Ravulizumab Versus Placebo in Adult Participants With Dermatomyositis

Phase 2

Terminated

Conditions: Dermatomyositis

Interventions: Drug: Ravulizumab
Drug: Placebo

Registration Number: NCT04999020

Lead Sponsor: Alexion Pharmaceuticals, Inc.

Brief Summary: This is a Phase 2/3, double-blind, randomized, placebo-controlled, parallel group, multicenter study to evaluate the efficacy, safety, pharmacokinetics, pharmacodynamics, and immunogenicity of ravulizumab in adult participants with dermatomyositis (DM).

Detailed Description: The study will be conducted in 2 parts: Part A (Phase 2) and Part B (Phase 3). There will be 3 periods in both Part A and Part B of this study: Screening Period, Randomized Controlled Period, and Open-Label Extension Period.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 38

Inclusion Criteria

18 years of age or older at the time of signing the informed consent.
Body weight ≥ 30 kilograms at the time of Screening.
Male or female.
Diagnosis: Meet 2017 American College of Rheumatology/European League Against Rheumatism classification criteria for definite or probable DM.
Participants who have an inadequate response or are intolerant to 1 or more DM treatments, including systemic corticosteroids or immunosuppressive/immunomodulatory therapies (for example, azathioprine, methotrexate, rituximab, intravenous immunoglobulin), either in combination or as monotherapy.
Vaccinated against Neisseria meningitidis within 3 years prior to initiating ravulizumab as per national and local guidelines. Participants must receive the vaccination at least 2 weeks before first study intervention. The sponsor recommends that national and local guidelines for prophylactic antibiotics should also be followed.
Female participants of childbearing potential and male participants must follow specified contraception guidance as described in the protocol.

Key

Exclusion Criteria

Participants who have been diagnosed with cancer within the last 3 years need to have appropriate negative cancer screening as per local standard of care within 6 months before Screening (basal or squamous cell skin cancer or carcinoma in situ of the cervix needs to have been excised and without evidence of residual disease for at least 3 months before Screening).
Evidence of active malignant disease or malignancies diagnosed within the previous 3 years including hematological malignancies and solid tumors.
Participants with other forms of myositis.
As per investigator discretion, participants with significant muscle damage (for example, severe muscle atrophy, end stage muscle disease, MRI with severe atrophy or fibrofatty replacement)
History of Neisseria meningitidis infection.
Human immunodeficiency virus (HIV) infection (evidenced by HIV Type 1 or Type 2 antibody titer).
Active systemic bacterial, viral, or fungal infection within 14 days prior to ravulizumab administration.
Presence of fever ≥ 38°Celsius (100.4°Fahrenheit) within 7 days prior to study drug administration on Day 1.
History of hypersensitivity to murine proteins or to 1 of the excipients of ravulizumab.
Pregnant, breastfeeding, or intending to conceive during the course of the study.
Inability or unwillingness to adhere to the protocol requirements.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Ravulizumab	Ravulizumab	Participants will receive ravulizumab in both Parts A and B.
Placebo	Placebo	Participants will receive placebo in both Parts A and B.

Primary Outcome Measures

Name	Time	Method
Number of Participants With International Myositis Assessment and Clinical Studies Total Improvement Score (IMACS-TIS) (TIS40) Response at Week 26 of the Randomized Controlled Period	Week 26	Data are presented for the number of participants with a TIS40 response, defined as an IMACS-TIS score ≥ 40 at Week 26. IMACS-TIS is a clinical instrument that encompasses 6 core set measure (CSMs) (physician, patient, extra-muscular global activity, muscle strength, Health Assessment Questionnaire \[HAQ\], and muscle enzyme levels). A Total Improvement Score (TIS: 0-100), was determined by summing scores in each CSM, and was based on the improvement and relative weight of each CSM. A higher score indicated greater improvement. TIS40 was considered a moderate improvement score.

Secondary Outcome Measures

Name	Time	Method
TIS at Week 26	Week 26	TIS scores ranged from 0-100 with higher scores indicating a greater improvement. Scores were determined by summing scores in each of the 6 CSMs of the IMAC (physician, patient, extra-muscular global activity, muscle strength, HAQ, and muscle enzyme levels). Clinically meaningful thresholds for improvement were defined as ≥ 20 point improvement response on IMACS-TIS (TIS20; mild), ≥ 40 point improvement response on IMACS TIS (TIS40; moderate) and ≥ 60 point improvement response on IMACS-TIS (TIS60; severe). Scores were based on the improvement and relative weight of each CSM. Data are presented for TIS (least squares mean) at Week 26.
Change From Baseline In Cutaneous Dermatomyositis Disease Area And Severity Index (CDASI) Activity Score at Week 26	Baseline, Week 26	The CDASI is an instrument that separately measures activity and damage in the skin of dermatomyositis (DM) participants. It contains 3 activity measures (erythema, scale, and erosion/ulceration) and 2 damage measures (poikiloderma and calcinosis). CDASI score is calculated by rating the severity of skin disease in 15 anatomical locations on the body based on the activity and damage components. CDASI was completed by the Clinician or Clinician-Investigator while examining the participant. Total CDASI scores ranged from 0-100, with higher scores indicating a greater disease severity. Change from baseline in CDASI Total Activity Score at Week 26 was analyzed using a mixed model repeated measures (MMRM). The MMRM model included the observed Total Activity Score values at post baseline visits (Week 26) as the dependent variable.
Number of Participants With Response Related to Muscle Enzymes: Normalization of Most Abnormal Baseline Enzyme at Week 26	Baseline, Week 26	Laboratory tests were conducted to measure serum activities of muscle associated enzymes including creatine kinase (CK), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and aldolase. Data are presented for the number of participants who had an abnormal muscle enzyme at baseline that had been normalized at Week 26.
Change From Baseline In IMACS CSMs: Extra-Muscular Disease Activity Based on Myositis Disease Activity Assessment Tool (MDAAT) at Week 26	Baseline, Week 26	The MDAAT assesses disease activity of extra-muscular organ systems and muscles in participants with DM. The validated MDAAT tool measures the degree of disease activity of extra-muscular organ systems and muscle on a 0-10 centimeter (cm) visual analog scale (VAS). Extra-muscular activity ranged between 0 and 10, where, 0 cm = absent and 10 cm = maximum disease activity.
Change From Baseline In IMACS CSMs: Physician Global Activity Assessment at Week 26	Baseline, Week 26	The physician global activity assessment provides an overall rating of disease activity related to myositis. Disease activity is judged by the physician based on all information available at the time of evaluation, including the participant's appearance, medical history, physical examination, laboratory testing, and prescribed medical therapy. The global disease activity score is recorded on a 10-cm VAS, where 0 cm= no evidence of disease activity and 10 cm= extremely severe disease activity.
Change From Baseline In IMACS CSMs: Patient Global Activity Assessment at Week 26	Baseline, Week 26	The patient global activity assessment provides an overall rating of disease activity related to myositis from the participant's perspective. Participants were asked to consider all of the active inflammation in their own muscles, skin, joints, intestines, heart, lungs, or other parts of the body that can improve with treatment. The patient global disease activity score was recorded on a 10-cm VAS that contained a smiley face at the 0-cm anchor and a sad face at the 10 cm anchor to help participants understand the scale. Scores ranged from 0 (no evidence of disease activity) to 10 (extremely active or severe disease activity).
Change From Baseline In IMACS CSMs: Manual Muscle Testing Subset 8 Muscles (MMT-8) at Week 26	Baseline, Week 26	The purpose of the MMT-8 was to measure muscle strength as part of the physical examination. It included a subset of 8 muscle groups: neck flexors, deltoids, biceps, wrist, extensors, gluteus maximus and medius, quadriceps, and ankle dorsiflexors. Total MMT8 scores ranged from 0 (lowest strength) to 150 (highest strength).
Change From Baseline In IMACS CSMs: Health Assessment Questionnaire (HAQ) at Week 26	Baseline, Week 26	The HAQ is a brief self-report questionnaire that assesses physical function pertaining to activities of daily living in a variety of domains. The HAQ includes 20 questions relating to 8 domains of function: dressing and grooming, arising, eating, walking, hygiene, reach, grip and usual activities. For each of the categories, participants reported the amount of difficulty they had in performing 2 or 3 specific subcategory items. The standard disability score is calculated from the 8 categories by dividing the sum of the individual categories by the number of categories answered, yielding a score from 0 (without any difficulty) to 3 (unable to do), with higher values indicating higher disability.
Number of Participants With CDASI Response (>=7-point Improvement) at Week 26	Week 26	The CDASI is an instrument that separately measures activity and damage in the skin of dermatomyositis (DM) participants. It contains 3 activity measures (erythema, scale, and erosion/ulceration) and 2 damage measures (poikiloderma and calcinosis). CDASI score is calculated by rating the severity of skin disease in 15 anatomical locations on the body based on the activity and damage components. CDASI was completed by the Clinician or Clinician-Investigator while examining the participant. Total CDASI scores ranged from 0-100, with higher scores indicating a greater disease severity. Data are presented for the number of participants with a CDASI response. Response was defined as a \>=7 point improvement in participants who did not have an intercurrent event at or prior to the relevant timepoint.
Number of Participants With Cutaneous Dermatomyositis Activity Physician's Global Assessment (CDA-IGA) Response at Week 26	Week 26	CDA-IGA is a scale that was created to measure disease severity in participants with skin disease. It is a 5-point scale (0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe) with morphologic descriptors for each score. The CDA-IGA was completed by the Investigator and was used to describe the overall appearance of lesions at a given time point. Data are presented for the number of participants with a CDA-IGA response at Week 26. A response was defined as participants with clear or almost clear skin (score of 0 or 1) who did not have an intercurrent event at or before the relevant timepoint.
Number of Participants With ≥ 20-Point Improvement Response on IMACS-TIS (TIS20) Response at Week 26	Week 26	TIS20 was defined as a ≥20-point improvement response on IMACS-TIS. IMACS-TIS is a clinical instrument that encompasses 6 CSMs (physician, patient, extra-muscular global activity, muscle strength, HAQ, and muscle enzyme levels). A Total Improvement Score (TIS: 0-100), was determined by summing scores in each CSM, and was based on the improvement and relative weight of each CSM. Higher scores indicated greater improvement/response. TIS20 is considered a mild improvement score.
Number of Participants With ≥ 60-Point Improvement Response on IMACS-TIS (TIS60) Response at Week 26	Week 26	TIS60 was defined as a ≥60-point improvement response on IMACS-TIS. IMACS-TIS is a clinical instrument that encompasses 6 CSMs (physician, patient, extra-muscular global activity, muscle strength, HAQ, and muscle enzyme levels). A Total Improvement Score (TIS: 0-100), was determined by summing scores in each CSM, and was based on the improvement and relative weight of each CSM. Higher scores indicated greater improvement/response. TIS60 is considered a severe improvement score.
Time to First Response of TIS20, TIS40, or TIS60	Baseline through Week 26	TIS20, 40 and 60 were defined as a ≥20, ≥40 and ≥60-point improvement response on IMACS-TIS respectively. IMACS-TIS is a clinical instrument that encompasses 6 CSMs (physician, patient, and extra-muscular global activity, muscle strength, HAQ, and muscle enzyme levels). A Total Improvement Score (TIS: 0-100), was determined by summing scores in each CSM, and was based on the improvement and relative weight of each CSM. Higher scores indicated greater improvement/response. TIS20, 40 and 60 were considered mild, moderate and severe improvement scores respectively. Data are presented for the time to first response of TIS20, TIS40, or TIS60. The median time to TIS20, TIS40, and TIS60 was defined at the time in which 50% of the participants experienced TIS20, TIS40, or TIS60, respectively, based on a Kaplan-Meier analysis.
Number of Participants With Clinical Worsening (CW) During the RCP At 2 Consecutive Visits	Baseline through Week 26	CW was defined as one of the following: 1. Physician's global activity VAS worsening ≥ 2 cm and MMT-8 worsening ≥ 20% compared to baseline 2. Global extra muscular activity worsening ≥ 2 cm on the MDAAT VAS compared to baseline 3. Any 3 of 5 CSMs (excluding muscle enzymes) worsening by ≥ 30% compared to baseline Data are presented for the number of participants with clinical worsening during the RCP at 2 consecutive visits.
Number of Participants Who Received Acute Rescue Therapy With Standard DM Treatment	Baseline through Week 26	Acute rescue therapy with standard DM treatment included an increased dose of a medication that was being taken for DM or the initiation of a new DM treatment (glucocorticoid and/or immunosuppressive/immunomodulatory therapy \[ISTs\]). Data are presented for the number of participants who received acute rescue therapy with standard DM treatment.