Safety and Efficacy Study of Zilucoplan in Subjects With Immune-Mediated Necrotizing Myopathy

A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Efficacy of Zilucoplan in Subjects With Immune-Mediated Necrotizing Myopathy

The purpose of the study is to evaluate the safety and efficacy of zilucoplan in patients with Immune-Mediated Necrotizing Myopathy (IMNM). Subjects will be randomized in a 1:1 ratio to receive daily SC doses of 0.3 mg/kg zilucoplan or matching placebo for 8 weeks.

Study Overview

• Status: Terminated
• Conditions: Immune Mediated Necrotizing Myopathy
• Intervention / Treatment: Drug: zilucoplan; Other: Placebo

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Paris, France, 75013
    • Hôpital Universitaire Pitié Salpêtrière
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Amsterdam UMC
• United Kingdom
  • London, United Kingdom, WC1N3BG
    • University College London Hospitals NHS Foundation Trust
  • Manchester, United Kingdom, M6 8HD
    • Salford Royal NHS Barnes Clinical Research Facility
• United States
  • California
    • Los Angeles, California, United States, 90095
      • University of California Los Angeles
    • Orange, California, United States, 92868
      • University of California Irvine
  • Florida
    • Jacksonville, Florida, United States, 32209
      • University of Florida Health Jacksonville
    • Tampa, Florida, United States, 33612
      • University of South Florida
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institute of Health
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine in Saint Louis
  • New York
    • Great Neck, New York, United States, 11021
      • Northwell Health Neuroscience Institute
  • Ohio
    • Columbus, Ohio, United States, 43221
      • The Ohio State University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
  • Tennessee
    • Memphis, Tennessee, United States, 38018
      • Wesley Neurology Clinic
  • Texas
    • Austin, Texas, United States, 78756
      • Austin Neuromuscular Center
    • Houston, Texas, United States, 77030
      • The University of Texas Health Science Center at Houston

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 71 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Clinical diagnosis of IMNM (Immune-Mediated Necrotizing Myopathy)
• Positive serology for anti-3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) or anti-signal recognition particle (SRP) autoantibodies
• Clinical evidence of weakness (≤ grade 4 out of 5) on manual muscle testing in at least one proximal limb muscle group
• Creatine kinase (CK) of >1000 U/L at Screening
• No change in corticosteroid dose for at least 30 days prior to Baseline or anticipated to occur during the first 8-weeks on study
• No changes in immunosuppressive therapy, including dose, for at least 30 days prior to Baseline or anticipated to occur during the first 8-weeks on study

Exclusion Criteria:

• History of meningococcal disease
• Current or recent systemic infection within 2 weeks prior to Screening or infection requiring intravenous (IV) antibiotics within 4 weeks prior to Screening
• Recent initiation of intravenous immunoglobulin (IVIG) (i.e., first cycle administered less than 90 days prior to Baseline)
• Rituximab use within 90 days prior to Baseline or anticipated to occur during study
• Statin use within 30 days prior to Baseline or anticipated to occur during study
• Plasma exchange within 4 weeks prior to Baseline or expected to occur during the 8-week Treatment Period

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
Experimental: 0.3 mg/kg zilucoplan; Daily subcutaneous (SC) injection	Drug: zilucoplan; Daily subcutaneous (SC) inection
Placebo Comparator: Placebo; Daily subcutaneous (SC) injection	Other: Placebo; Daily subcutaneous (SC) inection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage Change From Baseline to Week 8 in Serum Creatine Kinase (CK) Levels	All laboratory samples were obtained prior to administration of study drug at applicable visits. CK levels were measured by a central laboratory.	Baseline (Day 1) and end of Main Portion (Week 8)
Number of Participants Who Experienced a Treatment-Emergent Adverse Event (TEAE)	A TEAE was defined as: An adverse event (AE) that occurred after study treatment start that was not present at the time of treatment start.; An AE that increased in severity after treatment start if the event was present at the time of treatment start.	Baseline (Day 1) to end of Main Portion (Week 8)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Achieve at Least Minimal Response Based on the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Response Criteria Scale	The ACR/EULAR scale utilized a conjoint analysis-based continuous model using absolute percent change from Baseline in core set measures (physician, patient, and Myositis Disease Activity Assessment Tool (MDAAT); muscle strength; Health Assessment Questionnaire (HAQ); and muscle enzyme levels). A total improvement score (range 0-100) was determined by summing scores for each core set measure and comparing improvement in each respective core set measure. The threshold for minimal improvement was ≥20 in the total improvement score with higher scores indicating a better outcome.	Baseline (Day 1) and end of Main Portion (Week 8)
Change From Baseline to Week 8 in Triple Timed Up and Go Test (3TUG) Time	The 3TUG test involved the ambulatory participant getting up from a seated position in a chair, walking at their normal pace for 3 meters, turning around, walking back to the chair, and sitting down. This sequence was repeated 3 times without rest, and the 3TUG test time is the average of the 3 lap times. A negative change from baseline indicated a better outcome.	Baseline (Day 1) and end of Main Portion (Week 8)
Change From Baseline to Week 8 in Proximal Manual Muscle Testing (MMT) Score	The proximal MMT assessed muscle strength using manual muscle testing in 7 muscle groups (left and right sides assessed separately). The total MMT score for this study, inclusive of both sides, could range from 0-140, where 0 means no strength in any muscles and 140 means full strength in all the muscles examined. A negative change from Baseline indicated a worse outcome.	Baseline (Day 1) and end of Main Portion (Week 8)
Change From Baseline to Week 8 in Physician Global Activity Visual Analogue Scale (VAS) Score	The Physician Global Activity VAS Score measured the treating physician's global evaluation of the participant's overall disease activity using a 10 cm VAS labelled with "no activity" at the left end and "maximum activity" at the right end. The Physician Global Activity VAS Score ranged from 0 (absent extramuscular disease activity) to 10 (maximum extramuscular disease activity). A negative change from Baseline indicated a better outcome.	Baseline (Day 1) and end of Main Portion (Week 8)
Change From Baseline to Week 8 in Patient Global Activity VAS Score	The Patient Global Activity VAS Score measured the treating participant's global evaluation of their overall disease activity using a 10 cm VAS labelled with "no activity" at the left end and "maximum activity" at the right end. The Patient Global Activity VAS score ranged from 0 (absent extramuscular disease activity) to 10 (maximum extramuscular disease activity). A negative change from Baseline indicated a better outcome.	Baseline (Day 1) and end of Main Portion (Week 8)
Change From Baseline to Week 8 in HAQ Score	The HAQ had 8 sections: dressing, arising, eating, walking, hygiene, reach, grip, and activities with 2 to 3 questions for each section. Scoring within each section ranged from 0 (without any difficulty) to 3 (unable to do). The total HAQ score was then calculated by summing the scores and dividing by the number of categories answered. The total HAQ score for this study could range from 0-3, where 0 means no functional impairment and 3 means complete functional impairment. A negative change from Baseline indicated a better outcome.	Baseline (Day 1) and end of Main Portion (Week 8)
Change From Baseline to Week 8 in MDAAT Extramuscular Disease Activity VAS Score	The MDAAT extramuscular disease activity VAS score measured the degree of disease activity of extramuscular organ systems and muscle. The scoring was performed by the physician and ranged from 0 (absent extramuscular disease activity) to 10 (maximum extramuscular disease activity). A negative change from Baseline indicated a better outcome.	Baseline (Day 1) and end of Main Portion (Week 8)
Change From Baseline to Week 8 in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score	The FACIT-Fatigue Scale is a 13-item tool which measured an individual's level of fatigue during their usual daily activities over the past week. The level of fatigue was measured on a 4-point Likert scale. The total FACIT-Fatigue Scale score for this study could range from 0-52, where 0 means the participants were very much fatigued during their usual daily activities and 52 means the participants were not at all fatigued during their usual daily activities. A negative change from Baseline indicated a worse outcome.	Baseline (Day 1) and end of Main Portion (Week 8)

Collaborators and Investigators

• Sponsor: Ra Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): November 7, 2019
• Primary Completion (Actual): March 4, 2021
• Study Completion (Actual): June 14, 2021

Study Registration Dates

• First Submitted: July 17, 2019
• First Submitted That Met QC Criteria: July 17, 2019
• First Posted (Actual): July 19, 2019

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: Nervous System Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Muscular Diseases
• Other Study ID Numbers: RA101495-02.202

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; Statistical Analysis Plan (SAP); Clinical Study Report (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