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

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

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.

Study Overview

• Status: Terminated
• Conditions: Myasthenia Gravis
• Intervention / Treatment: Drug: eculizumab; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada
      • The Northern Alberta Clinical Trials and Research Centre
• United Kingdom
  • Glasgow, United Kingdom
    • Institute of Neurological Sciences, Department of Neurology, Southern General Hospital,
  • London, United Kingdom
    • Institute of Neurology
  • Oxford, United Kingdom
    • Department of Clinical Neurology, West Wing, John Radcliffe Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University Of Alabama At Birmingham
  • California
    • Orange, California, United States, 92868
      • University of California, Irvine
    • Sacramento, California, United States, 95817
      • University of California - Davis
  • Florida
    • Jacksonville, Florida, United States, 32209
      • University of Florida & Shands Neuroscience Institute
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Wishard Hospital
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University School of Medicine
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02135
      • Caritas St. Elizabeths' Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Wayne State University
  • New York
    • New York, New York, United States, 10029-6574
      • Mount Sinai School of Medicine
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-1651
      • University of North Carolina at Chapel Hill
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44106-5098
      • University Hospitals - Case Medical Center
    • Columbus, Ohio, United States, 43210
      • The Ohio State University
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • The Warren Alpert Medical School of Brown University
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical School
  • Vermont
    • Burlington, Vermont, United States, 05405
      • The University of Vermont College of Medicine
  • Virginia
    • Charlottesville, Virginia, United States, 22908-0394
      • University of Virginia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

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

Collaborators and Investigators

• Sponsor: Alexion Pharmaceuticals

Publications and helpful links

General Publications

• Howard JF Jr, Barohn RJ, Cutter GR, Freimer M, Juel VC, Mozaffar T, Mellion ML, Benatar MG, Farrugia ME, Wang JJ, Malhotra SS, Kissel JT; MG Study Group. A randomized, double-blind, placebo-controlled phase II study of eculizumab in patients with refractory generalized myasthenia gravis. Muscle Nerve. 2013 Jul;48(1):76-84. doi: 10.1002/mus.23839. Epub 2013 Apr 30.

Study record dates

Study Major Dates

• Study Start: October 1, 2008
• Primary Completion (Actual): March 1, 2011
• Study Completion (Actual): July 1, 2011

Study Registration Dates

• First Submitted: July 30, 2008
• First Submitted That Met QC Criteria: July 30, 2008
• First Posted (Estimate): August 1, 2008

Study Record Updates

• Last Update Posted (Actual): September 24, 2019
• Last Update Submitted That Met QC Criteria: September 13, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Neoplasms; Autoimmune Diseases of the Nervous System; Autoimmune Diseases; Neoplasms by Site; Neurologic Manifestations; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Neuromuscular Manifestations; Nervous System Neoplasms; Paraneoplastic Syndromes, Nervous System; Paraneoplastic Syndromes; Neuromuscular Junction Diseases; Muscle Weakness; Myasthenia Gravis; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Complement Inactivating Agents; Eculizumab
• Other Study ID Numbers: C08-001