A Study of Nipocalimab Administered to Adults With Generalized Myasthenia Gravis

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of nipocalimab compared to placebo in participants with generalized myasthenia gravis (gMG).

Detailed Description
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Myasthenia gravis (MG) is a rare, heterogeneous, neuromuscular disease characterized by fluctuating, fatigable muscle weakness. MG is caused by pathogenic autoantibodies that impair cholinergic transmission in the postsynaptic membrane at the neuromuscular junction and impair or prevent muscle contraction. Nipocalimab (also referred to as JNJ-80202135 or M281) is a fully human, aglycosylated immunoglobulin (Ig)G1 monoclonal antibody (mAb) designed to selectively bind, saturate, and block the IgG binding site on the endogenous neonatal Fc receptor (FcRn). This study will consist of a screening phase (up to 4 weeks), treatment phase (a 24-week double-blind placebo-controlled phase, and an open-label extension [OLE] phase [up to 2 years]) and a follow-up safety visit (up to 8 weeks after last infusion of study intervention). Efficacy evaluations will include assessments such as Myasthenia Gravis - Activities of Daily Living (MG-ADL) score. Safety evaluations (such as adverse events, physical examination, vital signs, electrocardiogram [ECG], and clinical laboratory tests) will be performed. The overall duration of study will be up to 4 years and 8 months.

Official Title
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Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Nipocalimab Administered to Adults With Generalized Myasthenia Gravis

Conditions
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Myasthenia Gravis

Intervention / Treatment
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* Drug: Nipocalimab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of myasthenia gravis (MG) with generalized muscle weakness meeting the clinical criteria for generalized myasthenia gravis (gMG) as defined by the Myasthenia Gravis Foundation of America (MGFA) Clinical Classification Class II a/b, III a/b, or IVa/b at screening Myasthenia Gravis - Activities of Daily Living (MG-ADL) score of greater than or equal to (>=) 6 at screening and baseline Has sufficient venous access to allow drug administration by infusion and blood sampling as per the protocol A woman of childbearing potential must have a negative highly sensitive serum (beta-human chorionic gonadotropin [beta-hCG]) at screening and a negative urine pregnancy test at Day 1 prior to administration of study intervention 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 Exclusion Criteria: 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 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) Has had a thymectomy within 12 months prior to screening, or thymectomy is planned during the study Has known allergies, hypersensitivity, or intolerance to nipocalimab or its excipients Has experienced myocardial infarction, unstable ischemic heart disease, or stroke within 12 weeks of screening

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nipocalimab<br>Double-blind Placebo-controlled Phase: Participants will receive nipocalimab intravenous (IV) infusions once every 2 weeks (q2w) up to 24 weeks during double-blind placebo-controlled phase. Open-label Extension (OLE) Phase: Participants who complete the double-blind placebo-controlled phase will enter the OLE phase and continue to receive nipocalimab q2w IV infusion till study end. | Drug: Nipocalimab<br>* Nipocalimab will be administered as an IV infusion.<br>* Other names: JNJ-80202135, M281;|
| Placebo Comparator: Placebo<br>Double-blind Placebo-controlled Phase: Participants will receive matching placebo of nipocalimab IV infusion q2w up to 24 weeks during double-blind placebo-controlled phase. | Drug: Placebo<br>* Matching placebo will be administered as an IV infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average Change from Baseline in Myasthenia Gravis - Activities of Daily Living (MG-ADL) Score | Average change from baseline in MG-ADL score over Weeks 22, 23 and 24 of the double-blind placebo-controlled phase will be reported. Averaging over multiple time points (Weeks 22, 23 and 24) will be done to get a single measure. The MG-ADL provides a rapid assessment of the participant's MG symptom severity. Eight functions (talking, chewing, swallowing, breathing, impairment of ability to brush teeth or comb hair, impairment of ability to arise from a chair, double vision, eyelid droop) are rated on a 4-point scale: 0 (no impairment) to 3 (severe impairment). The total score will be sum of eight function scores and can range from 0 to 24. A higher score indicates greater symptom severity. | Baseline up to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average Change in Quantitative Myasthenia Gravis (QMG) Score Over Weeks 22 and 24 of the Double-blind Placebo-controlled Phase | Average change in QMG score over Weeks 22 and 24 of the double-blind placebo-controlled phase will be reported. The QMG test is a standardized quantitative strength assessment comprising 13 components. The quantitative results of each strength component are mapped to the following 4-point scale: 0 equals to (=) none, 1 = mild, 2 = moderate and 3 = severe. The total score will be sum of 13 components scores and can range from 0 to 39. A higher score indicates greater weakness. | Up to Weeks 22 and 24 | 
| Percentage of Participants whose Average MG-ADL Total Score Over Weeks 22, 23, and 24 is at least a 2-Point Improvement from Baseline of the Double-blind Placebo-controlled Phase | Percentage of participants whose average MG-ADL total score over Weeks 22, 23, and 24 is at least a 2-point improvement from baseline of the double-blind placebo-controlled phase will be reported. | Baseline up to Weeks 22, 23 and 24 | 
| Percentage of Participants with Improvement in MG-ADL Total Score Greater Than Or Equal to (>=) 2 Points at Week 1 and/or Week 2 of the Double-blind Placebo-controlled Phase | Percentage of participants with improvement in MG-ADL total score >= 2 points at Week 1 and/or Week 2 of the double-blind placebo-controlled phase will be reported. | Weeks 1 and 2 | 
| Percentage of Participants with Improvement in MG-ADL Total Score >= 2 Points at Week 4 through Week 24 of the Double-blind Placebo-controlled Phase with No More Than 2 Non-consecutive Excursions Allowed Between Weeks 6 through Week 23 | Percentage of participants with improvement in MG-ADL total score >= 2 points at Week 4 through Week 24 of the double-blind placebo-controlled phase with no more than 2 non-consecutive excursions allowed between Weeks 6 through Week 23 (excursion is defined as loss of improvement in MG-ADL score >= 2 points from baseline) will be reported. | Week 4 up to Week 24 | 
| Percentage of Participants whose Average Improvement in MG-ADL Total Score Over Weeks 22, 23, and 24 of the Double-blind, Placebo-controlled Phase is at Least a 50% Improvement from Baseline | Percentage of participants whose average improvement in MG-ADL total score over Weeks 22, 23, and 24 of the double-blind, placebo-controlled phase is at least a 50% improvement from baseline will be reported. | Baseline, Weeks 22, 23 and 24 | 
| Percentage of Participants with Adverse Events (AEs) | An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. | Up to Week 24 of double-blind placebo-controlled phase and up to extension Week 24 of open-label extension phase (up to Week 48) | 
| Percentage of Participants with Serious Adverse Events (SAEs) | A SAE is any untoward medical occurrence that at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is a suspected transmission of any infectious agent via a medicinal product; is medically important. | Up to Week 24 of double-blind placebo-controlled phase and up to extension Week 24 of open-label extension phase (up to Week 48) | 
| Percentage of Participants with Adverse Events of Special Interest (AESIs) | Percentage of participants with AESIs will be reported. Treatment-emergent AEs associated with the following situations are considered as AESI: 1) severe or medically significant or immediately life-threatening infections requiring intravenous (IV) anti-infective or operative/invasive intervention or requiring hospitalization or prolongation of existing hospitalization; 2) hypoalbuminemia with albumin less than (<) 20 grams per liter (g/L). Treatment-emergent AEs are defined as AEs with onset or worsening on or after date of first dose of study treatment. | Up to Week 24 of double-blind placebo-controlled phase and up to extension Week 24 of open-label extension phase (up to Week 48) | 
| Percentage of Participants with Change in Vital Signs | Percentage of participants with change in vital signs (temperature, blood pressure and heart rate) will be reported. | Up to Week 24 of double-blind placebo-controlled phase and up to extension Week 24 of open-label extension phase (up to Week 48) | 
| Percentage of Participants with Change in Clinical Laboratory Values | Percentage of participants with change in clinical laboratory (serum chemistry, hematology, lipid profiles and urinalysis) values will be reported. | Up to Week 24 of double-blind placebo-controlled phase and up to extension Week 24 of open-label extension phase (up to Week 48) | 
| Percentage of Participants with Change in Columbia-Suicide Severity Rating Scale (C-SSRS) Score | Percentage of participants with change in C-SSRS scale score will be reported. C-SSRS is semi structured clinician-administered questionnaire designed to solicit the occurrence, severity, and frequency of suicide-related ideation and behaviors. Total score ranges from 1 to 10. Higher scores indicate greater severity. | Up to Week 24 of double-blind placebo-controlled phase and up to extension Week 24 of open-label extension phase (up to Week 48) | 
| Percentage of Participants with Improvement in QMG Score of >= 3 Points from Baseline at Week 2 through Week 24 of the Double-blind Placebo-controlled Phase with No More than 2 Non-consecutive Excursions Allowed at Weeks 4 through 22 | Percentage of participants with improvement in QMG score of >= 3 points from baseline at Week 2 through Week 24 of the double-blind placebo-controlled phase with no more than 2 non-consecutive excursions allowed at weeks 4 through 22 (excursions defined as loss of improvement in QMG score of >= 3 points from baseline) will be reported. | Week 2 up to Week 24 | 
| Average Change From Baseline in the Fatigue Items of the Quality of Life in Neurological Disorders Scale (Neuro-QoL Fatigue) Total Score Over Weeks 22 and 24 of Double-blind Placebo-controlled Phase | Average change from baseline in the Neuro-QoL Fatigue total score over Weeks 22 and 24 of double-blind placebo-controlled phase will be reported. Neuro-QoL fatigue is a 19-item questionnaire developed and validated for use in common neurological conditions which assesses patient-reported fatigue and associated impact on physical, mental, and social activities during the past 7 days. Each item included in the Neuro-QoL Fatigue questionnaire is graded on a 5-point Likert-type scale (1=Never; 2=Rarely; 3=Sometimes; 4=Often; 5=Always). The total scores are calculated by summing 19 items score and can range from 19-95. Higher score reflects more fatigue. | Baseline up to Weeks 22 and 24 | 
| Average Change from Baseline in the Revised Myasthenia Gravis Quality of Life - 15 Scale (MG-Qol15r) Score Over Weeks 22 And 24 of the Double-blind Placebo-controlled Phase | Average change from baseline in the MG-QoL15r score over Weeks 22 and 24 of the double-blind placebo-controlled phase will be reported. The MG-QoL15r is a participant-reported outcome instrument that measures MG-specific health-related quality of life. The MG-QoL15r contains 15 items that evaluate patients' experience related to Myasthenia Gravis over the past few weeks on a 3-point Likert-type scale (0=Not at all; 1=Somewhat; 2=Very much). The total score of the MG-QoL15r can be calculated by summing 15 items score and can range from 0 to 30. A higher score indicates poorer health related quality of life. | Baseline up to Weeks 22 and 24 | 
| Change from Baseline in the Visual Analog Scale (VAS) Score of European Quality of Life (EuroQol) 5-Dimension 5-Level (EQ-5D-5L) Scale Over 24 Weeks of the Double-blind Placebo-controlled Phase | Change from baseline in the VAS score of EQ-5D-5L scale over 24 weeks of the double-blind placebo-controlled phase will be reported. EQ-5D-5L is a 2-part instrument for use as a measure of health outcome, designed for self-completion by respondents. It consists of EQ-5D-5L descriptive system and EQ VAS. The EQ VAS self-rating records the respondent's own assessment of his or her overall health status at the time of completion, on a scale of 0 (worst imaginable health state) to 100 (best imaginable health state). Positive change in score indicates improvement. | Baseline up to 24 weeks | 
| Change from Baseline in the Health Status Index of the EQ-5D-5L Scale Over 24 Weeks of the Double-blind Placebo-controlled Phase | Change from baseline in health status index of EQ-5D-5L scale over 24 weeks of double-blind placebo-controlled phase will be reported. EQ-5D-5L is standardized instrument for use as measure of health outcome, primarily designed for self-completion by respondents. It consists of EQ-5D-5L descriptive system and EQ-VAS. EQ-5D-5L descriptive system comprises following 5 dimensions: Mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each of 5 dimensions is divided into 5 levels of perceived problems (1 indicating no problem, 2 indicating slight problems, 3 indicating moderate problems, 4 indicating severe problems, 5 indicating extreme problems). Participant selects an answer for each of 5 dimensions considering response that best matches his or her health today. The responses to 5 dimensions are used to compute a single score ranging from zero (0.0- worst health state) to 1 (1.0- better health state) representing the general health status of the individual. | Baseline up to 24 weeks | 
| Serum Nipocalimab Concentrations Over Time | Serum nipocalimab concentrations over time will be reported. | Up to 4 years and 8 months | 
| Number of Participants with Antibodies to Nipocalimab (Anti-Drug Antibodies [ADAs] and Neutralizing Antibodies [NAbs]) | Number of participants with antibodies to nipocalimab (ADAs and NAbs) will be reported. | Up to 4 years and 8 months | 
| Percentage of Participants with MG-ADL Score of 0 or 1 Over Time in the Double-blind, Placebo-controlled Phase | Percentage of participants with MG-ADL score of 0 or 1 over time in the double-blind, placebo-controlled phase will be reported. | Up to Week 24 | 
| Percentage of Participants with MG-ADL Score of 0 or 1 at Any Time During the Double-blind, Placebo-controlled Phase | Percentage of participants with MG-ADL score of 0 or 1 at any time during the double-blind, placebo-controlled phase will be reported. | Up to Week 24 | 
| Percentage of Participants with MG-ADL Score of 0 or 1 at 50% of Timepoints During the Double-blind, Placebo-controlled Phase | Percentage of participants with MG-ADL score of 0 or 1 at 50% of timepoints during the double-blind, placebo-controlled phase will be reported. | Up to Week 24 | 
| Percentage of Participants with MG-ADL Score of 0 or 1 at 75% of Timepoints During the Double-blind, Placebo-controlled Phase | Percentage of participants with MG-ADL score of 0 or 1 at 75% of timepoints during the double-blind, placebo-controlled phase will be reported. | Up to Week 24 | 
| Change in Total Serum Immunoglobulin G (IgG) Concentrations | Change in total serum IgG concentrations will be reported. | Up to 4 years and 8 months | 
| Change in Levels of Autoantibodies Associated with Generalized Myasthenia Gravis (gMG) | Change in levels of autoantibodies associated with gMG will be reported. | Up to 4 years and 8 months | 
| Change from Baseline in MG-ADL Score as a Function of IgG | Change from baseline in MG-ADL score as a function of IgG will be reported. | Baseline up to 4 years and 8 months | 
| Change from Baseline in QMG Score as a Function of IgG | Change from baseline in QMG score as a function of IgG will be reported. | Baseline up to 4 years and 8 months | 
| Change From Baseline in MG-ADL Score as a Response to Percent Change in Autoantibody Levels, in Seropositive Participants Treated with Nipocalimab | Change from baseline in MG-ADL as a response to percent change in autoantibody levels, in seropositive participants (anti-acetylcholine receptor [anti-AChR], anti-muscle-specific kinase [anti-MuSK], anti-lipoprotein-related protein receptor 4 [anti-LRP4]) treated with nipocalimab will be reported. | Baseline up to 4 years and 8 months | 
| Change From Baseline in QMG Score as a Response to Percent Change in Autoantibody Levels, in Seropositive Participants Treated with Nipocalimab | Change from baseline in QMG score as a response to percent change in autoantibody levels, in seropositive participants (anti-AChR, anti-MuSK, anti-LRP4) treated with nipocalimab will be reported. | Baseline up to 4 years and 8 months |