissues this may include the autoreactive B
cell compartment. This mobilization would expose these cells to more efficient
depletion by rituximab. Continuing belimumab after a single course of rituximab
would then suppress the B-lymphocyte stimulator (BLyS) elevation observed after
rituximab monotherapy, thus suppressing the signal which leads to rapid
repopulation of B cells, including autoreactive B cells. This study will assess
whether co-administration of belimumab and a single cycle of rituximab may
optimize (registered) treatment with belimumab, resulting in improvements in
clinical status with a favorable safety profile.
Protocol amendment 3: addition of a sub study (the effect of the study
medication on B cells; 6 times approx. 10 mL blood).
Study objective
Primary:
To evaluate the efficacy of belimumab and a single cycle of rituximab
administered in a combination regimen to adult participants with SLE.
Secondary:
Other aspects of efficacy. Safety and tolerability. Questionnaires.
Study design
Phase 3, 3-arm randomized double-blind placebo-controlled 104 week study.
Randomization (1:2:1) to:
D. Belimumab plus 1 course of rituximab placebo
E. Belimumab plus 1 course of rituximab
F. Belimumab plus standard therapy with immunosuppressants (open-label).
Belimumab will be administered weekly (200 mg subcutaneously) for 51 weeks
(Arms A and B) or 104 weeks (Arm C).
Rituximab (or placebo) will be administered in week 4 and 6 (intravenously).
Premedication 30 min prior to infusions (incl. methylprednisolone 100 mg IV).
Standard therapy in Arm C will be administered for 104 weeks.
After the initial 12 weeks of study treatment, a protocol-specified
corticosteroid taper will be initiated and conducted under the direction of the
investigator for participants in all 3 arms. See protocol page 14 for details.
Participants in Arms A and B will enter into the 52-week observational phase of
the study without belimumab and/or rituximab treatment after completing Week 52
(Weeks 53 through 104).
Blinded independent assessors will conduct the SLEDAI-2K at key time points.
An Independent Data Monitoring Committee (IDMC) will regularly review the
safety data.
At least 200 subjects (400 to be screened).
Intervention
Treatment with belimumab with or without rituximab.
Down titration (and potential discontinuation) of corticosteroids.
Study burden and risks
Risk: Adverse events of belimumab with or without rituximab. Decrease of
disease control.
Burden:
Visits every 4 weeks (year 1), every 8 weeks (year 8).
Belimumab SC injection (ca 1 mL) during 1 (Arms A, B) or 2 (Arm C) years. 2 IV
infusions with rituximab (or placebo) (250 mL) and IV pre-medication met
methylprednisolone (2,5 mL) (arm A, B).
Physical examination: every visit.
SLEDAI-2K score: every visit.
Blood draws: every visit (30-150 mL, 1.200 mL blood in total).
Pregnancy test: every visit.
Alcohol en drugs screen: at screening.
ECG: at screening.
Diary (data on administration belimumab): 1-2 years (as long as belimumab is
administered).
Questionnaires: C-SSRS every visit, FACIT-fatigue, Lupus QoL, WPAI, global
assessment 9 times in total.
Optional: genetics blood sample (6 ml), 6 blood samples of approx. 10 mL for
optional research on B cells.
Van Asch van Wijckstraat 55H
Amersfoort 3811 LP
NL
Van Asch van Wijckstraat 55H
Amersfoort 3811 LP
NL
Listed location countries
Age
Inclusion criteria
* Males and females ><= 18 years of age.
* SLE according to the ACR criteria (at least 4/11 criteria).
* Screening SLEDAI-2K score *6 (total score).
* Unequivocally positive autoantibody test results. See protocol page 49 for
details.
* Stable SLE treatment regimen consisting of any of the following medications
(alone or in combination) for a period of at least 30 days prior to Day 1:
corticosteroids, immunosuppressants, anti-malarials, NSAIDs. See protocol page
49-50 for details.
* Female participant of childbearing potential who agrees to follow the
contraceptive guidance in appendix 3 of the protocol during the treatment
period and for at least 16 weeks after the last dose of belimumab or at least
12 months after the last dose of rituximab (or placebo).
Exclusion criteria
* Symptomatic herpes zoster within 3 months prior to screening.
* Evidence of active or latent tuberculosis. See protocol page 50 for details
* Clinical evidence of significant unstable or uncontrolled acute or chronic
diseases not due to SLE. See protocol page 51 for details.
* Acute or chronic infection requiring management. See protocol page 51 for
details.
* Severe lupus kidney disease. See protocol page 52 for details.
* Live vaccine within 1 month prior to screening, or plans to receive such
vaccines during the screening period or during the study.
* Use in the past year of belimumab, rituximab, abatacept, any B-cell targeted
therapy, biologic investigational agent other than B cell targeted therapy. See
protocol page 52 for details.
* 3 or more courses of systemic corticosteroids within the past year.
* Use in the 90 days prior to study day 1: anti-TNF therapy, anakinra, IV
immunoglobulins, >100 mg prednisone per day, plasmapheresis.
* Use in the 60 days prior to study day 1: non-biologic investigational drug,
IV cyclophosphamide, any steroid injection.
* Positive HIV, hepatitis B or C test.
* Pregnancy or breastfeeding.
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 | EUCTR2016-003050-32-NL |
| CCMO | NL63490.100.17 |
| Other | www.gskclinicalstudyregister.com 205646 |