E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Generalized Myasthenia Gravis (gMG) |
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E.1.1.1 | Medical condition in easily understood language |
Myasthenia gravis is a rare neuromuscular disorder that causes weakness in the skeletal muscles. Myasthenia gravis affecting multiple muscle groups throughout the body is called gMG. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
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 | 10028417 |
E.1.2 | Term | Myasthenia gravis |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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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 |
• To evaluate the efficacy of satralizumab versus placebo on function in daily life in the acetylcholine receptor antibody seropositive (AChR+) population |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of satralizumab versus placebo on function in daily life in the overall population (OP) • To evaluate the efficacy of satralizumab versus placebo in the AChR+ and OP on QMG, QoL, Fatigue, Clinical status and Disease severity • To evaluate the durability of the efficacy of satralizumab versus placebo in the AChR+ population and the OP • To evaluate the safety of satralizumab versus placebo • To confirm target engagement and pathway inhibition in response to satralizumab • To investigate the pharmacokinetics (PK) of satralizumab • To evaluate the immune response to satralizumab
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Age >=12 years at time of signing Informed Consent Form • Confirmed diagnosis of gMG • MGFA class II, III or IV at screening • A total MG-ADL score of >=5 points at screening with more than 50% of this score attributed to non-ocular items • Ongoing gMG treatment at a stable dose and not exceeding the maximum protocol allowed doses • For female patients of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use adequate contraception during the treatment period and for at least 3 months after the final dose of satralizumab
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E.4 | Principal exclusion criteria |
Exclusion Criteria Related to Myasthenia Gravis (MG): • History of thymic cysts, thymoma, thymic carcinoma or other neoplasm of the thymus as defined by the 2015 WHO classification of tumors of the thymus unless deemed cured by adequate treatment with no evidence of recurrence for >=5 years before screening • History of thymectomy within 6 months prior to screening • Ocular MG (Myasthenia Gravis Foundation of America [MGFA] Class I) • Myasthenic crisis within the last 3 months prior to screening (MGFA Class V) • Known disease other than gMG that would interfere with the course and conduct of the study
Exclusion Criteria Related to Previous or Concomitant Therapy: • Use of IVIg or subcutaneous immunoglobulin (SCIg) within 6 weeks prior to randomization (Day 1) • Use of PE within 8 weeks prior to randomization (Day 1) • Treatment with IL-6 inhibitory therapy (e.g., tocilizumab) at any time, • Treatment with total body irradiation, or bone marrow transplantation at any time • Treatment with B and/or T cell-depleting agents • Treatment with anti-CD20 within 6 months prior to screening, unless CD19 counts are within normal range, as assessed by the central laboratory at screening • Treatment with C5 complement inhibitors (e.g., eculizumab or ravulizumab) within 6 months prior to screening • Treatment with neonatal Fc receptor antagonists within 6 months prior to screening • Treatment with anti-B-lymphocyte stimulator monoclonal antibody at any time • Treatment with cyclophosphamide IV within 6 months prior to screening • Treatment with oral cyclophosphamide at any time • Treatment with methotrexate within 8 weeks prior to screening • Treatment with any investigational agent within 24 weeks prior to screening or 5 drug-elimination half-lives of the investigational drug (whichever is longer) • Use of more than one IST as background therapy except for the combination of an oral corticosteroids (OCS) with another permitted IST drug
General Safety Exclusion Criteria: • Any surgical procedure (except for non-ophthalmic minor surgeries) within 4 weeks prior to baseline • Planned surgical procedure (exceptophthalmic minor surgeries) during the study • Evidence of progressive multifocal leukoencephalopathy • Evidence of serious uncontrolled concomitant diseases that may preclude patient participation • Congenital or acquired immunodeficiency, including human immunodeficiency virus (HIV) infection • Active or presence of recurrent bacterial, viral, fungal, mycobacterial infection, or other infection, excluding fungal infection of nail beds or dental caries at baseline • Infection requiring hospitalization or treatment with IV anti-infective agents within 4 weeks prior to baseline visit or oral anti-infective agents within 2 weeks prior to baseline visit • Positive screening tests for hepatitis B and C • History of drug or alcohol abuse within 1 year prior to baseline • History of diverticulitis or concurrent severe gastrointestinal (GI) disorders that, in the investigator’s opinion, may lead to increased risk of complications such as GI perforation • Evidence of latent or active tuberculosis • Receipt of live or live attenuated vaccine within 6 weeks prior to baseline • History of blood donation (one unit or more), plasma donation or platelet donation within 90 days prior to screening and Day 1 • History of malignancy within the last 5 years, including solid tumors, hematologic malignancies and in situ carcinoma • History of severe allergic reaction to a biologic agent • Active suicidal ideation within 6 months prior to screening or history of suicide attempt within 3 years prior to screening • Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study • Pregnant or breastfeeding, or intending to become pregnant during the study or within 3 months after the final dose of satralizumab
Laboratory Exclusion Criteria (at Screening): • White blood cells (WBC) <3.0*10^3/microliter • Absolute neutrophil count (ANC) <2.0*10^3/microliter • Absolute lymphocyte count <0.5*10^3/microliter • Platelet count <10*10^4/microliter • Aspartate aminotransferase (AST) or alanine transaminase (ALT) >1.5*upper limit of normal (ULN) |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Mean change from baseline in total MG-ADL score (AChR+ population) Week 24 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. From baseline to Week 24 |
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E.5.2 | Secondary end point(s) |
1. Mean change from baseline in total MG-ADL score (OP population) 2. Mean change from baseline in QMG score, MG-QOL 15r total score and Neuro-QoL Fatigue Subscale total score 3. Mean change from baseline in total Myasthenia Gravis Composite (MGC) score 4. Percentage of patients with a >=2-point reduction from baseline in total MG-ADL score 5. Percentage of patients with a >=3-point reduction from baseline in QMG score 6. Percentage of patients with a >=3-point reduction from baseline in total MGC score 7. Proportion of patients who have achieved minimal disease manifestation (total MG-ADL score of 0 or 1) 8. Proportion of patients with at least one gMG-related exacerbation and receiving rescue therapy between baseline and Week 24 9. Annualized rate of gMG-related exacerbations 10. Duration (average number of consecutive months) of meaningful improvement, defined as >=2-point reduction from baseline in total MG-ADL score 11. Absolute values of biomarkers interleukin-6 (IL-6) and soluble interleukin-6 receptor (sIL-6R) 12. Serum concentrations of satralizumab at specified timepoints 13. Apparent clearance (CL/F) of satralizumab at specified timepoints 14. Volume of distribution (V/F) of satralizumab at specified timepoints 15. Area under the concentration-time curve (AUC) of satralizumab at specified timepoints 16. Incidence of ADAs against satralizumab during the study 17. Prevalence of anti-drug antibodies (ADAs) against satralizumab at baseline 18. Incidence and severity of adverse events, with severity determined according to NCI CTCAE v5.0 grading 19. Change from baseline in targeted vital signs, ECG results, physical examination findings, targeted clinical laboratory test results, and suicidality
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-3. Baseline and Week 24 4-8. At Week 24 9. Baseline to Week 24 10-11. Baseline to Week 24 12-16. At Day 1, Weeks 2, 4, 8, 12, 16, 20, and 24 17. Predefined timepoints 18-19. Baseline to 24 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 | 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 | 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 |
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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) | 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 | Yes |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 37 |
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 |
Australia |
Brazil |
Canada |
China |
Japan |
United States |
Russian Federation |
Turkey |
Czechia |
Denmark |
France |
Germany |
Italy |
Netherlands |
Poland |
Spain |
Korea, Republic of |
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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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LPLV, or the date at which the last data point required for statistical analysis or SFU is received from the last patient, whichever occurs later. |
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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 | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
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 | 0 |