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Eculizumab

Complement System Proteins

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In the Primary Evaluation Treatment Period (26 weeks), eculizumab will be administered weekly during the initial induction phase and every 2 weeks during the maintenance phase.

In the Extension Period (up to 208 weeks), participants will continue to receive eculizumab every 2 weeks.

Eculizumab will be administered at doses of 300, 600, 900, or 1200 milligrams (mg), based on the participant's current body weight.

Eculizumab will be administered by IV infusion.

The purpose of this study is to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of eculizumab in the treatment of pediatric refractory gMG based on change from Baseline in the Quantitative Myasthenia Gravis (QMG) score for disease severity.

The study will consist of an up to 4-week Screening Period, 26-week Primary Evaluation Treatment Period, an additional (up to) to 208-week Extension Period, and an 8-week Safety Follow-up Period.

A Phase 3 Open-Label Study of Eculizumab in Pediatric Participants With Refractory Generalized Myasthenia Gravis (gMG)

An Open-Label, Multicenter Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Eculizumab in Pediatric Patients With Refractory Generalized Myasthenia Gravis

The QMG scoring system consists of 13 items: ocular (2 items), facial (1 item), bulbar (2 items), gross motor (6 items), axial (1 item), and respiratory (1 item). Each item is graded from 0 to 3, (0 = none, 1 = mild, 2 = moderate, and 3 = severe). The range of total QMG score is 0 to 39, with higher score indicating more severe disease.

The MG-ADL is an 8-point questionnaire that focuses on relevant symptoms and functional performance of activities of daily living in participants with myasthenia gravis (MG). The 8 items of the MG-ADL are derived from symptom-based components of the original 13-item QMG to assess disability secondary to ocular (2 items), bulbar (3 items), respiratory (1 item), and gross motor or limb (2 items) impairment related to effects from MG. In this functional status instrument, each response is graded from 0 (normal) to 3 (most severe). The range of total MG-ADL score is 0 to 24, with higher score indicating more severe disease.

The MG-ADL is an 8-point questionnaire that focuses on relevant symptoms and functional performance of activities of daily living in participants with MG. The 8 items of the MG-ADL are derived from symptom-based components of the original 13-item QMG to assess disability secondary to ocular (2 items), bulbar (3 items), respiratory (1 item), and gross motor or limb (2 items) impairment related to effects from MG. In this functional status instrument, each response is graded from 0 (normal) to 3 (most severe). The range of total MG-ADL score is 0 to 24, with higher score indicating more severe disease.

The MGC is a validated assessment tool for measuring clinical status of participants with MG. The MGC assesses 10 important functional areas most frequently affected by MG: ocular (2 items), facial (1 item), bulbar (3 items), respiratory (1 item), axial (1 item), and gross motor (2 items). The scales are weighted for clinical significance that incorporates patient-reported outcomes. The MGC total score ranges from 0 to 50, with lower scores indicating less functional impairment and higher scores indicating greater functional impairment.

The EQ-5D-Y is a reliable and validated survey of health status in 5 areas: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, each of which is completed by the participant for participants ≥12 years of age (at time of assessment) and completed by the participant's caregiver or with caregiver assistance for participant \<12 years of age. Each area has 3 levels: Level 1 (no problems), Level 2 (some problems), and Level 3 (extreme problems). The EQ visual analogue scale (VAS) records the participant's self-rated health on a vertical, 20 cm VAS where the endpoints are labelled 'Best imaginable health state, marked as 100' and 'Worst imaginable health state, marked as 0'.

The Neuro-QoL Pediatric Fatigue questionnaire is a reliable and validated brief 11-item survey of fatigue, completed by the participant for participants ≥12 years of age (at time of assessment) and completed by the participant's caregiver or with caregiver assistance for participants \<12 years of age. Each item was scored on a scale of 1 to 5 (1=Not at all, 2=A little bit, 3=Somewhat, 4=Quite a bit, 5=Very much). Total score is the sum of each item's score and it ranges from 11 to 55. Higher scores indicate greater fatigue and greater impact of MG on activities.

The MG clinical state (improved, unchanged, and worse) was assessed using the MGFAPIS.

Rescue therapy (for example, high dose corticosteroid, plasma exchange \[PE\], or intravenous immunoglobulin \[IVIg\]) was to be allowed when a participant experienced clinical deterioration. Clinical deterioration was defined as follows: Participants who experienced an MG crisis, which was defined as weakness due to MG that was severe enough to necessitate intubation or to delay extubation following surgery; or, Significant symptomatic worsening that required rescue medication in the opinion of the Investigator; or, Participants for whom the Investigator believed that the participants' health was in jeopardy if rescue therapy was not given.

Alexion Pharmaceuticals, Inc.

Safety analysis set included all participants who received at least 1 dose of eculizumab.

Participants received eculizumab weekly by IV infusion during the Primary Evaluation Treatment Period (26 weeks) and the Extension Period (up to 208 weeks). Dosing was initiated with a weekly weight-based induction regimen (Induction Phase) and, thereafter, participants were dosed every 2 weeks (Maintenance Phase). Eculizumab was administered at doses of 300, 600, 900, or 1200 mg, based on the participant's current body weight.

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race

Race/Ethnicity, Customized

The QMG scoring system consists of 13 items: ocular (2 items), facial (1 item), bulbar (2 items), gross motor (6 items), axial (1 item), and respiratory (1 item). Each item is graded from 0 to 3, (0 = none, 1 = mild, 2 = moderate, and 3 = severe). The range of total QMG score is 0 to 39, with higher score indicating most severe disease.

QMG Total Score

Full analysis set included all participants who received at least 1 dose of eculizumab.

Modified full analysis set (mFAS) included participants 12 to \<18 years of age who received at least 1 dose of eculizumab. Overall number of participants analyzed = participants evaluable for this outcome measure.

Change From Baseline in the QMG Total Score at Week 26 Regardless of Rescue Treatment

mFAS included participants 12 to \<18 years of age who received at least 1 dose of eculizumab. Overall number of participants analyzed = participants evaluable for this outcome measure.

Change From Baseline in the Myasthenia Gravis Activities of Daily Living (MG-ADL) Total Score at Week 26 Regardless of Rescue Treatment

Percentage of Participants With ≥3-Point Reduction in the MG-ADL Total Score With No Rescue Treatment

Percentage of Participants With ≥3-Point Reduction in the MG-ADL Total Score Regardless of Rescue Treatment

Percentage of Participants With ≥5-Point Reduction in the QMG Total Score With No Rescue Treatment

Percentage of Participants With ≥5-Point Reduction in the QMG Total Score Regardless of Rescue Treatment

Change From Baseline in the Myasthenia Gravis Composite (MGC) Scale Total Score at Week 26 Regardless of Rescue Treatment

Change From Baseline in the European Quality of Life 5-Dimension Youth Version (EQ-5D-Y) Scale Score at Week 26 Regardless of Rescue Treatment

Change From Baseline in the Neurological Quality of Life-Fatigue Questionnaire (Neuro-QoL Pediatric Fatigue) Total Score at Week 26 Regardless of Rescue Treatment

Number of Participants in Each Category of the Myasthenia Gravis Foundation of America Post-Intervention Status (MGFAPIS) Regardless of Rescue Treatment at Week 26

Clinical Deterioration

MG Crisis

Requiring Rescue Therapy

mFAS included participants 12 to \<18 years of age who received at least 1 dose of eculizumab.

Percentage of Participants With Clinical Deteriorations, Myasthenic Crises, and Rescue Therapy Use

Day 1, 24 hours postdose (n = 11)

Week 12, Predose

Week 12, 60 minutes postdose

Week 26, Predose

PK analysis set included participants who had PK data assessments during this study. Here, number analyzed = participants evaluable at specified timepoint.

Pharmacokinetics (PK): Serum Concentration Of Eculizumab

Baseline

Day 1, 24 hours postdose

PD analysis set included participants who had PD data assessments during this study. Here, number analyzed = participants evaluable at specified timepoint.

Pharmacodynamics (PD): Serum Free Complement Component 5 (C5) Concentrations

PD analysis set included participants who had PD data assessments during this study. Here, 'Overall number of participants analyzed' = participants evaluable for this endpoint. Number analyzed = participants evaluable at specified timepoint.

PD: Percentage of Hemolysis (In Vitro Assay)

Participants received eculizumab weekly by intravenous (IV) infusion during the Primary Evaluation Treatment Period (26 weeks) and the Extension Period (up to 208 weeks). Dosing was initiated with a weekly weight-based induction regimen (Induction Phase) and, thereafter, participants were dosed every 2 weeks (Maintenance Phase). Eculizumab was administered at doses of 300, 600, 900, or 1200 milligrams (mg), based on the participant's current body weight.

Primary Evaluation Period (26 Weeks)

Extension Period (Up to 208 Weeks)

Blood and Lymph Conditions

Hyperplasia

Thymoma

Thymus Neoplasms

Thymus Hyperplasia

Neoplasms by Histologic Type

Thoracic Neoplasms

Lymphatic Diseases

Patients with myasthenia gravis who are receiving medical treatment and treatment of crisis as plasmapheresis

Drug treatment of myasthenia gravis and treatment of crisis

Nourelhoda AA Haridy, Lecturer

Eman MH Khedr, Professor

Asmaa MM Hasan, Lecturer

This study aims to characterize the clinical features, frequency of different subgroups of MG, and identify predictors of treatment responsiveness among different subgroups of MG. The predictors are including primary outcome (percentage of changes in MG scales at baseline at time of enrollment and after 3 months) and secondary outcome (treatment-related adverse events). Also it aims to determine the frequency of patients with refractory MG.

This information will be used to understand the trends and mechanisms of disease relapse, and optimal management strategies.

Myasthenia gravis (MG) is a rare acquired autoimmune disease affecting the neuromuscular junction (NMJ), caused by autoantibodies that target the post-synaptic membrane. It's overall prevalence ranged from 150 to 250 cases per million. The most common autoantibodies are those directed to the nicotinic acetylcholine receptor (AChR), but there is smaller proportion of cases, in whom, other antibodies can be present and they included antibodies directed to muscle specific tyrosine kinase (MuSK) or to lipoprotein receptor-related protein 4 (Lrp-4). The manifestation of MG is in form of fatigable skeletal muscle weakness, affecting ocular, bulbar and limb muscles. In general, the disease diagnosis is confirmed by presence of this characteristic muscle weakness with positive autoantibodies in the serum. The main current treatment of the disease is symptomatic and immunomodulating therapies which are efficient in managing the disease manifestation. The disease prognosis is mostly favorable and about 15%, is considered medically refractory to the conventional therapy. MG can be classified into different subgroups according to different factors which included the autoantibody status, age of onset, and degree of muscle affection. These subgroups are significantly influencing the therapeutic decisions. Moreover, this proposed classification could explain the distinct immunopathological, clinical, therapeutic, and prognostic differences among these subgroups.

Current standard immunotherapies have a broad-spectrum of immune suppression, and potential side effects associated with their use can significantly impact quality of life, especially as they are usually needed life-long. Significant heterogeneity in treatment responsiveness and outcomes exists among the various subgroups of MG based on epidemiology, clinical presentation, autoantibody status, and comorbidities. In MG clinical trials, the evaluation is mainly depending on the short-term clinical efficacy, but the long-term benefits and impact on patient's quality of life and other disease burdens, (i.e., treatment-related side effects, financial impact), were not measured. The outcomes of MG were assessed in many studies and they included the reduction in quality of life, the negative impact on social and physical health, that related to the disease itself and the immunomodulators used for its treatment. Based on these factors, the investigators aimed to conduct this study to find the disease characteristics in the participants, the patient-tailored targeted treatment strategies, treatment outcomes, disease progression and quality of life.

Predictors and Prognostic Factors of Myasthenia Gravis Outcome

The MG Activities of Daily Living (MG- ADL) Scale an easily administered, 8-item questionnaire. Each item is graded on a 4- point symptom severity scale (0 = normal, 3 = most severe), with the total score ranging from 0 to 24. Test items emphasize the functional impact of muscle weakness (eg, the ability to comb one's hair or brush one's teeth instead of hand grip or outstretched arm strength tests) rather than its quantitation. The MG-ADL requires no special equipment or training and can be administered in 10 minutes. The MG-ADL test domains include ocular (2 items), oropharyngeal (3 items), respiratory (1 item), and extremity/limb (2 items).

Everyday clinical use led to the development of an abbreviated 15-item version, the MG-QOL15. These 15 items were derived from the mobility (9 items), symptoms (3 items), general contentment (1 item), and emotional well-being (2 items) domains of the 60-item version. Each of the items/statements (eg, "I have limited my social activity because of my condition") is scored by patients on a 5-point scale ranging from 0 ("not at all") to 4("very much") based on their experience over the previous 4 weeks; the item scores are summed to generate a total score ranging from 0 to 60.

The MG-MMT assesses the strength or function of 30 muscle groups typically affected by MG and includes a total of 18 items, with 12 assessed bilaterally, and 6 assessed as single items (lid closure, cheek puff, tongue protrusion, jaw closure, neck flexion, and neck extension). Each item is scored on a 5- point severity scale, based on the severity of muscle weakness \[0 = no weakness, 1 = weak/mild (25%) impairment, 2 = weak/moderate (50%) impairment, 3 = weak/severe (75%) impairment, 4 = paralyzed/unable to perform\]. Bilateral scores are summed for a total item score, and all item scores are summed for a total MG-MMT score. MG-MMT scores range from 0 to 120; domains include ocular (3 items, including eyelid closure), facial/oropharyngeal (3 items), axial strength (neck flexion/extension; 2 items), and limb strength (10 items).

The MG Composite (MGC) Scale is considered a mixed outcome measure that incorporates both physician-evaluated and patient-reported outcome items. In creating this composite scale, the developers sought to minimize the number of items (and thus administration time), to maximize the sensitivity and clinical relevance of each item, and to weight items (as recommended by the Myasthenia Gravis Foundation of America MGFA task force) commensurate with their impact on functional status, QOL, overall health status, and prognosis.13 The MGC Scale is composed of individual items from outcome measures (including the quantitative myasthenia gravis score (QMG), the MG-ADL, and the MG-MMT). Total score spans from 0 to 50.

Adverse effects of treatment of myasthenia gravis

Clinical statuses of patients are assessed and categorized according to Myasthenia Gravis Foundation of America (MGFA) postintervention status (PIS). It assesses the clinical state of MG patients at any time after institution of treatment for MG

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Phase 3 Open-Label Study of Eculizumab in Pediatric Participants With Refractory Generalized Myasthenia Gravis (gMG)	NCT03759366	Myasthenia Grav... Myasthenia Grav... Myasthenia Grav...	Eculizumab	6 Years - 17 Years	Alexion Pharmaceuticals, Inc.
A Phase 3 Open-Label Study of Eculizumab in Pediatric Participants With Refractory Generalized Myasthenia Gravis (gMG)	NCT03759366	Myasthenia Grav... Myasthenia Grav... Myasthenia Grav...	Eculizumab	6 Years - 17 Years	Alexion Pharmaceuticals, Inc.
Predictors and Prognostic Factors of Myasthenia Gravis Outcome	NCT05214612	Myasthenia Grav... Autoimmune Dise... Neuromuscular J... Thymoma Thymus Hyperpla... Nervous System ... Myasthenia Grav... Myasthenia Grav... Myasthenia Grav... Myasthenia Grav... Myasthenia Grav... Myasthenia Grav...	Drug treatment ...	16 Years -	Assiut University

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