Safety, Tolerability, and Efficacy of Zilucoplan in Subjects With Generalized Myasthenia Gravis (RAISE)

A Phase 3, Multicenter, Randomized, Double Blind, Placebo-Controlled Study to Confirm the Safety, Tolerability, and Efficacy of Zilucoplan in Subjects With Generalized Myasthenia Gravis

The RAISE study is a multicenter, randomized, double-blind, placebo controlled study to confirm the efficacy, safety, and tolerability of zilucoplan in subjects with generalized Myasthenia Gravis. Subjects will be randomized in a 1:1 ratio to receive daily SC doses of 0.3 mg/kg zilucoplan or placebo for 12 weeks.

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 174
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • London, Ontario, Canada, N6A 5A5
      • Site 44: London Health Sciences Centre University Hospital
  • Quebec
    • Montréal, Quebec, Canada, H3A 2B4
      • Site 11: Montreal Neurological Institute and Hospital (McGill University)
• France
  • Angers Cedex 9, France
    • Site 191: Centre Hosptitalier Universitaire d'Angers
  • Lille, France
    • Site 204: Centre Hospitalier Régional Universitaire de Lille
  • Nice, France, 06000
    • Site 118: Hôpital Pasteur
  • Paris, France, 75013
    • Site 105: Pitié-Salpêtrière University Hospital
  • Strasbourg, France, 67091
    • Site 137: Les Hôpitaux Universitaires de Strasbourg
• Germany
  • Göttingen, Germany, 37075
    • Site 150: Universitätsmedizin Göttingen
  • Tübingen, Germany, 72076
    • Site 129: Universitätsklinikum Tübingen
• Italy
  • Milan, Italy, 20133
    • Site 126: Fondazione IRCCS Istituto Neurologico Carlo Besta
  • Roma, Italy, 20123
    • Site 132: Università Cattolica del Sacro Cuore - Campus di Milano
• Japan
  • Chiba, Japan, 260-8677
    • Site 151: Chiba University Hospital
  • Iwata, Japan, 025-0075
    • Site 136: General Hanamaki Hospital
  • Kita-gun, Japan
    • Site 179: Kagawa University Hospital - Collagen disease/Rheumatic int
  • Nagasaki, Japan, 852-8501
    • Site 146: Nagasaki University Hospital
  • Sapporo, Japan, 063-0005
    • Site 152: Hokkaido Medical Center
  • Sendai, Japan, 983-8520
    • Site 144: Sendai Medical Center
  • Tokyo, Japan, 153-8515
    • Site 153: Toho University Ohashi Medical Center
  • Tokyo, Japan, 160-0023
    • Site 163: Tokyo Medical University Hospital
  • Tokyo, Japan, 160-8582
    • Site 141: Keio University Hospital
  • Tokyo, Japan, 565-0871
    • Site 165: Osaka University Hospital
  • Chiba
    • Narita, Chiba, Japan, 286-8520
      • Site 169: International University of Health and Welfare Narita Hospital
• Norway
  • Bergen, Norway, 5021
    • Site 140: Haukeland University Hospital / Health Bergen
  • Oslo, Norway, 0450
    • Site 143: Oslo Universitetssykehus
• Poland
  • Kraków, Poland
    • Site 193: Krakowska Akademia Neurologii - Centrum Neurologii Kliniczne
  • Kraków, Poland
    • Site 211: Specjalistyczne Gabinety Sp. z o.o.
  • Lublin, Poland, 20-093
    • Site 210: Clinhouse Centrum Medyczne
  • Lubelskie
    • Lublin, Lubelskie, Poland, 20-093
      • Site 205: Prywatny Gabinet Lekarski Urszula Chyrchel-Paszkiewicz
  • Lubuskie
    • Nowa Sól, Lubuskie, Poland, 67-100
      • Site 194: Twoja Przychodnia - Centrum Medyczne Nowa Sól
  • Lódzkie
    • Łódź, Lódzkie, Poland, 90-644
      • Site 214: AmiCare Centrum Medyczne
  • Malopolskie
    • Kraków, Malopolskie, Poland, 31-202
      • Site 192: Krakowski Szpital Specjalistyczny im. Jana Pawła II
  • Mazowieckie
    • Warszawa, Mazowieckie, Poland, 01-868
      • Site 201: Centrum Medyczne Pratia - Warszawa
  • Slaskie
    • Katowice, Slaskie, Poland, 40-123
      • Site 195: Wielospecjalistyczna Poradnia Lekarska Synapsis
    • Katowice, Slaskie, Poland, 40-650
      • Site 213: Niepubliczny Zakład Opieki Zdrowotnej NOVO-MED
  • Wielkopolskie
    • Poznań, Wielkopolskie, Poland, 61-853
      • Site 209: Niepubliczny Zakład Opieki Zdrowotnej NEURO - KARD
• Spain
  • Barcelona, Spain, 08035
    • Site 133: Hospital Universitari Vall d'Hebrón
  • Barcelona, Spain
    • Site 168: Hospital de la Santa Creu i Sant Pau
  • Bilbao, Spain, 48013
    • Site 138: Hospital Universitario de Basurto
• United Kingdom
  • Oxford, United Kingdom, OX3 9DU
    • Site 119: Oxford University Hospitals NHS Foundation Trust
  • Sheffield, United Kingdom, S10 2JF
    • Site 130: Royal Hallamshire Hospital
• United States
  • Alabama
    • Mobile, Alabama, United States, 36604
      • Site 41: Diagnostic and Medical Clinic
  • Arizona
    • Phoenix, Arizona, United States, 85028
      • Site 116: Neuromuscular Clinic and Research Center
  • California
    • Los Angeles, California, United States, 90033
      • Site 4: University of Southern California
    • Orange, California, United States, 92868
      • Site 31: University of California Irvine
    • Pasadena, California, United States, 91101
      • Site 220: Investigator Site
    • San Francisco, California, United States, 94115
      • Site 160: Forbes Norris MDA/ALS Research and Treatment Center
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Site 24: Yale University
  • District of Columbia
    • Washington, District of Columbia, United States, 20037
      • Site 27: George Washington University
  • Florida
    • Miami, Florida, United States, 33175
      • Site 182: Gelasio Baras Neurology
    • Tampa, Florida, United States, 33612
      • Site 25: University of South Florida
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Site 135: Augusta University Medical Center
  • Hawaii
    • Honolulu, Hawaii, United States, 96817
      • Site 176: Hawaii Pacific Neuroscience
  • Illinois
    • Glenview, Illinois, United States, 60026-1339
      • Site 188: North Shore Medical Group - Glenview
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Site 156: Indiana University Health Neuroscience Center
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • Site 32: Kansas University Medical Center Research Institute
    • Kansas City, Kansas, United States, 66160
      • Site 156: University of Kansas Medical Center
  • Massachusetts
    • Foxboro, Massachusetts, United States, 02035
      • Site 221: Neurology Center of New England
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Site 33: Detroit medical Center - University Health Center
    • East Lansing, Michigan, United States, 48824
      • Site 49: Michigan State University
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Site 127: University of Minnesota
  • Missouri
    • Columbia, Missouri, United States, 65212
      • Site 134: Neurology and Sleep Disorders Clinic
  • Nevada
    • Las Vegas, Nevada, United States, 89145
      • Site 117: Las Vegas Clinic
  • New York
    • Great Neck, New York, United States, 11021
      • Site 123: Northwell Health Neuroscience Institute
    • New York, New York, United States, 10021
      • Site 23: Hospital for Special Surgery
    • New York, New York, United States, 10029
      • Site 47: Mount Sinai Hospital
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • Site 22: University of North Carolina
    • Durham, North Carolina, United States, 27710
      • Site 15: Duke University
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Site 122: Cleveland Clinic
    • Columbus, Ohio, United States, 43210
      • Site 38: Ohio State University
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15212
      • Site 40: Allegheny Neurological Associates
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Site 128: Medical University of South Carolina
  • Tennessee
    • Cordova, Tennessee, United States, 38018
      • Site 185: Neurology Clinic Cordova
  • Texas
    • Austin, Texas, United States, 78756
      • Site 131: Austin Neuromuscular Center
    • Dallas, Texas, United States, 75390
      • Site 19: University of Texas Southwestern
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • Site 39: University of Utah
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • Site 164: University of Virginia Health System
  • Washington
    • Seattle, Washington, United States, 98195
      • Site 154: University of Washington
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53215
      • Site 45: Center for Neurological Disorders

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 74 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of gMG [Myasthenia Gravis Foundation of America (MGFA) Class II-IV] at Screening
• Positive serology for acetylcholine receptor (AChR) autoantibodies
• MG-ADL Score of ≥ 6 at Screening and Baseline
• QMG score ≥ 12 at Screening and Baseline
• No change in corticosteroid dose for at least 30 days prior to Baseline or anticipated to occur during the 12-week Treatment Period
• No change in immunosuppressive therapy, including dose, for at least 30 days prior to Baseline or anticipated to occur during the 12-week Treatment Period

Exclusion Criteria:

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline (CFB) to Week 12 in Myasthenia Gravis-Activities of Daily Living (MG-ADL) Total Score	The MG-ADL is an 8-item patient-reported outcome measure assessing MG symptoms and their effects on daily activities. Each item in the scale scored 0 to 3 (0=None, 3=severe disease) point scale. The total score was the sum of all individual item scores and ranged from 0 to 24. Higher scores indicated more severe disability due to MG. A decrease from Baseline score indicated improvement.	From Baseline to End of Treatment (Week 12)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Week 12 in the Quantitative Myasthenia Gravis (QMG) Total Score	The QMG is a standardized and validated quantitative strength scoring system that was developed specifically for MG. The scale consisted of 13 items. Each item in the scale scored on a 0 to 3-point scale, ranging from 0 (no weakness) to 3 (severe weakness), summing up to the overall score range from 0 to 39. Higher scores indicated more severe impairment. A decrease from Baseline score indicated improvement.	From Baseline to End of Treatment (Week 12)
Change From Baseline to Week 12 in the Myasthenia Gravis Composite (MGC) Scale Total Score	The total MGC score was sum of responses to 10 individual items : 1. Ptosis upward gaze (0 to 3), 2. Double vision on lateral gaze, left or right (0, to 4), 3. Eye closure (0 to 2), 4. Talking (0 to 6), 5. Chewing (0 to 6), 6. Swallowing [0 to 6], 7. Breathing (0 to 9), 8. Neck flexion or extension (0 to 4), 9. Shoulder abduction (0 to 5), 10. Hip flexion (0 to 5). The higher score for each item indicated severity. The total score ranged 0 to 50 with higher score indicative of severe disease activity). A decrease from Baseline score showed improvement.	From Baseline to End of Treatment (Week 12)
Change From Baseline to Week 12 in the Myasthenia Gravis - Quality of Life Revised (MG-QoL15r) Scale Total Score	The MG-QoL15r is a 15-item patient-reported outcome measure designed to assess quality of life in patients with MG. Each item in the scale scored on a 0 to 2-point scale (0=Not much at all, 1=Somewhat, 2=Very much). The total score was the sum of the 15 individual item scores, ranging from 0 to 30. Higher scores indicated more severe impact of the disease on aspects of the patient's life. A decrease from Baseline score indicated improvement.	From Baseline to End of Treatment (Week 12)
Time to First Receipt of Rescue Therapy Over the 12-week Treatment Period	Time to first receipt of rescue therapy over the 12-week treatment period (in days) was defined as the date of first rescue therapy use minus date of first Investigational Medicinal Product (IMP) + 1.	From Baseline to End of Treatment (Week 12)
Percentage of Participants Achieving Minimal Symptom Expression (MSE) at Week 12 Without Rescue Therapy	Percentage of Participants achieving MSE was defined as achieving a MG-ADL value of a 0 (No MG symptoms) or 1 (Mild MG symptoms) at Week 12 and not having taken rescue therapy. Any participant with an event of death, myasthenic crisis or rescue therapy was considered as non-responders. Any other missing data was imputed using the missing at Random (MAR) assumption.	End of Treatment (Week 12)
Percentage of Participants Achieving a ≥ 3-point Reduction in MG-ADL Score at Week 12 Without Rescue Therapy	Percentage of participants achieving a ≥ 3-point reduction in MG-ADL Score at Week 12 without rescue therapy were reported. The MG-ADL is an 8-item patient-reported outcome measure assessing MG symptoms and their effects on daily activities. Each item in the scale scored on a 0 to 3 (0=None, 3=severe disease) point scale. The total score was the sum of all individual item scores and ranged from 0 to 24. Higher scores indicated more severe disability due to MG. Any participant with an event of death, myasthenic crisis or rescue therapy was considered as non-responders. Any other missing data was imputed using the MAR assumption.	End of Treatment (Week 12)
Percentage of Participants Achieving a ≥5-point Reduction in QMG Score Without Rescue Therapy at Week 12	Percentage of participants achieving a ≥5-point reduction in QMG Score without rescue therapy at Week 12 were reported. The QMG is a standardized and validated quantitative strength scoring system that was developed specifically for MG. The scale consisted of 13 items. Each item in the scale scored on a 0 to 3-point scale, ranging from 0 (no weakness) to 3 (severe weakness), summing up to the overall score range from 0 to 39. Higher scores indicated more severe impairment. Any participant with an event of death, myasthenic crisis or rescue therapy was considered as non-responders. Any other missing data was imputed using the MAR assumption.	End of Treatment (Week 12)
Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)	A TEAE is defined as an AE starting on or after the time of first administration of IMP and up to and including 40 days after the final dose (or last contact depending on which occurs first). Adverse events starting before the date of the first administration of IMP were not considered TEAEs.	From Baseline (Day 1) to Safety Follow-up visit (19 Weeks [12 weeks Treatment Period plus up to 7 weeks Follow-up])

Collaborators and Investigators

• Sponsor: Ra Pharmaceuticals, Inc.
• Investigators: Study Director: UCB Cares, 0018445992273 (UCB)

Publications and helpful links

General Publications

• Howard JF Jr, Bresch S, Genge A, Hewamadduma C, Hinton J, Hussain Y, Juntas-Morales R, Kaminski HJ, Maniaol A, Mantegazza R, Masuda M, Sivakumar K, Smilowski M, Utsugisawa K, Vu T, Weiss MD, Zajda M, Boroojerdi B, Brock M, de la Borderie G, Duda PW, Lowcock R, Vanderkelen M, Leite MI; RAISE Study Team. Safety and efficacy of zilucoplan in patients with generalised myasthenia gravis (RAISE): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Neurol. 2023 May;22(5):395-406. doi: 10.1016/S1474-4422(23)00080-7.

Study record dates

Study Major Dates

• Study Start (Actual): September 17, 2019
• Primary Completion (Actual): December 30, 2021
• Study Completion (Actual): December 30, 2021

Study Registration Dates

• First Submitted: October 2, 2019
• First Submitted That Met QC Criteria: October 2, 2019
• First Posted (Actual): October 4, 2019

Study Record Updates

• Last Update Posted (Actual): May 3, 2023
• Last Update Submitted That Met QC Criteria: May 2, 2023
• Last Verified: May 1, 2023

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: RA101495-02.301

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data from this trial may be requested by qualified researchers six months after product approval in the US and/or Europe, or global development is discontinued, and 18 months after trial completion. Investigators may request access to anonymized individual patient-level data and redacted trial documents which may include: analysis-ready datasets, study protocol, annotated case report form, statistical analysis plan, dataset specifications, and clinical study report. Prior to use of the data, proposals need to be approved by an independent review panel at www.Vivli.org and a signed data sharing agreement will need to be executed. All documents are available in English only, for a prespecified time, typically 12 months, on a password protected portal. This plan may change if the risk of re-identifying trial participants is determined to be too high after the trial is completed;in this case and to protect participants, individual patient-level data would not be made available.
• IPD Sharing Time Frame: Data from this trial may be requested by qualified researchers six months after product approval in the US and/or Europe or global development is discontinued, and 18 months after trial completion.
• IPD Sharing Access Criteria: Qualified researchers may request access to anonymized IPD and redacted study documents which may include: raw datasets, analysis-ready datasets, study protocol, blank case report form, annotated case report form, statistical analysis plan, dataset specifications, and clinical study report. Prior to use of the data, proposals need to be approved by an independent review panel at www.Vivli.org and a signed data sharing agreement will need to be executed. All documents are available in English only, for a pre-specified time, typically 12 months, on a password protected portal.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

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