| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Myasthenia gravis, a neuromuscular disease. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| 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 evaluate the efficacy of nipocalimab compared to placebo based on the Myasthenia Gravis-Activities of Daily Living (MG-ADL) scale, in
seropositive generalized myasthenia gravis (gMG) participants when treatment is taken as directed. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy of nipocalimab compared to placebo based on the Quantitative Myasthenia Gravis (QMG) scale, in seropositive gMG participants when treatment is taken as directed.
- To evaluate the effect of nipocalimab compared to placebo in achieving the minimum clinically important difference or better based on the MGADL scale, in seropositive gMG participants when treatment is taken as directed.
- To evaluate the efficacy of nipocalimab loading dose compared to placebo based on the MG-ADL scale, in seropositive gMG participants when treatment is taken as directed.
- To evaluate sustainability of therapeutic response of nipocalimab compared to placebo based on the MGADL scale, in seropositive gMG participants when treatment is taken as directed.
-To evaluate the effect of nipocalimab compared to placebo on the percentage of participants achieving ≥50% symptom improvement based on the MG-ADL scale, in seropositive gMG participants when treatment is taken as directed. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
RANDOMIZED PHASE:
1. ≥18 years of age at the time of consent (and must meet the legal age of consent).
2. Diagnosis of MG with generalized muscle weakness meeting the clinical criteria for gMG as defined by the MGFA Clinical Classification Class II a/b, III a/b, or IVa/b at screening. (Seronegative participants are no longer being recruited; all participants must have a positive serologic test for a gMG-related pathogenic autoantibody (anti-AChR, anti-MuSK and/or anti-LRP4 autoantibodies), confirmed prior to randomization.)
3. MG-ADL score of ≥6 at screening and baseline.
4. Has suboptimal response to current stable therapy for gMG according to the investigator.
Stable therapy is defined in the protocol.
5. A participant using herbal, naturopathic, traditional Chinese remedies, ayurvedic or nutritional supplements, or medical marijuana is eligible if the use is acceptable to the investigator.
6. Participants who have undergone splenectomy must be at least 3 months post resection prior to screening and must be vaccinated as per the United States Center for Disease Control and Prevention annual Recommended Immunization Schedule for Adults Aged 19 Years or Older, United States. (https://www.cdc.gov) OR must be vaccinated as per country- or territory-specific guidelines or local regulations.
7. Has sufficient venous access to allow drug administration by infusion and blood sampling as per the protocol.
8. Is recommended to be up to date on all age-appropriate vaccinations prior to screening as per routine local medical guidelines. It is recommended to have COVID-19 vaccination at least 2 weeks prior study visits.
9. Man or woman (according to their reproductive organs and functions assigned by
chromosomal complement).
10. A woman of childbearing potential must have a negative highly sensitive serum at Screening and a negative urine pregnancy test at Day 1 prior to administration of study intervention.
11. A woman must be
a. Not of childbearing potential
b. Of childbearing potential and
- Practicing a highly effective, preferably user-independent method of contraception and agrees to remain on a highly effective method while receiving study intervention and until 60 days after last dose. The investigator should evaluate the potential for contraceptive method failure in relationship to the first dose of study intervention.
12. A woman must agree not to donate eggs (ova, oocytes), or freeze for future use for the purposes of assisted reproduction, during the study and for a period of 30 days after the administration of study intervention.
13. A male participant must wear a condom when engaging in any activity that allows for passage of ejaculate to another person during the study and for at least 90 days after receiving the last administration of study intervention. In addition, male participants with partners who are a woman of childbearing potential are highly encouraged to inform their partner to use highly effective contraception methods that result in a low
failure rate (less than 1% per year).
14. A male participant must agree not to donate sperm for the purpose of reproduction during the study and for a minimum 90 days after receiving the last administration of study intervention.
15. Must sign an ICF indicating that the participant understands the purpose of, and procedures required for, the study and is willing to voluntarily participate in the study and comply with all study procedures.
16. Must be able to read and write.
OLE PHASE:
Participants who have completed the 24-week double-blind placebo-controlled phase are eligible to enter the OLE phase.
Participants who had study intervention discontinued for a reason other than the need for hospitalization or rescue therapy (IVIg, plasmapheresis), and who completed the scheduled of assessments for the full 24-week double-blind placebo-controlled phase, may enter the OLE based on the investigator’s discretion.
Participants affected by interruption of theMOM-M281-005 study due to the COVID 19 pandemic must meet the following Inclusion Criteria:
1. The investigator has confirmed that the participant is not receiving, or has not received since the interruption of the Phase 2 study, any medication that might put the participant at risk when receiving nipocalimab or might interfere with the assessment of the safety of nipocalimab.
2. Randomized inclusion point 6
3. Randomized inclusion point 7
4. Is recommended to be up to date on all age-appropriate vaccinations prior to screening as
per routine local medical guidelines. It is strongly recommended to have COVID-19 vaccination at least 2 weeks before the study visits.
5. Sex and Contraceptive/Barrier Requirements as outlined in Double-blind
Placebo-Controlled Phase inclusion criteria # 9, #10, #11, #12, #13, and #14 above.
6. Randomized inclusion point 15
|
|
| E.4 | Principal exclusion criteria |
1. Has a history of severe and/or uncontrolled hepatic (eg,
viral/alcoholic/autoimmune hepatitis/cirrhosis and/or metabolic liver
disease), gastrointestinal, renal, pulmonary, cardiovascular, psychiatric, neurological or musculoskeletal disorder, hypertension or, any other medical disorder(s) (eg, diabetes mellitus), or clinically significant
abnormalities in screening laboratory, that, in the opinion of the investigator, might interfere with the patient's full participation in the study, and/or might jeopardize the safety of the participant or the
validity of the study results.
2. Has any confirmed or suspected clinical immunodeficiency syndrome not related to treatment of his/her gMG, or has a family history of congenital or hereditary immunodeficiency unless confirmed absent in the participant.
3. Has MGFA Class I disease or presence of MG crisis (MGFA Class V) at screening, history of MG crisis within 1 month of screening, or fixed weakness (and/or ‘burnt out’ MG).
4. Is dependent on gastric tube for nutritional needs or is ventilator-dependent.
5. Is actively undergoing radiation or chemotherapy for an unresected thymoma/malignant thymoma.
6. Has had a thymectomy within 12 months prior to screening, or thymectomy is planned during the study.
7. Has current or a history of any neurologic disorder other than MG that might interfere with the accuracy of study assessments.
8. Currently has a malignancy or has a history of malignancy within 3 years before screening.
9. Has known allergies, hypersensitivity, or intolerance to nipocalimab or its excipients (refer to the IB).
10. Has shown a previous severe immediate hypersensitivity reaction, such as anaphylaxis to therapeutic proteins (eg, monoclonal antibodies).
11. Has experienced myocardial infarction, unstable ischemic heart disease, or stroke within 12 weeks of screening.
12. Is planning to father a child while enrolled in this study or donate sperm within 90 days after the last administration of IMP.
13. Is currently breastfeeding, pregnant, planning pregnancy, or egg donation during the study or within 30 days after the last dose of IMP.
14. History of moderate or severe substance or alcohol use
15. Is currently taking IgG Fc-related protein therapeutics, or Fc-conjugated therapeutic agents, including factor or enzyme replacement.
16. Has received, rituximab within 6 months prior to first administration of IMP, except for returning Phase 2 participants.
17. Has received, or is expected to receive, a live vaccine within 4 weeks prior to screening or has a known need to receive a live vaccine during the study, or within 8 weeks after the last administration of study intervention.
18. Has received plasmapheresis, immunoadsorption therapy, or IVIg within 6 weeks prior to baseline.
19. Has another medical condition that requires corticosteroids unless the dose has been stable for at least 4 weeks prior to baseline and is expected to remain stable during the study.
20. Has another medical condition that requires an immunosuppressive agent unless the medication has been used for at least 6 months, the dose has been stable for at least 3 months prior to baseline and the medication and the dose are expected to remain stable during the study.
21. Has previously received nipocalimab. (Not applicable to returning Phase 2 participants)
22. Is receiving or has received an investigational intervention (including investigational vaccines) within 3 months or 5 half-lives (whichever is longer) or used an invasive investigational medical device within 3 months before the planned first dose administration of IMP.
23. Has a severe infection including opportunistic infections requiring parenteral anti-infectives and/or hospitalization, and/or is assessed as serious/clinically significant by the investigator, within 8 weeks prior to screening. The participant may be rescreened after the 8-week exclusionary period has passed.
24. Has a chronic infection or requires chronic treatment with anti-infectives.
25. Tests positive for hepatitis B virus infection
26. Is seropositive for antibodies to hepatitis C virus unless they satisfy 1 of the following conditions listed in the protocol.
27. History of being human immunodeficiency virus (HIV)1 or HIV2 antibody-positive, or tests positive for HIV at screening.
28. COVID-19 infection or contact with infected persons as per the protocol
29. Has current suicidal ideation evidenced by a “yes” response to Questions 4 or 5 in the C-SSRS at screening or baseline, or a history of suicidal ideation/behavior in the past year prior to screening.
30. Had major surgery within 3 months before screening, or will not have fully recovered from surgery, or has surgery planned during the time of participation in the study.
31. Criterion removed per Am 1.
32. Is an employee of the investigator or study site |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Average change from baseline (screening and Day 1) in MG-ADL total score over Weeks 22, 23 and 24. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Throughout the double-blind phase of the study.
|
|
| E.5.2 | Secondary end point(s) |
1. The average change in the QMG score over Weeks 22 and 24. Analyzed using a similar method (appropriate for the region) as for the primary efficacy endpoint, but since the QMG is not assessed at Week 23, the contrast will average the change from baseline over Weeks 22 and 24 of the double-blind placebo-controlled phase.
2. Percentage of participants whose average MG-ADL total score over weeks 22, 23 and 24 of the double blind, placebo-controlled phase is at least a 2-point improvement compared to baseline. The average score for a participant is the average of the non-missing values at Weeks 22, 23 and 24. A participant must have a non-missing value at Week 24 and at least 1 non-missing value at Week 22 or 23 in order to have a nonmissing average score. A participant with a missing average score will be considered a nonresponder. Analyzed by Cochran-Mantel-Haenszel test controlling for the baseline MG-ADL total score randomization strata (≤ 9, >9), autoantibody status, and region.
3. Loading dose response, defined for each participant as improvement in the MG-ADL total ≥2 points at Week 1 and/or Week 2. A participant with a missing assessment at either time point will be considered a nonresponder at that time point. Analyzed by Cochran-Mantel-Haenszel test controlling for the baseline MG-ADL total score randomization strata (≤9, >9), autoantibody status, and region.
4. Sustainability of therapeutic response, defined as the percentage of participants with improvement in MG-ADL total score of ≥ 2 points at Week 4 through Week 24, with no more than 2 non-consecutive excursions allowed between Week 6 through Week 23 (excursions defined as loss of improvement in MG-ADL score of ≥ 2 points from baseline). A participant with a missing assessment at a time point will be considered a nonresponder at that time point. Analyzed by CochranMantel-Haenszel test controlling for the baseline MG-ADL total score randomization strata (≤9, >9), autoantibody status, and region.
5. Percentage of participants whose average MG-ADL total score over weeks 22, 23 and 24 of the double-blind, placebo-controlled phase is at least a 50% improvement compared to baseline. The average score for a participant is the average of the non-missing values at Weeks 22, 23 and 24. A participant must have a non-missing value at Week 24 and at least 1 non-missing value at Week 22 or 23 in order to have a non-missing average score. A participant with a missing average score will be considered a nonresponder. Analyzed by Cochran-Mantel-Haenszel test controlling for the baseline MG-ADL total score randomization strata (≤ 9, >9), autoantibody status, and region.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- QMG score over Weeks 22 and 24.
- MG-ADL total score over weeks 22, 23 and 24
- Loading dose response at Week 1 and/or Week 2.
- Sustainability of therapeutic response Week 4 through Week 24
- Average MG-ADL total score over weeks 22, 23 and 24 |
|
| 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 | 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 |
| Randomized, double blind, placebo controlled phase followed by an Open Label extension phase. |
|
| 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 | 44 |
| 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 |
| Australia |
| Canada |
| China |
| Japan |
| Korea, Republic of |
| Mexico |
| Taiwan |
| United States |
| Belgium |
| Czechia |
| Denmark |
| France |
| Germany |
| Italy |
| Poland |
| Spain |
| Sweden |
|
| 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 end of study is considered as the last visit for the last participant in the study. |
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | 28 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 22 |
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