| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Systemic Lupus Erythematosus (SLE) or Lupus |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 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 |
|
| 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 |
| To evaluate the efficacy of belimumab and a single cycle of rituximab administered in a combination regimen to adult participants with SLE. |
|
| E.2.2 | Secondary objectives of the trial |
To assess the safety and tolerability of belimumab and a single cycle of rituximab
administered in a combination regimen to adult participants with SLE
To assess the impact of belimumab and a single cycle of rituximab administered in a combination regimen to adult participants with SLE on PROs |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Participant must be ≥ 18 years of age at the time of signing the informed consent.
2. Have a clinical diagnosis of SLE based on 4 or more of the 11 American College of
Rheumatology (ACR) criteria.
3. Have a screening SLEDAI-2K score ≥6 (This refers to the total score.
Serological activity, i.e., anti-double
stranded deoxyribonucleic acid [dsDNA]) positivity and/or hypocomplementemia is not required to be
present in SLEDAI-2K assessment, but are scored if present).
4. Have unequivocally positive autoantibody test results defined as an anti-nuclear (ANA) titer ≥ 1:80 and/or a positive anti-dsDNA ( ≥30 IU/mL) serum antibody test from 2 independent time points as follows:
Positive test results from 2 independent time points within the study screening period. Screening results must be based on the study's central laboratory results
OR
One positive historical test result and 1 positive test result during the screening
period.
NOTE: Historical documentation of a positive test of ANA (e.g., ANA by HEp-2
titer) and anti-dsDNA (e.g., anti-dsDNA by Farr assay) that must include the
date and type of the test, the name of the testing laboratory and numerical reference range, whenever available. Only unequivocally positive values as defined in the laboratory's
reference range are acceptable; borderline values will not be accepted.
5. Are on a 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 (i.e., day of first dose of study treatment) with the exception that switching one agent for another of the same class for tolerability or availability reasons, which will be allowed within 30 days of Day 1.
∙Corticosteroids (prednisone or prednisone equivalent)
∙For those subjects on alternating daily doses of steroids, use the average of 2
daily doses to calculate the average daily steroid dose.
∙Any immunosuppressant or immunomodulatory agents including methotrexate, azathioprine, leflunomide, mycophenolate (including mycophenolate mofetil, mycophenolate mofetil hydrochloride, and
mycophenolate sodium), calcineurin inhibitors (e.g. tacrolimus, cyclosporine), sirolimus, cyclophosphamide, 6- mercaptopurine, mizoribine, or thalidomide. (Note: oral cyclophosphamide use is exclusionary in Germany)
∙Anti-malarials (e.g., hydroxychloroquine, chloroquine, quinacrine).
∙Non-steroidal anti-inflammatory drugs (NSAIDs).
NOTES:
Corticosteroids may be added as a new medication or their doses adjusted up to 30 days prior to Day 1.
New SLE therapy other than corticosteroids must not be added within 60 days
prior to Day 1.
6. Male and/or female
A female participant is eligible to participate if she is not pregnant (see Appendix 3 of the study protocol), not breastfeeding, and at least one of the following conditions applies:
(i) Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 (of the study protocol)
OR
(ii) A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 (of the study 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 rituximab placebo, whichever is later.
7. Capable of giving signed informed consent as described in Appendix 4 (of the study protocol) which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. |
|
| E.4 | Principal exclusion criteria |
1. Symptomatic herpes zoster within 3 months prior to screening.
2. Evidence of active or latent tuberculosis (TB). Documentation may include medical history and examination, chest X-rays (posterior, anterior, and lateral), and TB testing
3. Significant allergies to humanized monoclonal antibodies.
4. History of hypersensitivity to belimumab and/or rituximab or known to have titers of human anti-mouse antibody or history of hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal antibodies.
5. Lymphoma, leukemia, or any malignancy within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years.
6. Alanine transferase (ALT) >2x upper limit of normal (ULN).
7. Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is
fractionated and direct bilirubin <35%).
8. IgA deficiency (IgA level < 10 mg/dL).
9. IgG < 250 mg/dL. (Note: <400 mg/dL for Germany only)
10. Neutrophils < 1.5 x 10 to the power of 9
11. Current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.
12. Severe heart failure (New York Heart Association Class IV) or other severe,
uncontrolled cardiac disease.
13. QTc >450 msec or QTc >480 msec in participants with bundle branch block.
14. Have a history of a major organ transplant or hematopoietic stem cell/marrow transplant.
15. Have clinical evidence of significant unstable or uncontrolled acute or chronic
diseases not due to SLE which, in the opinion of the principal investigator, could confound the results of the study or put the subject at undue risk.
16. Have an acute or chronic infection requiring management as follows:
Currently on any suppressive therapy for a chronic infection
∙Hospitalization for treatment of infection within 60 days of Day 1.
∙Have had infection requiring treatment with parenteral (IV or IM) antibiotics within 60 days of Day 1. Prophylactic anti-infective treatment is allowed.
17. Have severe lupus kidney disease (defined by proteinuria >6 g/24 hour or equivalent using spot urine protein to creatinine ratio, or serum creatinine >2.5 mg/dL), or have severe active nephritis requiring induction therapy not permitted by protocol, or have required hemodialysis or high dose prednisone or equivalent (>100 mg/day) within 90 days of Day 1.
18. Have severe active central nervous system (CNS) lupus (including seizures, psychosis, organic brain syndrome, cerebrovascular accident (CVA), cerebritis, or
CNS vasculitis) requiring therapeutic intervention within 60 days of Day 1.
19. Have a planned surgical procedure, laboratory abnormality, or condition that, in the opinion of the principal investigator, makes the subject unsuitable for the study.
20. Have evidence of serious suicide risk, including any history of suicidal behavior in the last 6 months and/or any suicidal ideation of type 4 or 5 on the C-SSRS in the last 2 months or who, in the investigator's opinion, pose a significant suicide risk.
21. Have a history of an anaphylaxis reaction to parenteral administration of contrast agents, human or murine proteins, or monoclonal antibodies.
22. Live vaccine(s) within 1 month prior to screening, or plans to receive such vaccines during the screening period or during the study.
23. Have received any of the following within 364 days of Day 1:
∙Belimumab.
∙Rituximab.
∙Abatacept.
∙Any B cell targeted therapy anti-Interferon alpha agents or anti-BLyS other than belimumab).
∙A biologic investigational agent other than B cell targeted therapy
24. Have required 3 or more courses of systemic corticosteroids (e.g., IV pulse therapy or high dose oral treatment) within 364 days of Day 1. (Topical or inhaled steroids are permitted.)
25. Have received any of the following within 90 days of Day 1:
∙Anti-TNF therapy
∙Interleukin-1 receptor antagonist
∙ Intravenous immunoglobulin
∙ High dose prednisone or equivalent
∙Plasmapheresis
26. Have received any of the following within 60 days of Day 1:
∙A non-biologic investigational agent
∙Intravenous (IV) cyclophosphamide or oral cyclophosphamide and, for Germany only, oral cyclophosphamide
∙Any steroid injection
27. Positive immunodeficiency virus (HIV) antibody test.
28. Positive serology for Hepatitis B, defined as (i) HB surface antigen positive
(HBsAg+) OR (ii) HB core antibody positive (HBcAb+).
29. Positive Hepatitis C (HCV) antibody test.
30. Have current drug or alcohol dependence, or a history of drug or alcohol abuse or dependence within 364 days prior to Day 1.
See Study Protocol Section 6.2 for full list of exclusion critieria |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Proportion of participants with a state of disease control defined as a SLEDAI- 2K
score ≤2, achieved without immunosuppressants and with corticosteroids at a prednisone equivalent dose of ≤5mg/day at Week 52. (Serological activity, i.e., anti-dsDNA positivity and/or hypocomplementemia, is scored in the SLEDAI-2K endpoint.) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Proportion of participants with a state of clinical remission defined as a Clinical
SLEDAI-2K score =0, achieved without immuno-suppressants and with
corticosteroids at a prednisone equivalent dose of 0 mg/day at Week 64. (Serological activity score, i.e., anti-dsDNA positivity and/or hypocomplementemia, is excluded from the Clinical SLEDAI-2K endpoint.)
Proportion of participants with a state of disease control defined as a SLEDAI-2K
score ≤2, achieved without immunosuppressants and withcorticosteroids at a prednisone equivalent dose of ≤5 mg/day at Week 104.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| 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) | No |
| 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 | 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Brazil |
| Canada |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | 3 |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 3 |
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