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 | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10042947 |
E.1.2 | Term | Systemic lupus erythematosus synd |
E.1.2 | System Organ Class | 100000004859 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10029142 |
E.1.2 | Term | Nephritis systemic lupus erythematosus |
E.1.2 | System Organ Class | 100000004857 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10042948 |
E.1.2 | Term | Systemic lupus erythematosus syndrome aggravated |
E.1.2 | System Organ Class | 100000004859 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
In this study the primary objective is to assess long-term efficacy of the combination treatment of belimumab with rituximab (BLM+RTX) compared to standard of care with mycophenolate and steroids and the association with more effective and sustained B-cell depletion. The primary clinical efficacy parameter is treatment failure rate during the 2 year study period. The main functional and immunological parameter for autoreactive B-cells is the reduction of disease relevant autoantibodies, in particular anti-dsDNA autoantibodies, at 28 weeks after treatment. |
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E.2.2 | Secondary objectives of the trial |
The evaluation of long-term effects of BLM+RTX with respect to clinical response correlated to immunological parameters in comparison to standard of care with mycophenolate+steroids; a.the sustained reduction of pathogenic autoantibodies, in particular anti-dsDNA autoantibodies at 28+104 weeks b.seroconversion of pathogenic autoantibodies, in particular anti-dsDNA autoantibodies at 28+104 weeks c.the reduction of memory B-cells at 28+104 weeks d.the regression of excessive NET formation at 28+104 weeks e.the feasibility of the combination treatment with tapering of concomitant immunosuppression f.the safety of the combination treatment according to the Common toxicity Criteria developed by the National Cancer Institute g.the clinical response other than treatment failure;reduction in SLEDAI scores and no worsening of PGA, in case of lupus nephritis:the number of partial and complete renal responders, the number of moderate or severe flares and renal flares, time to treatment failure |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects enrolled in the study must meet the following inclusion criteria: 1) Age 16 years, 2) Have a clinical diagnosis of SLE according to the SLICC criteria 2012 (see appendix 1) 3) Severe, active SLE disease (see also section 5.3.3.2.), defined as a situation in which 1 or more of the following criteria are met: a. SLEDAI (SLE Disease Activity Index) with 12 or more points b. New or worse SLE-related activity of major organs, i.e.: CNS-SLE (includes NPSLE), vasculitis, nephritis, pericarditis and/or myocarditis, myositis, thrombocytopenia < 60, hemolytic anemia < 4.4mmol/L (=7.0g/dL) c. high disease activity that requires or warrants induction treatment by switching to or increasing dosage of oral mycophenolate 4) Persisting or progressive disease activity despite the use of conventional maintenance immunosuppressive treatment (e.g. mycophenolate or azathioprine) 5) Positive for relevant SLE-specific autoantibodies defined as a situation in which 1 or more of the following criteria are met: a. 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. b. 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. 6) Female subjects are eligible to enter the study if she is: - Not pregnant or nursing - Of non-child-bearing potential (i.e. after hyseterectomy, postmenopausal, bilateral ovariectomy or documented bilateral tubal ligation or other permanent female sterilization procedure) - Use of effective contraception: • Complete abstinence from intercourse from 2 weeks prior to administration of the 1st dose of study agent until 16 weeks after the last dose of study agent (Sexual inactivity by abstinence must be consistent with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception; OR • Consistent and correct use of 1 of the following acceptable methods of birth control for 1 month prior to the start of the study agent, during the study, and 16 weeks after the last dose of study agent: o Oral contraceptive, either combined or progestogen alone o Injectable progestogen o Implants of levonorgestrel or etonogestrel o Estrogenic vaginal ring o Percutaneous contraceptive patches o Intrauterine device (IUD) or intrauterine system (IUS) with <1% failure rate as stated in the product label o Male partner sterilisation (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject. For this definition, “documented” refers to the outcome of the investigator's/designee’s medical examination of the subject or review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject’s medical records. o Double barrier method: condom and occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent (foam/gel/film/cream/suppository) • These allowed methods of contraception are only effective when used consistently, correctly and in accordance with the product label. The investigator is responsible for ensuring subjects understand how to properly use these methods of contraception. • Female subjects using mycophenolate mofetil (MMF) should be made aware that MMF affects the metabolism of oral contraceptives and may reduce their effectiveness. As such, women receiving MMF who are using oral contraceptives for birth control should employ an additional method (e.g., barrier method).
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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 hypogammaglobulinemia (IgG < 4.0 g/L) or an IgA deficiency (IgA < 0.1 g/L) 3) Immunization with a live vaccine 1 month before screening 4) Active infection at time of screening, as follows: - Hospitalization for treatment of infection within previous 60 days 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 60 days of day 0 of the study - Serological evidence of uncontrolled, active viral hepatitis defined as: patients positive for HbsAg test or HBcAb or a positive hepatitis C antibody not treated with antiviral medication 5) Have a historically positive HIV test or test positive at screening for HIV 6) Have a history of a primary immunodeficiency 7) Have a neutrophil count of < 1.5x10E9/L 8) Have a significant infection history that in the opinion of the investigator would make the candidate unsuitable for the study 9) Have a history of an anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies 10) Have any other clinically significant abnormal laboratory value in the opinion of the investigator 11) Have current drugs or alcohol abuse or dependence within 365 days prior to Day 0 of the study 12) Have an active malignant neoplasm or one in the history of 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 13) Have evidence of serious suicide risk including any history of suicidal behavior in the last 6 months and/or any suicidal ideation in the last 2 months or who, in the investigator’s opinion, poses a significant suicide risk 14) Have any other clinically significant abnormal laboratory value, any intercurrent significant medical or psychiatric illness that in the opinion of the investigator would make the candidate unsuitable for the study
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E.5 End points |
E.5.1 | Primary end point(s) |
With the above-described detailed evaluations, in order to assess the study’s primary endpoint, we will compare the treatment failure rate during the 2 years study period between the two treatment arms. |
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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) |
In order to assess the study’s main secondary endpoints, the percentage reduction in absolute serum levels of anti-dsDNA autoantibodies per patient at week 28 compared to baseline values. For other secondary endpointswe will: Ad a. A sustained reduction of serum levels of anti-dsDNA autoantibodies will be defined as the absence of a doubling of serum level on at least 2 consecutive visits or a seroconversion to positive on at least 2 consecutive visits
Ad b. Seroconversion of anti-dsDNA autoantibodies will be defined by the immunofluorescence assay when changed from (strongly) positive to negative or to ‘weakly’ positive
Ad c. The reduction of memory B-cells will be assessed by flowcytometry and quantified as the percentage reduction in absolute CD19+CD27+ memory B-cell counts
Ad d. A sustained reduction of CD19+CD27+ memory B-cell will be defined as the absence of an increase in their absolute number on flowcytometry on at least 2 consecutive visits
Ad e. A regression in excessive NET formation will be quantified by an in-house established assay where ‘normal’ amount of NET formation is assessed by serum from normal human subjects. The regression in sera from SLE patients is calculated in relation to the negative control of normal human serum, as described by the assay.
Ad f. A sustained regression of excessive NET formation will be defined as the absence of a doubling of NET formation on at least 2 consecutive visits Ad g & h. Feasibility and safety of combination treatment will be assessed by monitoring the occurrence of hypogammaglobulinemia, infectious events and allergic events
Ad i. Clinical responses will be evaluated.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Relevant study parameters will be evaluated after 28 weeks, 60 weeks and 104 weeks |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Immunological secondairy endpoints to assess whether a combination treatment of belimumab with rituximab will lead to the improvement of pivotal, SLE-specific autoimmune phenomena compared SLE patients treated with conventional immunosuppression |
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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) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
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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last visit of the last subject |
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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 | 7 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |