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 |
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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 | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10042945 |
E.1.2 | Term | Systemic lupus erythematosus |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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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 |
Evaluate the safety, efficacy, and immunological effects of anti-BAFF treatment Belimumab in lupus patients after B cell depletion therapy. |
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E.2.2 | Secondary objectives of the trial |
1. Anti-dsDNA antibody levels at 24 and 64 weeks. 2. Incidence of adverse events 3. Incidence of infections 4. Incidence of flare as defined as BILAG A or 2 B flares 5. Time to flare as defined as BILAG A or 2 B flares 6. Proportion of patients with a BILAG A or 2 B flare within 24, 52 and 64 weeks after randomisation. 7. SLEDAI 2000 at 52 weeks 8. Subject Global Assessment of Disease Activity (SGADA) at 52 weeks 9. C3 and C4 levels 10. Immunoglobulin levels 11. BAFF (measurement of RNA from whole blood). 12. Cumulative glucocorticoids dose 13. Proportion of patients decreasing the steroid dose by 50% without flaring, or if below 10mg/day reduce to 5mg/day or the proportion of patients who discontinue glucocorticoids with stable disease. 14. Lupus Quality of Life (Lupus QoL), SF-36 and EQ5D 15. C-SSRS (suicide assessment) 16. Kinetics of B cell repopulation, B and T cell phenotype and function during repopulation using Flow Cytometry (experimenta |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age between 18 and 75 years 2. Patients with 4 or more criteria for SLE according to the American College of Rheumatology (ACR) 1997 criteria or SLICC 2012 criteria or biopsy proven lupus nephritis with one additional supportive test on at least two occasions (positive ANA, anti-dsDNA antibodies or anti-Sm antibodies) 3. History of anti-dsDNA antibodies detectable at least once in the past. 4. Patients have received the first infusion of this cycle of B cell depletion therapy (rituximab) 4-6 weeks before randomisation (week 0, see participant timeline). 5. No contraindications to the use of belimumab. 6. Ability to provide informed consent |
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E.4 | Principal exclusion criteria |
Exclusion criteria: 1. Severe “critical” SLE flare defined as BILAG A flare in CNS system or any SLE manifestation requiring more immunosuppression than allowed within the protocol in the physician's opinion 2. Pregnancy and/or Breast Feeding patients 3. At risk of pregnancy and unwilling to use an acceptable form of birth control contraception (see section 6.3.1.4) 4. Prior use of Belimumab, Atacicept or any biologic therapy (except rituximab, but no other B cell depleting therapies) 5. Participation in any other interventional trial within the last 6 months 6. eGFR <30mls/min at screening 7. Active infections, including but not limited to: i. Current or past infection with hepatitis B or C as defined by: A. Hepatitis B surface antigen positive B. Hepatitis B surface antibody positive and hepatitis B core antibody positive C. Hepatitis C antibody positive ii. Historically positive HIV test or test positive at screening for HIV iii. Active TB. 8. Infection history: i. Currently on any suppressive therapy for a chronic infection (such as tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical mycobacteria) ii. Hospitalization for treatment of infection within 60 days of Day 0 iii. Use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or anti parasitic agents) within 60 days of Day 0 9. Receipt of a live-attenuated vaccine within 3 months of week 0 (see participant timeline) 10. In the investigator’s opinion, patients that are at high risk for infection (including but not limited to in dwelling catheter, dysphagia with aspiration, decubitus ulcer, history of prior aspiration pneumonia or recurrent severe urinary tract infection) 11. IgG levels below 4.0 g/L, IgA level < 10 mg/dL (IgG and IgA test must be performed no more than 10 days before study drug commenced for the second inclusion/exclusion criteria assessment at week 0) 12. Primary immunodeficiency 13. History of malignant neoplasm within the last 5 years 14. History of cervical dysplasia CIN Grade III cervical high risk human papillomavirus or abnormal cervical cytology other than abnormal squamous cells of undetermined significance (ASCUS) within the past 3 years. The patient will be eligible after the condition has resolved (e.g., follow-up HPV test is negative or cervical abnormality has been effectively treated >1 year ago) 15. Severe, progressive, or uncontrolled renal, hepatic, haematological, gastrointestinal, pulmonary, cardiac, or neurological disease or, in the investigator’s opinion, any other concomitant medical condition or significant abnormal laboratory value that places the participant at risk by participating in this study with the exception of diseases or conditions related to active SLE. 16. Comorbidities currently requiring systemic corticosteroid therapy. 17. 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 judgement, pose a significant risk. 18. History of an anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies. 19. Current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or dependence within 364 days prior to Day 0 20. White blood cells (WBC) <1.5 x 109/L, Neutrophils <1 x 109/L measured up to 10 days before week 0 (study drug commenced)
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome is Anti dsDNA-antibody levels at 52 weeks. |
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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) |
1. Anti-dsDNA antibody levels at 24 and 68 weeks. 2. Incidence of adverse events 3. Incidence of infections 4. Incidence of flare as defined as BILAG A or 2 B flares 5. Time to flare as defined as BILAG A or 2 B flares 6. Proportion of patients with a BILAG A or 2 B flare within 24, 52 and 64 weeks after randomisation. 7. SLEDAI 2000 at 52 weeks 8. Subject Global Assessment of Disease Activity (SGADA) at 52 weeks 9. C3 and C4 levels 10. Immunoglobulin levels 11. BAFF (measurement of RNA from whole blood). 12. Cumulative glucocorticoids dose 13. Proportion of patients decreasing the steroid dose by 50% without flaring, or if below 10mg/day reduce to 5mg/day or the proportion of patients who discontinue glucocorticoids with stable disease. 14. Lupus Quality of Life (Lupus QoL), SF-36 and EQ5D 15. C-SSRS (suicide assessment) 16. Kinetics of B cell repopulation, B and T cell phenotype and function during repopulation using Flow Cytometry. |
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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 | Yes |
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 | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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 | Yes |
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 | 16 |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 1 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 1 |