Safety and Efficacy Study of Eculizumab in Patients With Refractory Generalized Myasthenia Gravis

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine whether eculizumab is safe and effective in the treatment of patients with generalized myasthenia gravis despite treatment with various immunosuppressants, such as prednisone, methotrexate, Cellcept, cyclosporine, and cyclophosphamide, that are currently available.

Official Title
-----------------
A Randomized, Double-Blind, Placebo-Controlled, Cross-Over, Multi-Center Study of Eculizumab in Patients With Generalized Myasthenia Gravis (gMG) Who Have Moderate to Severe Muscle Weakness Despite Treatment With Immunosuppressants

Conditions
-----------------
Myasthenia Gravis

Intervention / Treatment
-----------------
* Drug: eculizumab
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Generalized MG MGFA Clinical Classification Class II, III or IVa. QMG total score ≥12 Minimum score of two (2) in four (4) or more test items in the QMG Able to give informed consent. Have failed at least two immunosuppressants after one year of treatment A positive serologic test for binding anti-acetylcholine receptor Abs at Screening and one of the following a) history of abnormal neuromuscular transmission test demonstrated by single-fiber electromyography or repetitive nerve stimulation, or b) history of positive anticholinesterase test, eg, edrophonium chloride test, or c) patient has demonstrated improvement in MG signs on acetylcholinesterase inhibitors as assessed by treating physician. Exclusion Criteria: History of thymoma or other neoplasms of the thymus. History of thymectomy within 12 months prior to screening. Pregnancy or lactation Current or chronic use of plasmapheresis/plasma exchange IVIG treatment within 8 weeks prior to screening. Use of etanercept within 2 months prior to screening. Use of rituximab (RITUXAN®) within 6 months prior to screening. MGFA Class I, IVb, and V Crisis or impending crisis

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>eculizumab | Drug: eculizumab<br>* eculizumab 600 mg IV weekly for 4 doses followed by eculizumab 900 mg IV every two weeks for 7 doses<br>* Other names: Soliris;|
| Placebo Comparator: 2<br>Placebo | Drug: Placebo<br>* Placebo IV weekly for 4 doses then every two weeks for 7 doses<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quantitative Myasthenia Gravis (QMG): The Primary Efficacy Endpoint in This Study Was the Percentage of Patients With a 3-point Reduction From Baseline in the QMG Total Score for Disease Severity. | The QMG scoring system is considered to be an objective evaluation of muscle strength based on quantitative testing of sentinel muscle groups. The MGFA task force has recommended that the QMG score be used in prospective studies of therapy for MG. | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in QMG Total Score | The QMG scoring system is considered to be an objective evaluation of muscle strength based on quantitative testing of sentinel muscle groups. The Myasthenia Gravis Foundation of America task force has recommended that the QMG score be used in prospective studies of therapy for MG. The QMG scoring system consists of 13 items. Each item is graded 0 to 3, with 3 being the most severe. The range of total QMG score is 0-39. | 16 weeks | 
| Change From Baseline in the MGFA Post-Intervention Status (PIS) | The MGFA PIS is designed to assess the clinical state of MG patients at any time after treatment of MG is initiated. Change in status categories of Improved, Unchanged, Worse, Exacerbation, and Died of MG was to be assessed and recorded at every visit from Visits 3 to 24 (Weeks 1 to 16). Minimal manifestations were to be assessed at these visits. | 16 weeks | 
| Change From Baseline in the MG-Activity of Daily Living Profile (MG-ADL) | The MG-ADL is an 8-point questionnaire that focuses on relevant symptoms and functional performance of activities of daily living (ADL) in MG patients. The 8 items of the MG-ADL were 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 0 (normal) to 3 (most severe). The range of total MG-ADL score is 0 - 24. MG-ADL was to be performed at every study visit. The recall period for MG-ADL was since the preceding study visit (1 or 2 weeks). | 16 weeks | 
| Change From Baseline in the QoL Instrument, SF-36. | The SF-36 is a multi-purpose, short-form health survey with 36 questions. It yields an 8-scale profile of functional health and well-being scores (physical functioning, role-physical, bodily pain, general health, mental health, role-emotional, social functioning and vitality) as well as psychometrically-based physical and mental health summary measures. It is a generic measure, as opposed to one that targets a specific age, disease or treatment group. The lower the score the more disability; the higher the score the less disability. Norm-based scoring involving a linear T-score transformation method was used so that scores for each of the health domain scales and component summary measures have a mean of 50 and a standard deviation of 10 based on the 1998 US general population. Thus, scores above and below 50 are above and below the average, respectively, in the 1998 US general. | 16 weeks | 
| Change From Baseline in Respiratory Function Tests to Characterize the Degree of Involvement of Respiratory Muscles. | Change from Baseline in Forced Vital Capacity | 16 weeks | 
| Change From Baseline in Respiratory Function Tests to Characterize the Degree of Involvement of Respiratory Muscles. | Change from Baseline in Negative Inspiratory Force. NIF is a measurement of respiratory muscle strength and ventilator reserve. NIF is represented by centimeters of water pressure (cmH2O). A normal NIF measurement is negative 60 cmH2O, or as 100% predicted value. | 16 weeks | 
| Change From Baseline to the End of Treatment (16 Weeks) in the Two Most Affected QMG Items for Disease Severity (Individual Test Item: Double Vision) | The QMG scoring system is considered to be an objective evaluation of muscle strength based on quantitative testing of sentinel muscle groups. The MGFA task force has recommended that the QMG score be used in prospective studies of therapy for MG. All individual QMG items are scored 0 to 3, with 3 being the most severe. Negative values imply an improvement in QMG Item Score. | 16 weeks | 
| Change From Baseline to the End of Treatment (16 Weeks) in the Two Most Affected QMG Items for Disease Severity (Individual Test Item: Ptosis) | The QMG scoring system is considered to be an objective evaluation of muscle strength based on quantitative testing of sentinel muscle groups. The MGFA task force has recommended that the QMG score be used in prospective studies of therapy for MG. All individual QMG items are scored 0 to 3, with 3 being the most severe. Negative values imply an improvement in QMG Item Score. | 16 weeks |