E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Generalized Myasthenia Gravis |
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E.1.1.1 | Medical condition in easily understood language |
Generalized Myasthenia Gravis |
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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 effect of pozelimab + cemdisiran and cemdisiran monotherapy on daily functioning that is impacted by signs and symptoms in patients with symptomatic generalized myasthenia gravis (gMG) |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the effect of pozelimab + cemdisiran (ie, combination) and cemdisiran monotherapy on: − Clinician-assessed signs of MG and muscle strength − Proportion of patients with improvements in daily function impacted by signs and symptoms of MG − Proportion of patients that have improvements in clinician-assessed signs of MG and muscle strength − Health related quality of life − Proportion of patients with minimal MG symptoms − Patient- and clinician-reported signs and symptoms of MG • To evaluate the safety and tolerability of pozelimab + cemdisiran and cemdisiran monotherapy • To assess the: − Concentration of total of pozelimab in serum - Concentration of total C5 in plasma − Concentrations of cemdisiran and its metabolites in plasma − Immunogenicity of pozelimab - Immunogenicity of cemdisiran • To study the effect of pozelimab + cemdisiran and cemdisiran monotherapy on complement activation |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Future Biomedical Research (Optional) Patients who agree to participate in the FBR sub-study will be required to consent to this optional sub-study before samples are banked for FBR. Additional samples will be collected for FBR. The samples may be utilized for FBR that may or may not be directly related to the study, including being used as reference samples and assay development or validation.
Pharmacogenomic Analysis (Optional) Patients who agree to participate in the genomics sub-study will be required to consent to this optional sub-study before collection of the samples. DNA and RNA samples will be collected for pharmacogenomics analyses to understand the genetic determinants of efficacy and safety associated with the treatments in this study and the molecular basis of MG and related diseases. |
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E.3 | Principal inclusion criteria |
1. Male or female patients ≥18 years of age at screening (or ≥ legal age of adulthood based on local regulations, whichever is older) 2. Patient with documented diagnosis of myasthenia gravis (MG) based on medical history and supported by previous evaluations as described in the protocol 3. Documented prior history of positive serologic test or a positive result during screening of anti-acetylcholine receptor (AChR) antibodies or anti-LRP4 antibodies. 4. Myasthenia Gravis Foundation of America (MGFA) Clinical Classification Class II to IVa at screening 5. Myasthenia Gravis-Activities of Daily Living (MG-ADL) score ≥6 at screening. Ocular items should not contribute more than 50% of MG-ADL total score 6. Currently receiving an acetylcholinesterase inhibitor or documented reason for not using acetylcholinesterase inhibitor therapy per investigator 7. Currently receiving an immunosuppressive therapy (IST) for MG, or documented reason why the patient is not taking an IST per investigator 8. If currently receiving an IST, not anticipated to have IST dosage changed before randomization or during double-blind treatment period (DBTP). 9. Willing and able to comply with clinic visits and study-related procedures, including completion of the primary series of the meningococcal vaccinations required per protocol
NOTE: Other Inclusion Criteria apply |
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E.4 | Principal exclusion criteria |
1. Patients with antibody profile that is only positive for MuSK (MuSK positivity is based on a documented prior history of positive serologic test for antibodies to MuSK or a positive result during screening) 2. History of thymectomy within 12 months prior to screening or planned during the study 3. History of malignant thymoma (patients with stage 1 may be enrolled), or history of cancer within the past 5 years, except for adequately treated basal cell skin cancer, squamous cell skin cancer, or in situ cervical cancer 4. Myasthenic crisis or Myasthenia Gravis Foundation of America (MGFA) Class V within 1 month of screening 5. Not meeting meningococcal vaccination requirements and, at a minimum, documentation of quadrivalent meningococcal vaccination within 5 years prior to the screening visit and serotype B vaccine within 3 years prior to the screening visit as described in the protocol 6. Known contraindication to meningococcal vaccines (group ACWY conjugate and group B vaccines) as described in the protocol 7. Patients who require antibiotics for meningococcal prophylaxis and have a contraindication, warning, or precaution precluding the use of penicillin class and penicillin-alternative antibiotics planned to be used for prophylaxis, or a history of intolerance leading to the discontinuation of these antibiotics 8. Positive hepatitis B surface antigen or hepatitis C virus ribonucleic acid (RNA) during screening. Note: Cases with unclear interpretation should be discussed with the medical monitor 9. History of HIV infection or a positive test at screening per local requirements
NOTE: Other Exclusion Criteria apply |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in Myasthenia Gravis-Activities of Daily Living (MG-ADL) total score |
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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. Change from baseline in Quantitative Myasthenia Gravis (QMG) score 2. Proportion of patients responding on the MG-ADL, with a responder defined as one with a ≥3-point improvement 3. Proportion of patients responding on the QMG, with a responder defined as one with a ≥5-point improvement 4. Proportion of patients with consistent response on the MG-ADL, defined as patients with at least a 2-point MG-ADL improvement on 2 or more consecutive assessments spanning 4 or more weeks during the DBTP 5. Proportion of patients with minimal symptom expression (MSE, defined by a score of 0 to 1 on the MG-ADL) 6. Change from baseline in the Myasthenia Gravis Composite (MGC) total score 7. Change from baseline in Myasthenia Gravis Quality of Life (MG QOL15r) total score 8. Proportion of patients with improvement point thresholds of ≥2, 4, 5, 6, 7, 8, 9, or 10 on MG-ADL 9. Proportion of patients with improvement point thresholds of ≥3, 4, 6, 7, 8, 9, or 10 on QMG 10. Incidence and severity of treatment-related adverse events (TEAEs), serious adverse events (SAEs), and adverse events of special interest (AESIs) in patients treated with pozelimab + cemdisiran, cemdisiran monotherapy, or placebo 11. Concentrations of total pozelimab in serum at nominal time points 12. Concentrations of total complement component 5 (C5) in plasma at nominal timepoints 13. Concentrations of cemdisiran and its metabolites in plasma at nominal time points 14. Incidence of treatment-emergent anti-drug antibodies (ADAs) to pozelimab after repeated doses over time 15. Incidence of treatment-emergent ADAs to cemdisiran after repeated doses over time 16. Change and percent change in CH50 over time
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1,5-7: Week 24 2-4, 8-9, Baseline to Week 24 10: Through week 24 11-15: Though study duration, approximately 172 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 | Yes |
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 | 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 | 34 |
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 |
Taiwan |
Australia |
Brazil |
Canada |
China |
Georgia |
India |
Japan |
Korea, Republic of |
Serbia |
United Kingdom |
United States |
Belgium |
Denmark |
France |
Germany |
Italy |
Poland |
Spain |
Türkiye |
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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 study is defined as the date the last patient completes the last study visit, withdraws from the study, or is lost to follow-up (ie, the study patient can no longer be contacted by the investigator). |
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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 | 6 |
E.8.9.1 | In the Member State concerned days | |
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 |