| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Myasthenia Gravis which is either due to acetylcholine receptor antibodies (AChR) or muscle specific kinase antibodies (MuSK). | |
| E.1.1.1 | Medical condition in easily understood language | | Myasthenia gravis (MG) is a rare autoimmune disorder, caused by binding of antibodies to the acetylcholine receptor (AChR) or functionally related molecules on the postsynaptic neuromuscular junction. | |
| 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 | 10028417 | | E.1.2 | Term | Myasthenia gravis | | E.1.2 | System Organ Class | 10029205 - Nervous system disorders | |
| 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 assess whether inebilizumab can reduce MG-related
disability. | |
| E.2.2 | Secondary objectives of the trial | - To evaluate whether inebilizumab can reduce the frequency of MG exacerbations.
- To evaluate whether inebilizumab can improve MG-related quality of life.
- To evaluate the safety and tolerability of inebilizumab in MG.
- To characterize the pharmacokinetic (PK) profile and immunogenicity of inebilizumab in patients with MG. | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | 1. Age ≥ 18 years
2. Diagnosis of MG with anti-AChR or anti-MuSK antibody.
3. MGFA Clinical Classification Class II, III, or IV.
4. MG-ADL score of 6 or greater at screening and at randomization with >50% of this score attributed to non-ocular items.
5. QMG score of 11 or greater.
6. Subjects must be on:
a. Corticosteroids only, with no dose increase within 4 weeks prior to randomization, or
b. One allowed non-steroidal IST, with continuous use for at least 6 months prior to randomization and no dose increase within 4 months prior to randomization, or
c. Combination of (1) corticosteroids with no dose increase within 4 weeks prior to randomization and (2) one allowed nonsteroidal IST with continuous use for at least 6 months prior to randomization and no dose increase within 4 months prior to randomization.
Allowed ISTs, alone or in combination with corticosteroids, are azathioprine, mycophenolate mofetil, and mycophenolic acid.
7. Females of childbearing potential who are sexually active with a nonsterilized
male partner must use at least one highly effective
contraception method from the time of screening and for 6 months after
the final dose of IP. Periodic abstinence, the rhythm method, and the
withdrawal method are not acceptable methods of contraception.
8. Non-sterilized males who are sexually active with a female partner of
childbearing potential must use a condom from Day 1 for the duration of
the study and for 3 months after the last dose of IP. Because male
condom is not a highly effective contraception method, it is strongly
recommended that female partners of a male study subject also use a
highly effective method of contraception throughout this period
| |
| E.4 | Principal exclusion criteria | 1.Lactating or pregnant females, or females who intend to become pregnant anytime from signing the informed consent form (ICF) throughout the RCP plus 6 months following last dose of IP.
2.Known immunodeficiency disorder, including human immunodeficiency virus (HIV) infection.
3.Thymectomy within ≤ 12 months prior to baseline (Day 1) visit or planned thymectomy during the duration of the RCP.
4.Receipt of the following medications or treatments at any time prior to randomization:
a.Alemtuzumab (Lemtrada®, Campath®)
b.Total lymphoid irradiation
c.Bone marrow transplant
d.T-cell vaccination therapy
e.Natalizumab (Tysabri®)
5.Receipt of rituximab (MabThera®, Rituxan®), ocrelizumab (Ocrevus®), ofatumumab (Arzerra®), obinutuzumab (Gazyva®), inebilizumab, or any experimental B-cell depleting agent within the 6 months prior to Day 1, unless the subject has a CD19+ B-cell count ≥ 40 cells/µL according to the central laboratory at screening.
6.Receipt within the 3 months prior to Day 1:
a.Tocilizumab (Actemra®)
b.Belimumab (Benlysta®)
c.Eculizumab (Soliris®)
d.Cyclophosphamide (Cytoxan®)
7.Receipt within the 4 weeks prior to Day 1:
a.Cyclosporine (except eye drops)
b.Tacrolimus (except topical)
c.Methotrexate
d.Intravenous immunoglobulin (IVIg)
e.Plasma exchange (PLEX) treatment
8.Current use of:
a.Prednisone > 40 mg/day or > 80 mg over a 2-day period (or equivalent dose of other corticosteroids)
b.Pyridostigmine > 480 mg/day or unstable dose in the 2 weeks prior to Day 1
c.Azathioprine > 3 mg/kg/day
d.Mycophenolate mofetil > 3 g/day or mycophenolic acid > 1440 mg/day
9.Receipt of a live attenuated vaccine within 4 weeks prior to randomization. Administration of inactivated (killed) vaccines is acceptable.
10.Unresected thymoma (Note: subjects with a benign thymoma resected > 1 year prior to screening may enroll. Benign is defined as no known metastases and no extension into or beyond the capsule on pathological examination. Imaging to evaluate for thymoma must have been performed prior to randomization per standard of care).
11.History of cancer, except for the following:
a.In situ carcinoma of the cervix treated with apparent success with curative therapy for > 12 months prior to screening
b.Cutaneous basal cell or squamous cell carcinoma treated with apparent success with curative therapy for > 12 months prior to screening
c.Prostate cancer treated with radical prostatectomy or radiation therapy with curative intent > 3 years prior to screening and without known recurrence or current treatment
d.Malignant thymoma resected > 5 years prior to screening with no evidence of active disease and no therapy received over the previous 5 years.
12.Any of the following laboratory abnormalities at screening (one repeat test may be conducted to confirm results prior to randomization within the same screening period):
a.Elevated liver enzymes (aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × upper limit of normal (ULN)).
b.Total bilirubin > 1.5 × ULN (unless due to Gilbert’s syndrome)
c.Estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m2
d.CD19+ B-cell count < 40 cells/µL
e.Absolute neutrophil count (ANC) < 1.2 × 103 cells/µl
f.Platelet count < 75,000/μL (or < 75 × 109/L)
g.Hemoglobin < 8.0 g/dL
h.Total immunoglobulin < 600 mg/dL
13.Positive test for chronic hepatitis B infection at screening, defined as either (1) positive hepatitis B surface antigen (HBsAg) or (2) a positive hepatitis B core antibody (anti‑HBc) PLUS negative hepatitis B surface antibody (anti-HBs).
Note: Subjects with a positive anti-HBs only, or a positive anti-HBc plus positive anti‑HBs and negative HBsAg, are eligible to enroll.
14.Positive test for hepatitis C virus antibody.
15.Positive HIV test.
16.History of active or latent tuberculosis (TB), or a positive QuantiFERON®-TB Gold test at screening, unless treatment for tuberculosis was completed per local guidelines. Subjects with latent TB or a positive QuantiFERON®-TB Gold test who are actively on anti-TB treatment can enroll if they have completed at least 1 month of anti-TB treatment and intend to complete the full course of anti-TB treatment. Subjects with an indeterminate QuantiFERON®-TB Gold test result can enroll if a repeat QuantiFERON®-TB Gold is negative or a tuberculin skin test is negative.
| |
| E.5 End points |
| E.5.1 | Primary end point(s) | | Change from baseline in Myasthenia Gravis Activities of Daily Living (MG-ADL) Profile score at end of the RCP | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | | Week 52 for AChR-Ab+ population and Week 26 for MuSK-Ab+ population | |
| E.5.2 | Secondary end point(s) | Key secondary endpoints:
- Change in Quantitative Myasthenia Gravis (QMG) scores at the end of the RCP.
- Proportion of subjects with both (1) ≥ 3-point improvement in MG-ADL at end of RCP and (2) no use of rescue therapy.
- Change in MG-ADL at Week 26 in the AChR-Ab+ population.
Additional secondary endpoints:
- Time to first exacerbation.
- Change in Myasthenia Gravis Composite (MGC) score.
- Change in Myasthenia Gravis Quality of Life-15, revised (MGQOL-15r) score .
- Change in Patient Global Impression of Change (PGIC) score.
- The safety and tolerability of inebilizumab as measured by the incidence of TEAEs, adverse events of special interest (AESIs), and TESAEs. Laboratory measurements will also be evaluated as part of safety.
- PK profile of inebilizumab.
- ADA status and titer.
| |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | | Week 52 for AChR-Ab+ population and Week 26 for MuSK-Ab+ population | |
| 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 | 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 | 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 | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description | | The second part of trial is optional and open label | |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 | | Belarus | | Brazil | | Canada | | China | | Denmark | | Finland | | France | | Germany | | Guatemala | | India | | Israel | | Italy | | Japan | | Poland | | Russian Federation | | Spain | | Turkey | | Ukraine | | 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 | | The study will be complete when the last active subject completes the Day 547 visit of the OLP, discontinues the OLP, or (for patients who have opted out of the OLP) completes the RCP. | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| 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 |
