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

Myasthenia Gravis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03759366
• Other study ID #: ECU-MG-303
• Status: Completed
• Phase: Phase 3
• Start date: December 21, 2018
• Est. completion date: November 6, 2023

Study information

• Verified date: November 2023
• Source: Alexion Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 11
• Est. completion date: November 6, 2023
• Est. primary completion date: January 6, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Years to 17 Years

Eligibility

Inclusion Criteria:

• Male or female pediatric participants 6 to <18 years of age at time of assent/consent.
• Vaccinated against Neisseria meningitidis.
• Documented vaccination against Haemophilus influenzae and Streptococcus pneumoniae infections prior to dosing as per local and country specific immunization guidelines for the appropriate age group.
• Diagnosis of MG confirmed by positive serologic test for anti-acetylcholine receptor antibodies at Screening, and 1 of the following: (a) history of abnormal neuromuscular transmission test demonstrated by single-fiber electromyography or repetitive nerve stimulation; (b) history of positive anticholinesterase test (for example, edrophonium chloride or neostigmine test); or (c) participant demonstrated improvement in MG signs on oral acetylcholinesterase inhibitors, as assessed by the Investigator.
• Presence of refractory gMG, defined as participants with gMG who have 1 or more of the following: (a) failed treatment =1 year with at least 1 immunosuppressive therapies (IST), defined as follows: (1) persistent weakness with impairment of activities of daily living; (2) myasthenia gravis (MG) exacerbation and/or crisis while on treatment; or (3) intolerance to ISTs due to side effect or comorbid condition(s). (b) Require maintenance plasma exchange (PE) or intravenous immunoglobulin (IVIg) to control symptoms; and/or (c) in the opinion of the Investigator, MG poses a significant functional burden despite current MG treatment.
• MGFA Clinical Classification of Class II to IV at Screening.
• In patients aged 12 to 18 years, QMG total score = 12 at Screening; in patients aged 6 to 11 years, no minimum QMG is required for inclusion; however, patients must have documented limb weakness in at least one limb.
• All MG-specific treatment has been administered at a stable dosing regimen of adequate duration prior to Screening.

Exclusion Criteria:

• Parent or legal guardian is an Alexion employee.
• Any active or untreated thymoma. History of thymic carcinoma or thymic malignancy unless deemed cured by adequate treatment with no evidence of recurrence for =5 years before Screening.
• History of thymectomy within 12 months prior to Screening.
• Are pregnant or lactating.
• Any unresolved acute, or chronic, systemic bacterial or other infection, which is clinically significant in the opinion of the Investigator and has not been treated with appropriate antibiotics.
• Use of PE within 4 weeks prior to first dose.
• Use of rituximab within 6 months prior to first dose.
• Patients who are under 15 kg and are receiving maintenance IVIg.
• Participation in another interventional treatment study or use of any experimental therapy within 30 days before initiation of study drug on Day 1 in this study or within 5 half-lives of that investigational product, whichever is greater.
• Have previously received treatment with eculizumab or other complement inhibitors.

Related Conditions & MeSH terms

• Muscle Weakness
• Myasthenia Gravis
• Myasthenia Gravis, Generalized
• Myasthenia Gravis, Juvenile Form

Intervention

Drug:
• Eculizumab
Eculizumab will be administered by IV infusion.

Locations

Country	Name	City	State
Japan	Clinical Trial Site	Chiba-shi	Chiba-Ken
Japan	Clinical Trial Site	Mibu	Tochigi
Japan	Clinical Trial Site	Saitama	Iruma-gun
Japan	Clinical Trial Site	Tokyo	Itabasha-ku
Japan	Clinical Trial Site	Tokyo	Shinjuku-ku
Netherlands	Clinical Trial Site	Amsterdam
Netherlands	Clinical Trial Site	Leiden
United States	Clinical Trial Site	Akron	Ohio
United States	Clinical Trial Site	Chapel Hill	North Carolina
United States	Clinical Trial Site	Charleston	South Carolina
United States	Clinical Trial Site	Chicago	Illinois
United States	Clinical Trial Site	Columbia	Missouri
United States	Clinical Trial Site	Los Angeles	California
United States	Clinical Trial Site	Philadelphia	Pennsylvania
United States	Clinical Trial Site	Saint Louis	Missouri
United States	Clinical Trial Site	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Alexion Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Japan,  Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in the QMG Total Score at Week 26 Regardless of Rescue Treatment	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.	Baseline, Week 26
Secondary	Change From Baseline in the Myasthenia Gravis Activities of Daily Living (MG-ADL) Total Score at Week 26 Regardless of Rescue Treatment	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.	Baseline, Week 26
Secondary	Percentage of Participants With =3-Point Reduction in the MG-ADL Total Score With No Rescue Treatment	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.	Week 26
Secondary	Percentage of Participants With =3-Point Reduction in the MG-ADL Total Score Regardless of Rescue Treatment	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.	Week 26
Secondary	Percentage of Participants With =5-Point Reduction in the QMG Total Score With No Rescue Treatment	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.	Week 26
Secondary	Percentage of Participants With =5-Point Reduction in the QMG Total Score Regardless of Rescue Treatment	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.	Week 26
Secondary	Change From Baseline in the Myasthenia Gravis Composite (MGC) Scale Total Score at Week 26 Regardless of Rescue Treatment	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.	Baseline, Week 26
Secondary	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	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'.	Baseline, Week 26
Secondary	Change From Baseline in the Neurological Quality of Life-Fatigue Questionnaire (Neuro-QoL Pediatric Fatigue) Total Score at Week 26 Regardless of Rescue Treatment	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.	Baseline, Week 26
Secondary	Number of Participants in Each Category of the Myasthenia Gravis Foundation of America Post-Intervention Status (MGFAPIS) Regardless of Rescue Treatment at Week 26	The MG clinical state (improved, unchanged, and worse) was assessed using the MGFAPIS.	Week 26
Secondary	Percentage of Participants With Clinical Deteriorations, Myasthenic Crises, and Rescue Therapy Use	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.	Baseline up to Week 26
Secondary	Pharmacokinetics (PK): Serum Concentration Of Eculizumab		24 hours postdose on Day 1; predose and 60 minutes postdose at Week 12; predose at Week 26
Secondary	Pharmacodynamics (PD): Serum Free Complement Component 5 (C5) Concentrations		Baseline; 24 hours postdose on Day 1; predose and 60 minutes postdose at Week 12; predose at Week 26
Secondary	PD: Percentage of Hemolysis (In Vitro Assay)		Baseline; 24 hours postdose on Day 1; predose and 60 minutes postdose at Week 12; predose at Week 26