E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Systemic lupus erythematosus |
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E.1.1.1 | Medical condition in easily understood language |
systemic lupus erythematosus |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025139 |
E.1.2 | Term | Lupus erythematosus systemic |
E.1.2 | System Organ Class | 100000004859 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
In this proof-of-concept study the primary objective is to assess whether a combination treatment ofrituximab (anti-CD20) and belimumab (anti-BAFF) will lead to a sustained reduction of pathogenic autoantibodies and thereby inhibition of NET formation, which portentially forms the basis of a new therapeutic approach in severe SLE. |
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E.2.2 | Secondary objectives of the trial |
Secondary goals are to evaluate clinical improvement, reduction of circulating immune complexes, safety and feasibility. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
4.1. Inclusion criteria
Subjects enrolled in the study must meet the following inclusion criteria:
1) age 18 years,
2) ACR diagnosis of SLE (1997 revised criteria, see appendix 1)
3) 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.: CNS-SLE (includes NPSLE), vasculitis, nephritis, pericarditis and/or myocarditis, myositis, trombocytopenia < 60, hemolytic anemia < 4.4mmol/L (=7.0g/dL).
4) Refractory disease, defined as persisting or progressive disease activity (SLEDAI > 6 points) despite conventional immunosuppressive treatment and 1 or more of the following criteria:
- 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).
5) 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.
6) 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.
7) 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%
8) Use of effective contraception
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E.4 | Principal exclusion criteria |
Subjects will be excluded from participation if they meet any of the following exclusion criteria:
1) Active pregnancy, as proven by a positive urine beta-HCG test or a positive serum beta-HCG
2) Significant B-cell depletion (peripheral B-cell counts < 60x10E6)
3) Significant hypogammaglobulinemia (IgG < 8.0 g/L)
4) Immunization with a live vaccine 1 month before screening
5) 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-bacterials, anti-virals, anti-fungals or anti-parasitic agents) within previous 2 months of day 0 of the study
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E.5 End points |
E.5.1 | Primary end point(s) |
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 and thereby inhibition of NET formation. Therefore, the primary endpoints are:
- a sustained reduction of pathogenic autoantibodies, in particular anti-dsDNA autoantibodies, at 24 weeks after treatment start
- an inhibition of the formation of NETs at 24 weeks after treatment start
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
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 secondary endpoints measured at these times are:
- the effects on the reduction of pathogenic autoantibodies, in particular anti-dsDNA autoantibodies
- the inhibition of the formation of NETs
- seroconversion of pathogenic autoantibodies, in particular anti-dsDNA autoantibodies
- the normalization of complement usage, i.e. C3/C4 levels and C1Q-binding
Other secondary objectives are to evaluate:
- 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 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 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
4 weeks (short term), 24 weeks (intermediate term) and 104 weeks (long-term). |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The trial ends at the last visit of the last patient |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |