E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
LN is inflammation of the kidney that is caused by systemic lupus erythematous (SLE) which is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue. |
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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 | PT |
E.1.2 | Classification code | 10025140 |
E.1.2 | Term | Lupus nephritis |
E.1.2 | System Organ Class | 10038359 - Renal and urinary 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 |
To evaluate the efficacy of obinutuzumab compared with placebo based on proportion of patients who achieve a complete renal response (CRR) at Week 76 |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of obinutuzumab compared with placebo based on proportion of patients who achieve CRR with estimated glomerular filtration rate (eGFR) criterion at Week 76, overall renal response (ORR) at Week 50, change in anti-double stranded DNA antibody (anti-dsDNA) titer and C3 from baseline to Week 50, change eGFR from baseline to Week 76, change in SLE Disease Activity Index 2000 (SLEDAI-2K) from baseline to Week 76, time to onset of CRR and change in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) from baseline to Week 76.
• To evaluate the safety of obinutuzumab compared with placebo
• To characterize the obinutuzumab pharmacokinetic profile
• To evaluate the immune response to obinutuzumab
• To characterize the obinutuzumab-induced changes in circulating B-cells |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age 18-75 years
- Ability to comply with the study protocol, in the investigator's judgment
- International Society of Nephrology / Renal Pathology Society (ISN/RPS) 2003 Class III or IV LN by renal biopsy performed in the 6 months prior to screening or during screening
- Diagnosis of SLE according to the 2019 European League Against Rheumatism/ American College of Rheumatology (EULAR/ACR) Classification Criteria, which are met by the presence of Class III or IV LN (above) and: Current or past positive antinuclear antibody (ANA), as evidenced by ANA at a titer of >= 1:80 on HEp-2 cells or an equivalent positive ANA test at least once
- Urinary protein-to-creatinine ratio >= 1 on a 24-hour collection at screening
- Receipt of at least one dose of pulse methylprednisolone IV (>= 250 mg) or equivalent for treatment of the current episode of active LN during the 6 months prior to screening or during screening; a maximum of 3 g methylprednisolone IV or equivalent during the 4 weeks prior to screening or during screening is allowed.
- For women of childbearing potential: agreement to remain abstinent or use contraception, and agreement to refrain from donating eggs, women must remain abstinent or use two methods of contraception, including at least one method with a failure rate of < 1% per year, during study treatment and for 18 months after the final dose of obinutuzumab and 6 weeks after the final dose of mycophenolate mofetil (MMF)
- For men: agreement to remain abstinent or use contraceptive methods, and agreement to refrain from donating sperm, with a female partner of childbearing potential who is not pregnant, men who are not surgically sterile must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for 90 days after the final dose of MMF and for 90 days after the final dose of obinutuzumab study drug; With a pregnant female partner, men must remain abstinent or use a condom during the treatment period and for 90 days after the final dose of MMF and for 12 months after the final dose of obinutuzumab or placebo to avoid exposing the embryo.
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E.4 | Principal exclusion criteria |
- Pregnant or breastfeeding, or intending to become pregnant during the study or within 18 months after the final dose of obinutuzumab or placebo or within 6 weeks after the final dose of MMF
- Severe renal impairment, as defined by eGFR < 30 mL/min/1.73 m2 or the need for dialysis or renal transplantation
- Sclerosis in > 50% of glomeruli on renal biopsy
- Presence of rapidly progressive glomerulonephritis
- Receipt of an excluded therapy
- Severe, active central nervous system SLE, including retinitis, poorly-controlled seizure disorder, acute confusional state, myelitis, stroke, cerebellar ataxia, or dementia
- High risk for clinically-significant bleeding or any condition requiring plasmapheresis, intravenous immunoglobulin, or acute blood product transfusions
- Significant or uncontrolled medical disease which, in the investigators opinion, would preclude patient participation
- HIV and Tuberculosis infection; latent TB after completion of appropriate treatment is not exclusionary.
- Active infection of any kind, excluding fungal infection of the nail beds
- Any major episode of infection that required hospitalization or treatment with IV antibiotics or anti-infectives during the 8 weeks prior to screening or during screening; antibiotics or anti-infectives given in the absence of a major episode of infection are not exclusionary.
- History of serious recurrent or chronic infection
- History of progressive multifocal leukoencephalopathy
- History of cancer, including solid tumors, hematological malignancies, and carcinoma in situ, within the past 5 years
- Major surgery requiring hospitalization during the 4 weeks prior to screening or during screening
- Current alcohol or drug abuse or history of alcohol or drug abuse within 12 months prior to screening or during screening
- Intolerance or contraindication to study therapies
- Laboratory parameters
• AST or ALT > 2.5 × upper limit of normal (ULN)
• Amylase or lipase > 2 × ULN
• Neutrophils < 1.5 × 103/µL
• Positive hepatitis B surface antigen (HBsAg)
• Positive hepatitis C serology
• Hemoglobin < 7 g/dL, unless caused by autoimmune hemolytic anemia resulting from SLE
• Platelet count < 25,000/µL
• Positive serum human chorionic gonadotropin measured at screening
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E.5 End points |
E.5.1 | Primary end point(s) |
Proportion of patients who achieve a CRR at Week 76 |
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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. Proportion of patients who achieve CRR with eGFR criterion at Week 76
2. Proportion of patients who achieve an ORR, evaluated at Week 50
3. Change in anti-dsDNA titer from baseline to Week 50
4. Change in C3 from baseline to Week 50
5. Change in SLEDAI-2K from baseline to Week 76
6. Change in eGFR from baseline to Week 76
7. Time to onset of CRR over the course of 76 weeks
8. Change in FACIT-F scale from baseline to Week 76
9. Incidence and severity of adverse events, with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0
10. To characterize adverse events of special interest, including among others, IRRs, neutropenia, infections and thrombocytopenia.
11. Change from baseline in targeted vital signs
12. Change from baseline in targeted clinical laboratory test results
13. Maximum observed concentration (Cmax) of obinutuzumab
14. Minimum observed concentration (Cmix) of obinutuzumab
15. Area under concentration- time curve (AUC) of obinutuzumab
16. Clearance (CL) of obinutuzumab
17. Prevalence of anti-drug antibodies (ADAs) at baseline and incidence of ADAs post-treatment during the study
18. Total peripheral B-cell count at specified timepoints |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. At Week 76
2. At Week 50
3-4. Baseline (Day 1) to Week 50
5-8. Baseline to Week 76
9-10. Up to 8.5 years
11-12. Baseline to 8.5 years
13-16. Baseline, Week 2, 4, 12, 24, 26, 36, 50, 64, 76, 80, 106, 132,158, 184, every 6 months thereafter, unplanned visit (UV) and at study discontinuation (SD); open label extension(OLE): Baseline, Week 2, 4, 12, 24, 26, 36, 50, 64, 76, every 6 months thereafter, UV, SD
17. Baseline, Week 2, 4, 12, 24, 36, 50, 76, 80, 106, 132,158, 184, every 6 months thereafter, UV, SD; OLE: Baseline, Week 2, 12, 24, 36, 50, 76, every 6 months thereafter, UV, SD
18. Baseline, Week 4, 12, 24, 50, 76, 80, 106, 158, UV; OLE: Baseline, Week 4, 12, 24, 52, 76, UV
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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 | Yes |
E.6.6 | Pharmacokinetic | Yes |
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) | 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) | No |
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 | No |
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 | 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 |
Colombia |
France |
Germany |
Israel |
Italy |
Mexico |
Peru |
Poland |
Russian Federation |
South Africa |
Spain |
United Kingdom |
United States |
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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
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The end of this study is defined as the date when the last patient, last visit (LPLV), occurs or the date at which study follow-up is received from 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 | 11 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 11 |