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

• ClinicalTrials.gov Identifier: NCT03315130
• Recruitment Status: Completed
• First Posted: October 19, 2017
• Results First Posted: June 27, 2022
• Last Update Posted: July 27, 2022
• Sponsor: Ra Pharmaceuticals
• Information provided by (Responsible Party): UCB Pharma ( Ra Pharmaceuticals )

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Generalized Myasthenia Gravis	Drug: zilucoplan (RA101495); Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 45 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: October 11, 2017
• Actual Primary Completion Date: December 10, 2018
• Actual Study Completion Date: November 19, 2020

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Main Portion: Change From Baseline to Week 12 in Quantitative Myasthenia Gravis (QMG) Score [ Time Frame: From Baseline to Week 12 ]
   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.

Secondary Outcome Measures :

1. Main Portion: Change From Baseline to Week 12 in the Myasthenia Gravis - Activities of Daily Living (MG-ADL) Scale [ Time Frame: From Baseline to Week 12 ]
   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.
2. Main Portion: Change From Baseline to Week 12 in the Myasthenia Gravis - Quality of Life 15r (MG-QOL15r) Survey [ Time Frame: From Baseline to Week 12 ]
   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.
3. Main Portion: Change From Baseline to Week 12 in the MG Composite Scale Total Score [ Time Frame: From Baseline to Week 12 ]
   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.
4. Main Portion: Percentage of Participants With >= 3-point Reduction in QMG Total Score at Week 12 [ Time Frame: 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.
5. Main Portion: Percentage of Participants Who Required Rescue Therapy Over the 12-week Treatment Period [ Time Frame: Up to Week 12 ]
   Percentage of participants who used at least 1 dose of rescue medication were reported.
6. Main Portion: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: From Baseline to Week 12 ]
   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.
7. Main Portion: Change From Baseline in Sheep Red Blood Cell (sRBC) Lysis Assay at Week 12 (Pre-dose) [ Time Frame: Baseline and 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.
8. Main Portion: Change From Baseline in C5 Levels at Week 12 (Pre-dose) [ Time Frame: Baseline and Week 12 (Pre-dose) ]
   Blood samples were collected from participants to assess Complement Component 5C levels.
9. Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites [ Time Frame: 1, 3 and 6 hours postdose on Day 1; Pre-dose on Week 1, 2, 4, 8 and 12 ]
   RA102758 and RA103488 are the metabolites of RA101495.
10. Main Portion: Maximum Plasma Concentration (Cmax) on Day 1 [ Time Frame: Pre-dose, 1, 3 and 6 hours postdose on Day 1 ]
    Cmax is defined as the maximum observed plasma concentration.
11. Main Portion: Time Corresponding to Cmax (Tmax) on Day 1 [ Time Frame: Pre-dose, 1, 3 and 6 hours postdose on Day 1 ]
    Tmax is defined as the time to observe maximum plasma concentration.
12. Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio [ Time Frame: Pre-dose, 1, 3 and 6 hours postdose on Day 1; Pre-dose on Week 1, 2, 4, 8 and 12 ]
    RA102758 and RA103488 are the metabolites of RA101495.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, Alabama

Diagnostic and Medical Clinic - Mobile

Mobile, Alabama, United States, 36604

United States, California

The Research Center of Southern California

Carlsbad, California, United States, 92011

UCLA Medical Center

Los Angeles, California, United States, 90095

University of California Irvine Health ALS and Neuromuscular Center

Orange, California, United States, 92868

United States, Connecticut

Yale University

New Haven, Connecticut, United States, 06520

United States, District of Columbia

George Washington University

Washington, District of Columbia, United States, 20052

United States, Florida

University of Florida

Jacksonville, Florida, United States, 32209

University of South Florida

Tampa, Florida, United States, 33620

United States, Illinois

Rush University Medical Center

Chicago, Illinois, United States, 60612

United States, Kansas

University of Kansas Medical Center

Kansas City, Kansas, United States, 66160

United States, Maryland

University of Maryland

Baltimore, Maryland, United States, 21201

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

Lahey Hospital and Medical Center

Burlington, Massachusetts, United States, 01805

United States, Michigan

Wayne State University

Detroit, Michigan, United States, 48202

Michigan State University

East Lansing, Michigan, United States, 48864

United States, New York

University of Buffalo

Buffalo, New York, United States, 14260

Hospital for Special Surgery

New York, New York, United States, 10021

Mount Sinai Hospital

New York, New York, United States, 10029

United States, North Carolina

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, United States, 27599

United States, Ohio

Ohio State University

Columbus, Ohio, United States, 43210

United States, Pennsylvania

Allegheny Neurological Associates

Pittsburgh, Pennsylvania, United States, 15212

United States, Tennessee

Wesley Neurology Clinic

Cordova, Tennessee, United States, 38018

United States, Texas

University of Texas Southwestern

Dallas, Texas, United States, 75390

United States, Utah

University of Utah

Salt Lake City, Utah, United States, 84132

United States, Vermont

University of Vermont

Burlington, Vermont, United States, 05405

United States, Wisconsin

Center for Neurological Disorders

Milwaukee, Wisconsin, United States, 53215

Canada, Alberta

University of Alberta Hospital

Edmonton, Alberta, Canada, T6G 2B7

Canada, Ontario

London Health Sciences Centre University Hospital

London, Ontario, Canada, N6A 5A5

Toronto General Hospital

Toronto, Ontario, Canada, M5G 2C4

Canada, Quebec

Montreal Neurological Institute and Hospital

Montreal, Quebec, Canada, H3A 2B4

Sponsors and Collaborators

Ra Pharmaceuticals

Investigators

• Study Director: UCB Cares; 001 844 599 2273 (UCB)

  Study Documents (Full-Text)

Documents provided by UCB Pharma ( Ra Pharmaceuticals ):

Study Protocol  [PDF] April 10, 2019

Statistical Analysis Plan  [PDF] March 5, 2020

More Information

Publications of Results:

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.

• Responsible Party: Ra Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03315130
• Other Study ID Numbers: RA101495-02.201
• First Posted: October 19, 2017
• Results First Posted: June 27, 2022
• Last Update Posted: July 27, 2022
• Last Verified: July 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Myasthenia Gravis; Muscle Weakness; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Manifestations; Neurologic Manifestations; Nervous System Diseases; Pathologic Processes; Paraneoplastic Syndromes, Nervous System; Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Paraneoplastic Syndromes; Autoimmune Diseases of the Nervous System; Neurodegenerative Diseases; Neuromuscular Junction Diseases; Neuromuscular Diseases; Autoimmune Diseases; Immune System Diseases