Lupus Erythematosus, SystemicPhase 2SYNBIoSeNCT02284984
Synergetic B-cell Immodulation in SLE
A Phase 2 study testing Rituximab with belimumab in people with Lupus Erythematosus, Systemic, run by Leiden University Medical Center at 1 site in Netherlands.
Trial summary
The present study investigates the potential of a new therapeutic approach in lupus nephritis combining rituximab (anti-CD20) and belimumab (anti-BAFF). The main goal of the study is to assess the reduction (and seroconversion) of pathogenic autoantibodies, to evaluate clinical improvement and assess the safety and… Read more about this study
- Who is it for?
- Ages 18 to 64 years
- Conditions the study is for
- Lupus Erythematosus, Systemic
- What is being tested?
- Rituximab with belimumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 16 participants
- Where
- 1 siteNetherlands
- Study dates
- Mar 2014to 31 Oct 2018
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 64 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- age 18 years,
- American College of Rheumatology (ACR) diagnosis of SLE (1997 revised criteria, see appendix 1)
- Severe SLE flare at screening (see also section 5.2.3.2.), defined as a situation in which 1 or more of the following criteria are met:
- Increase in SLEDAI (SLE Disease Activity Index) with 12 or more points
- New or worse SLE-related activity of major organs, i.e.: central nervous system (CNS-) SLE (includes NPSLE), vasculitis, nephritis, pericarditis and/or myocarditis, myositis, thrombocytopenia < 60, hemolytic anemia < 4.4mmol/L (=7.0g/dL).
- Refractory disease, defined as persisting or progressive disease activity (SLEDAI > 6 points) despite conventional immunosuppressive treatment and 1 or more of the following criteria:
Show all 22Show fewer
- failure of the initial induction treatment at six months, for which a switch to another induction therapy regime has already been carried out;
- intolerance or contraindication for cyclophosphamide and mycophenolate mofetil (MMF);
- exceeding a cumulative dose of 15 gram of cyclophosphamide;
- a second relapse within two years after start of the initial induction therapy
- a relative contraindication for high-dose oral or intravenous (iv) prednisone, such as avascular osteonecrosis, previous psychosis on corticosteroids, osteoporosis and/or severe obesity (BMI =35 kg/m2).
- ANA seropositivity, as defined by a positive ANA-titer = 1:80, before and at screening :
- Positive test results from 2 independent time points within the study screening period; OR
- One positive historical test result and 1 positive result during the screening period. Historical documentation of a positive test of ANA (eg, ANA by HEp-2 titer, ANA by ELISA) must include the date of the test.
- Anti-DNA seropositivity, as defined by a positive anti-dsDNA serum antibody = 30 IU/mL, before and at screening:
- Positive test results from 2 independent time points within the study screening period.
- One positive historical test result and 1 positive result during the screening period. Historical documentation of a positive test of anti-dsDNA (eg, anti-dsDNA by Farr assay or ELISA) must include the date of the test.
- Immune-complex mediated complement usage, as defined by:
- a low C3 serum level = 0.9 g/L; OR
- a low C4 serum level = 95 mg/L; OR
- a reduced activation of the classical pathway < 75%
- Use of effective contraception
Who cannot join
- Active pregnancy, as proven by a positive urine beta-HCG (human chorionic gonadotropin) test or a positive serum beta-HCG
- Significant B-cell depletion (peripheral B-cell counts < 60x10E6)
- Significant hypogammaglobulinemia (IgG < 8.0 g/L)
- Immunization with a live vaccine 1 month before screening
- Active infection at time of screening, as follows:
- Hospitalization for treatment of infection within previous 2 months of day 0 of the study
- Use of parenteral (intravenous of intramuscular) antibiotics ( including anti-bacterial, anti-viral, anti-fungal or anti-parasitic agents) within previous 2 months of day 0 of the study
Trial locations and contacts
1 site in 1 country.
About this study
The present study investigates the potential of a new therapeutic approach in lupus nephritis combining rituximab (anti-CD20) and belimumab (anti-BAFF). The main goal of the study is to assess the reduction (and seroconversion) of pathogenic autoantibodies, to evaluate clinical improvement and assess the safety and feasibility of long-term B-cell depletion.
Read the detailed description
Introduction Systemic lupus erythematosus (SLE) affects predominantly young women with childbearing potential (20-40 years) and inflammation can occur in virtually every organ, including kidneys, lungs, heart or brain. The disease course in SLE patients is typically characterized by frequent flares, requiring immunosuppressive treatment. Current, evidence-based treatment modalities for SLE consist of immunosuppressive treatment with high dose corticosteroids, cyclophosphamide or mycophenolic mycophenolate acid, that non-specifically target the immune system to reduce inflammation. Side-effects of these treatment strategies are (opportunistic) infections in the short term and risk for malignancy and cardiovascular disease in the long-term. Treating SLE patients with biologicals is an attractive alternative because biologicals specifically target the immune system by blocking cytokines or deplete one specific cell population, thereby reducing the risk for infections or malignancies as compared to conventional immunosuppressants. Furthermore, the scarce treatment options underscore the need to exploit new therapeutic possibilities for SLE patients who frequently experience a flare of the disease. These considerations led to the present study involving a proof-of-concept study in refractory SLE patients to assess the immunological consequences of a combination treatment with rituximab (anti-CD20) and belimumab (anti-BAFF).
Objective of the study:
A proof-of-concept study in refractory SLE patients to assess the immunological consequences of a combination treatment with rituximab (anti-CD20) and belimumab (anti-BAFF) to achieve long-term B-cell depletion. The immunological and clinical monitoring of refractory SLE patients will be monitored and the safety and feasibility of this combination treatment evaluated.
Study design:
This is a single-center, non-randomized, phase 2A, proof-of-concept study to evaluate the effects of a combination treatment with rituximab and belimumab. This combination therapy is designed to induce long-term B-cell depletion to achieve significant reduction of autoantibody-mediated immune complexes. In addition to standard therapy, SLE patients will receive 2 infusions of rituximab 1000 mg on day 0 and 14 (week 2) and belimumab on day 28 (week 4) , 42 (week 6) and 56 (week 8), then every 28 days. The primary endpoint is at 24 weeks after which an extended follow-up will take place, for subjects continuing belimumab, until 104 weeks after treatment start.
Rituximab and Belimumab will be administered intravenously according to the manufacturer's instructions. Clinical and immunological parameters will be assessed every 8-12 weeks. The study medication is not blinded for patients nor physicians. The study intends to include 15 refractory SLE patients.
Study population:
Patients with systemic lupus erythematosus, older than 18 years with refractory disease as specified by the inclusion criteria (mentioned above)
Intervention:
Rituximab Patients will be intravenously treated with Rituximab 1000mg on day 0 and day 14. Before every infusion of Rituximab patients will receive intravenous hydrocortisone 100mg together with oral acetaminophen 1000 mg and intravenous Tavegil 2 mg.
Belimumab Patients will be intravenously treated with Belimumab 10mg/kg on day 28, day 42 and day 56. Thereafter, patients will receive Belimumab 10mg/kg every 4 weeks. No pre-medication is administered
Primary study parameters/outcome of the study:
In this proof-of-concept study the primary objective is to assess whether a combination treatment of rituximab and belimumab will lead to a sustained reduction of pathogenic autoantibodies.
Secondary study parameters/outcome of the study:
The main secondary objective is to evaluate the effects of long-term B-cell depletion which will involve assessments of the clinical response correlated with immunological parameters. To this end, the relevant study parameters will be evaluated after 4 weeks (short term), 24 weeks (intermediate term) and 104 weeks (long-term).
The safety and feasibility of the combination treatment according to the WHO toxicity criteria
The clinical response of refractory SLE patients upon long-term B-cell depletion by:
- a reduction in SLEDAI scores, no new BILAG (British Isles Lupus Assessment Group) A involvement and the SLE responder index
- in case of lupus nephritis: the number of partial and complete renal responders
- the number of moderate or severe flares and renal flares
- Conditions
- Lupus Erythematosus, Systemic
- Being tested
- Rituximab with belimumab
- Keywords
- Antibodies, Monoclonal, mabthera, benlysta, Antinuclear Antibodies
- Medical subject headings
- Lupus Erythematosus, Systemic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Rituximab with belimumabDrug
Also called Belimumab
Rituximab treatment on dag 0 and 14, 1000mg iv Belimumab 10mg/kg on day 28, day 42 and day 56. Thereafter, patients will receive Belimumab 10mg/kg every 4 weeks through 72 weeks.
| Study group | Role | What they receive |
|---|---|---|
| Rituximab with belimumab | Experimental | Rituximab 1000mg on day 0 and day 14 Belimumab 10mg/kg on day 28, day 42 and day 56. Thereafter, patients will receive Belimumab 10mg/kg every 4 weeks. Receives: Drug: Rituximab with belimumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Reduction of pathogenic autoantibodies
A sustained reduction of pathogenic autoantibodies, in particular anti-dsDNA autoantibodies, at 24 weeks after treatment start.
Measured: 24 weeks
Secondary outcomes (5)
Seroconversion of pathogenic autoantibodies, in particular anti-dsDNA autoantibodies
Measured: 4, 24, 104 weeks
Safety and feasibility: number of patients with (serious) adverse events
in accordance with the WHO toxicity criteria, including malignancy, suicidal thought/intent/behaviour
Measured: 4, 24, 104 weeks
Safety and feasibility: number of patients with infectious events
focused on serious, Varicella-zoster virus (VZV) and opportunistic infections
Measured: 4, 24, 104 weeks
Safety and feasibility: number of patients with serious hypersensitivity or infusion reactions
Measured: 4, 24, 104 weeks
Clinical response
- a reduction in SLEDAI scores, no new BILAG A involvement and the SLE responder index
- in case of lupus nephritis: the number of partial and complete renal responders
- the number of moderate or severe flares and renal flares
Measured: 4, 24, 104 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Nov 2014 (estimated)
- Study startMar 2014
- Primary completion31 Oct 2018
- Study completion31 Oct 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Lupus Erythematosus, SystemicStudies of the same condition, open and under way.
- More trials run by Leiden University Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 16 participants (actual)
Sponsor and investigators
- Lead sponsor
- Leiden University Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- Dutch Kidney Foundation, ZonMw: The Netherlands Organisation for Health Research and Development
- Responsible party
- Principal investigator, YTeng, Leiden University Medical Center
- Investigators
- Onno YK Teng, MD, PhD, Principal investigator, Leiden University Medical CenterA J Rabelink, MD, PhD, Principal investigator, Leiden University Medical CenterT WJ Huizinga, MD, PhD, Principal investigator, Leiden University Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02284984
- Sponsor's protocol ID
- NL4813605814
- Acronym
- SYNBIoSe
- Status last verified
- Feb 2019
- First submitted
- 15 Oct 2014
- Last updated
- 28 Feb 2019
- Results posted
- No
- Data monitoring committee
- No
Publications
Kraaij T, Kamerling SWA, de Rooij ENM, van Daele PLA, Bredewold OW, Bakker JA, Bajema IM, Scherer HU, Toes REM, Huizinga TJW, Rabelink TJ, van Kooten C, Teng YKO. The NET-effect of combining rituximab with belimumab in severe systemic lupus erythematosus. J Autoimmun. 2018 Jul;91:45-54. doi: 10.1016/j.jaut.2018.03.003. Epub 2018 Apr 7.
PubMed 29636274
Study at a glance
From the registry record, last updated by the sponsor on 28 Feb 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Synergetic B-cell Immodulation in SLE
- ClinicalTrials.gov ID
- NCT02284984
- Acronym / sponsor ID
- SYNBIoSe / NL4813605814
- Conditions
- Lupus Erythematosus, Systemic
- Keywords
- Antibodies, Monoclonal, mabthera, benlysta, Antinuclear Antibodies
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 16 participants (actual)
- Lead sponsor
- Leiden University Medical CenterUniversity, hospital or other
- Collaborators
- Dutch Kidney Foundation, ZonMw: The Netherlands Organisation for Health Research and Development
- Study start
- Mar 2014 (actual)
- Primary completion
- 31 Oct 2018 (actual)
- Study completion
- 31 Oct 2018 (actual)
- First posted
- 6 Nov 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The present study investigates the potential of a new therapeutic approach in lupus nephritis combining rituximab (anti-CD20) and belimumab (anti-BAFF). The main goal of the study is to assess the reduction (and seroconversion) of pathogenic autoantibodies, to evaluate clinical improvement and assess the safety and feasibility of long-term B-cell depletion.
Detailed description
Introduction Systemic lupus erythematosus (SLE) affects predominantly young women with childbearing potential (20-40 years) and inflammation can occur in virtually every organ, including kidneys, lungs, heart or brain. The disease course in SLE patients is typically characterized by frequent flares, requiring immunosuppressive treatment. Current, evidence-based treatment modalities for SLE consist of immunosuppressive treatment with high dose corticosteroids, cyclophosphamide or mycophenolic mycophenolate acid, that non-specifically target the immune system to reduce inflammation. Side-effects of these treatment strategies are (opportunistic) infections in the short term and risk for malignancy and cardiovascular disease in the long-term. Treating SLE patients with biologicals is an attractive alternative because biologicals specifically target the immune system by blocking cytokines or deplete one specific cell population, thereby reducing the risk for infections or malignancies as compared to conventional immunosuppressants. Furthermore, the scarce treatment options underscore the need to exploit new therapeutic possibilities for SLE patients who frequently experience a flare of the disease. These considerations led to the present study involving a proof-of-concept study in refractory SLE patients to assess the immunological consequences of a combination treatment with rituximab (anti-CD20) and belimumab (anti-BAFF).
Objective of the study:
A proof-of-concept study in refractory SLE patients to assess the immunological consequences of a combination treatment with rituximab (anti-CD20) and belimumab (anti-BAFF) to achieve long-term B-cell depletion. The immunological and clinical monitoring of refractory SLE patients will be monitored and the safety and feasibility of this combination treatment evaluated.
Study design:
This is a single-center, non-randomized, phase 2A, proof-of-concept study to evaluate the effects of a combination treatment with rituximab and belimumab. This combination therapy is designed to induce long-term B-cell depletion to achieve significant reduction of autoantibody-mediated immune complexes. In addition to standard therapy, SLE patients will receive 2 infusions of rituximab 1000 mg on day 0 and 14 (week 2) and belimumab on day 28 (week 4) , 42 (week 6) and 56 (week 8), then every 28 days. The primary endpoint is at 24 weeks after which an extended follow-up will take place, for subjects continuing belimumab, until 104 weeks after treatment start.
Rituximab and Belimumab will be administered intravenously according to the manufacturer's instructions. Clinical and immunological parameters will be assessed every 8-12 weeks. The study medication is not blinded for patients nor physicians. The study intends to include 15 refractory SLE patients.
Study population:
Patients with systemic lupus erythematosus, older than 18 years with refractory disease as specified by the inclusion criteria (mentioned above)
Intervention:
Rituximab Patients will be intravenously treated with Rituximab 1000mg on day 0 and day 14. Before every infusion of Rituximab patients will receive intravenous hydrocortisone 100mg together with oral acetaminophen 1000 mg and intravenous Tavegil 2 mg.
Belimumab Patients will be intravenously treated with Belimumab 10mg/kg on day 28, day 42 and day 56. Thereafter, patients will receive Belimumab 10mg/kg every 4 weeks. No pre-medication is administered
Primary study parameters/outcome of the study:
In this proof-of-concept study the primary objective is to assess whether a combination treatment of rituximab and belimumab will lead to a sustained reduction of pathogenic autoantibodies.
Secondary study parameters/outcome of the study:
The main secondary objective is to evaluate the effects of long-term B-cell depletion which will involve assessments of the clinical response correlated with immunological parameters. To this end, the relevant study parameters will be evaluated after 4 weeks (short term), 24 weeks (intermediate term) and 104 weeks (long-term).
The safety and feasibility of the combination treatment according to the WHO toxicity criteria
The clinical response of refractory SLE patients upon long-term B-cell depletion by:
- a reduction in SLEDAI scores, no new BILAG (British Isles Lupus Assessment Group) A involvement and the SLE responder index
- in case of lupus nephritis: the number of partial and complete renal responders
- the number of moderate or severe flares and renal flares
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Rituximab with belimumab | Experimental | Drug: Rituximab with belimumabRituximab 1000mg on day 0 and day 14 Belimumab 10mg/kg on day 28, day 42 and day 56. Thereafter, patients will receive Belimumab 10mg/kg every 4 weeks. |
Who may qualify
- Ages
- 18 to 64 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (22 listed)
- age 18 years,
- American College of Rheumatology (ACR) diagnosis of SLE (1997 revised criteria, see appendix 1)
- Severe SLE flare at screening (see also section 5.2.3.2.), defined as a situation in which 1 or more of the following criteria are met:
- Refractory disease, defined as persisting or progressive disease activity (SLEDAI > 6 points) despite conventional immunosuppressive treatment and 1 or more of the following criteria:
- ANA seropositivity, as defined by a positive ANA-titer = 1:80, before and at screening :
Key exclusion criteria (7 listed)
- Active pregnancy, as proven by a positive urine beta-HCG (human chorionic gonadotropin) test or a positive serum beta-HCG
- Significant B-cell depletion (peripheral B-cell counts < 60x10E6)
- Significant hypogammaglobulinemia (IgG < 8.0 g/L)
- Immunization with a live vaccine 1 month before screening
- Active infection at time of screening, as follows:
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Rituximab with belimumabAlso: BelimumabRituximab treatment on dag 0 and 14, 1000mg iv Belimumab 10mg/kg on day 28, day 42 and day 56. Thereafter, patients will receive Belimumab 10mg/kg every 4 weeks through 72 weeks. | Drug | Rituximab with belimumab |
Primary outcome
Reduction of pathogenic autoantibodies
Time frame: 24 weeks
A sustained reduction of pathogenic autoantibodies, in particular anti-dsDNA autoantibodies, at 24 weeks after treatment start.
5 secondary outcomes
Seroconversion of pathogenic autoantibodies, in particular anti-dsDNA autoantibodies
Time frame: 4, 24, 104 weeks
Safety and feasibility: number of patients with (serious) adverse events
Time frame: 4, 24, 104 weeks
Safety and feasibility: number of patients with infectious events
Time frame: 4, 24, 104 weeks
Safety and feasibility: number of patients with serious hypersensitivity or infusion reactions
Time frame: 4, 24, 104 weeks
Clinical response
Time frame: 4, 24, 104 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Feb 2019.
- Derived from this study: PubMed 29636274Kraaij T, Kamerling SWA, de Rooij ENM, van Daele PLA, Bredewold OW, Bakker JA, Bajema IM, Scherer HU, Toes REM, Huizinga TJW, Rabelink TJ, van Kooten C, Teng YKO. The NET-effect of combining rituximab with belimumab in severe systemic lupus erythematosus. J Autoimmun. 2018 Jul;91:45-54. doi: 10.1016/j.jaut.2018.03.003. Epub 2018 Apr 7.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Onno YK Teng, MD, PhD principal investigator
Leiden University Medical Center
A J Rabelink, MD, PhD principal investigator
Leiden University Medical Center
T WJ Huizinga, MD, PhD principal investigator
Leiden University Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Rituximab with belimumab in people with Lupus Erythematosus, Systemic, run by Leiden University Medical Center at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 22 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 28 Feb 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Reduction of pathogenic autoantibodies (time frame: 24 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02284984, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Feb 2019.