Safety and Efficacy Study of RA101495 in Subjects With Generalized Myasthenia Gravis

A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Preliminary Efficacy of RA101495 in Subjects With Generalized Myasthenia Gravis

The purpose of the study is to evaluate the safety and efficacy of RA101495 in patients with generalized Myasthenia Gravis (gMG). Subjects will be randomized in a 1:1:1 ratio to receive daily SC doses of 0.1 mg/kg RA101495, 0.3 mg/kg RA101495, or matching placebo for 12 weeks.

Study Overview

• Status: Completed
• Conditions: Generalized Myasthenia Gravis
• Intervention / Treatment: Drug: zilucoplan (RA101495); Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2B7
      • University of Alberta Hospital
  • Ontario
    • London, Ontario, Canada, N6A 5A5
      • London Health Sciences Centre University Hospital
    • Toronto, Ontario, Canada, M5G 2C4
      • Toronto General Hospital
  • Quebec
    • Montreal, Quebec, Canada, H3A 2B4
      • Montreal Neurological Institute and Hospital
• United States
  • Alabama
    • Mobile, Alabama, United States, 36604
      • Diagnostic and Medical Clinic - Mobile
  • California
    • Carlsbad, California, United States, 92011
      • The Research Center of Southern California
    • Los Angeles, California, United States, 90095
      • UCLA Medical Center
    • Orange, California, United States, 92868
      • University of California Irvine Health ALS and Neuromuscular Center
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University
  • District of Columbia
    • Washington, District of Columbia, United States, 20052
      • George Washington University
  • Florida
    • Jacksonville, Florida, United States, 32209
      • University of Florida
    • Tampa, Florida, United States, 33620
      • University of South Florida
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University Of Kansas Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Burlington, Massachusetts, United States, 01805
      • Lahey Hospital and Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Wayne State University
    • East Lansing, Michigan, United States, 48864
      • Michigan State University
  • New York
    • Buffalo, New York, United States, 14260
      • University of Buffalo
    • New York, New York, United States, 10021
      • Hospital for Special Surgery
    • New York, New York, United States, 10029
      • Mount Sinai Hospital
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina at Chapel Hill
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny Neurological Associates
  • Tennessee
    • Cordova, Tennessee, United States, 38018
      • Wesley Neurology Clinic
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah
  • Vermont
    • Burlington, Vermont, United States, 05405
      • University of Vermont
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53215
      • Center for Neurological Disorders

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of gMG [Myasthenia Gravis Foundation of America (MGFA) Class II-IVa] at Screening
• Positive serology for acetylcholine receptor (AChR) autoantibodies
• QMG score ≥ 12 at Screening and Randomization
• No change in corticosteroid dose for at least 30 days prior to Randomization or anticipated to occur during the 12-week Treatment Period
• No change in immunosuppressive therapy, including dose, for at least 30 days prior to Randomization or anticipated to occur during the 12-week Treatment Period

Exclusion Criteria:

• Thymectomy within 6 months prior to Randomization or scheduled to occur during the 12 week Treatment Period
• History of meningococcal disease
• Current or recent systemic infection within 2 weeks prior to Randomization or infection requiring intravenous (IV) antibiotics within 4 weeks prior to Randomization

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Daily subcutaneous (SC) injection
Experimental: 0.3 mg/kg zilucoplan (RA101495)	Drug: zilucoplan (RA101495); Daily subcutaneous (SC) injection
Experimental: 0.1 mg/kg zilucoplan (RA101495)	Drug: zilucoplan (RA101495); Daily subcutaneous (SC) injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Main Portion: Change From Baseline to Week 12 in Quantitative Myasthenia Gravis (QMG) Score	The QMG is a standardized and validated quantitative strength scoring system that was developed specifically for myasthenia gravis (MG). The scale consists of 13 individual assessments, each scored on a 0-3 point scale (i.e., 0=none, 1=mild, 2=moderate, and 3=severe). The total score is the sum of the individual scores with a range of 0-39. Higher scores are representative of more severe impairment.	From Baseline to Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Main Portion: Change From Baseline to Week 12 in the Myasthenia Gravis - Activities of Daily Living (MG-ADL) Scale	The MG-ADL is a brief 8-item survey designed to evaluate MG symptom severity. The scale consists of 8 items each scored on a 0-3 point scale (i.e., 0=none, 1=mild, 2=moderate, and 3=severe). The total score is the sum of the 8 individual scores with range of 0-24. Higher scores are associated with more severe symptoms of MG.	From Baseline to Week 12
Main Portion: Change From Baseline to Week 12 in the Myasthenia Gravis - Quality of Life 15r (MG-QOL15r) Survey	The MG-QOL15r is a 15-item survey that was designed to assess quality of life in participants with MG. The survey consisted of 15 questions and the corresponding responses were each scored on a 0-2 point scale (0=Not much at all, 1=Somewhat, 2=Very Much). The total score is the sum of the 15 individual item scores with a range of 0-30. Higher scores indicate more severe impact of the disease on aspects of the participant's life.	From Baseline to Week 12
Main Portion: Change From Baseline to Week 12 in the MG Composite Scale Total Score	The MG Composite is a 10-item scale that has been used to measure the clinical status of participants with MG, in order to evaluate treatment response. It consists of 10 items which included ptosis (score range=0 to 3), double vision on lateral gaze left/right/both (score range=0 to 4), eye closure (score range=0 to 2), talking (score range=0 to 6), chewing (score range=0 to 6), swallowing (score range=0 to 6), breathing (score range=0 to 9), neck flexion or extension (score range=0 to 4), shoulder abduction (score range=0 to 5) and hip flexion (score range= 0 to 5). The total score is the sum of the 10 individual scores with a range of 0-50. Higher scores in the MG Composite indicate more severe impairment due to the disease.	From Baseline to Week 12
Main Portion: Percentage of Participants With >= 3-point Reduction in QMG Total Score at Week 12	The QMG is a standardized and validated quantitative strength scoring system that was developed specifically for MG. The scale consists of 13 individual assessments, each scored on a 0-3 point scale (i.e., 0=none, 1=mild, 2=moderate, and 3=severe). The total score is the sum of the individual scores with a range of 0-39. Higher scores are representative of more severe impairment.	Week 12
Main Portion: Percentage of Participants Who Required Rescue Therapy Over the 12-week Treatment Period	Percentage of participants who used at least 1 dose of rescue medication were reported.	Up to Week 12
Main Portion: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	An adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A serious adverse event (SAE) is any untoward medical occurrence that at any dose resulted in death, life-threatening, significant or persistent disability/incapacity, congenital anomaly/birth defect, important medical event, initial inpatient hospitalization or prolongation of hospitalization.	From Baseline to Week 12
Main Portion: Change From Baseline in Sheep Red Blood Cell (sRBC) Lysis Assay at Week 12 (Pre-dose)	A BioTek ELx800 automated microplate reader is used to measure the optical density at 415 nanometer (nm) of human plasma samples to calculate the percent lysis of sheep erythrocytes that has occurred as a result of total complement activity. The measure of complement activity is determined by the degree of hemolysis of the erythrocytes.	Baseline and Week 12 (Pre-dose)
Main Portion: Change From Baseline in C5 Levels at Week 12 (Pre-dose)	Blood samples were collected from participants to assess Complement Component 5C levels.	Baseline and Week 12 (Pre-dose)
Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites	RA102758 and RA103488 are the metabolites of RA101495.	1, 3 and 6 hours postdose on Day 1; Pre-dose on Week 1, 2, 4, 8 and 12
Main Portion: Maximum Plasma Concentration (Cmax) on Day 1	Cmax is defined as the maximum observed plasma concentration.	Pre-dose, 1, 3 and 6 hours postdose on Day 1
Main Portion: Time Corresponding to Cmax (Tmax) on Day 1	Tmax is defined as the time to observe maximum plasma concentration.	Pre-dose, 1, 3 and 6 hours postdose on Day 1
Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio	RA102758 and RA103488 are the metabolites of RA101495.	Pre-dose, 1, 3 and 6 hours postdose on Day 1; Pre-dose on Week 1, 2, 4, 8 and 12

Collaborators and Investigators

• Sponsor: Ra Pharmaceuticals

Publications and helpful links

General Publications

• Howard JF Jr, Nowak RJ, Wolfe GI, Freimer ML, Vu TH, Hinton JL, Benatar M, Duda PW, MacDougall JE, Farzaneh-Far R, Kaminski HJ; Zilucoplan MG Study Group, Barohn R, Dimachkie M, Pasnoor M, Farmakidis C, Liu T, Colgan S, Benatar MG, Bertorini T, Pillai R, Henegar R, Bromberg M, Gibson S, Janecki T, Freimer M, Elsheikh B, Matisak P, Genge A, Guidon A, David W, Habib AA, Mathew V, Mozaffar T, Hinton JL, Hewitt W, Barnett D, Sullivan P, Ho D, Howard JF Jr, Traub RE, Chopra M, Kaminski HJ, Aly R, Bayat E, Abu-Rub M, Khan S, Lange D, Holzberg S, Khatri B, Lindman E, Olapo T, Sershon LM, Lisak RP, Bernitsas E, Jia K, Malik R, Lewis-Collins TD, Nicolle M, Nowak RJ, Sharma A, Roy B, Nye J, Pulley M, Berger A, Shabbir Y, Sachdev A, Patterson K, Siddiqi Z, Sivak M, Bratton J, Small G, Kohli A, Fetter M, Vu T, Lam L, Harvey B, Wolfe GI, Silvestri N, Patrick K, Zakalik K, Duda PW, MacDougall J, Farzaneh-Far R, Pontius A, Hoarty M. Clinical Effects of the Self-administered Subcutaneous Complement Inhibitor Zilucoplan in Patients With Moderate to Severe Generalized Myasthenia Gravis: Results of a Phase 2 Randomized, Double-Blind, Placebo-Controlled, Multicenter Clinical Trial. JAMA Neurol. 2020 May 1;77(5):582-592. doi: 10.1001/jamaneurol.2019.5125.

Study record dates

Study Major Dates

• Study Start (Actual): October 11, 2017
• Primary Completion (Actual): December 10, 2018
• Study Completion (Actual): November 19, 2020

Study Registration Dates

• First Submitted: October 16, 2017
• First Submitted That Met QC Criteria: October 18, 2017
• First Posted (Actual): October 19, 2017

Study Record Updates

• Last Update Posted (Actual): July 27, 2022
• Last Update Submitted That Met QC Criteria: July 26, 2022
• Last Verified: July 1, 2022

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
• Other Study ID Numbers: RA101495-02.201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No