A Study of Ustekinumab in Participants With Active Polymyositis and Dermatomyositis Who Have Not Adequately Responded to One or More Standard-of-care Treatments

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy of ustekinumab in participants with active polymyositis (PM)/dermatomyositis (DM) despite receiving 1 or more standard-of-care treatments (for example, glucocorticoids and/or immunomodulators).

Official Title
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A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Study of Ustekinumab in Participants With Active Polymyositis and Dermatomyositis Who Have Not Adequately Responded to One or More Standard-of-care Treatments

Conditions
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Polymyositis, Dermatomyositis

Intervention / Treatment
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* Drug: Ustekinumab 6 mg/kg
* Drug: Ustekinumab 90 mg
* Drug: Placebo IV
* Drug: Placebo SC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has a diagnosis of polymyositis (PM)/ dermatomyositis (DM) made or confirmed by a physician (such as a rheumatologist, neurologist, or dermatologist) experienced in treatment of PM/DM at least 6 weeks prior to first dose of the study drug Has PM or DM which is considered active despite receiving at least 1 standard-of-care treatment by the investigator Must be receiving 1 or more of the following protocol-permitted, systemic standard-of-care treatments: i) glucocorticoids, ii) 1 or 2 of the following immunomodulatory drugs: mycophenolate mofetil, azathioprine, oral methotrexate, oral tacrolimus, or oral cyclosporine A Regular or as needed treatment with topical use of glucocorticoids are permitted to treat skin lesions on a stable dose for greater than or equal to (>=) 2 weeks prior to first dose of the study drug Contraceptive (birth control) use by men or women should be consistent with local regulations regarding the acceptable methods of contraception for those participating in clinical studies Must be medically stable on the basis of clinical laboratory tests performed at screening. If the results of the clinical laboratory tests are outside the normal reference ranges, the participant may be included only if the investigator judges the abnormalities or deviations from normal to be not clinically significant Demonstrable muscle weakness at screening and Week 0 measured by the Manual Muscle Testing (MMT)-8 less than or equal to (<=)135 units Demonstrable muscle weakness at screening measured by any 2 or more of the followings: (i) PhGA greater than or equal to (>=) 1.5 centimeter (cm), (ii) 1 or more muscle enzymes (Creatine kinase [CK], and aldolase) >=1.4*upper limit of normal (ULN), (iii) Myositis disease activity assessment tool (MDAAT)-Extramuscular Global Assessment >=1.5 cm Exclusion Criteria: Has myositis other than PM/DM, including but not limited to amyopathic dermatomyositis (ADM), clinically amyopathic DM, juvenile DM, inclusion body myositis (IBM) immune-mediated necrotizing myopathy diagnosed based on muscle biopsy findings and positive anti-SRP or anti-HMGCR antibody, drug-induced myositis, PM associated with human immunodeficiency virus (HIV), and muscular dystrophy, congenital myopathy, metabolic myopathy, and mitochondrial myopathy Has other inflammatory diseases that might confound the evaluations of efficacy, including but not limited to rheumatoid arthritis (RA), psoriatic arthritis (PsA), systemic lupus erythematosus (SLE), psoriasis, or Crohn's disease Has severe respiratory muscle weakness confirmed by the investigator based on the consultation with a pulmonologist and the measures of respiratory muscle strength such as maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) and/or maximal voluntary ventilation (MVV) measurements and lung capacity such as forced vital capacity (FVC). The results need to be within population appropriate normal limits Has severe muscle damage (Myositis Damage Index-VAS [Muscle Damage] greater than (>) 7 centimeter [cm]), permanent weakness due to a non-IIM cause, or myositis with cardiac dysfunction Has glucocorticoid-induced myopathy which the investigator considers the primary cause of muscle weakness Has positive test result of anti-melanoma differentiation-associated protein 5 (MDA5) antibody (anti clinically amyopathic dermatomyositis (C-ADM)-140 antibody). Has had a nontuberculous mycobacterial infection or opportunistic infection Has a history of, or ongoing, chronic or recurrent infectious disease Has past history of severe Interstitial lung disease (ILD) flare, severe non-infectious lung inflammation which required active intervention, or multiple relapses of these conditions Presence or history of malignancy within 5 years before screening

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: Ustekinumab + Placebo<br>Participants will receive body weight-range based IV dosing of approximately 6 milligram per kilogram (mg/kg) of ustekinumab at Week 0 followed by ustekinumab 90 milligram (mg) subcutaneously (SC) at Week 8 and every 8 Weeks (q8w) administrations through Week 72. At Week 24, participants will receive IV dosing of placebo. | Drug: Ustekinumab 6 mg/kg<br>* Participants will receive body weight-range based IV dosing of 6 mg/kg of ustekinumab at Week 0 in Group 1 and at Week 24 in Group 2.<br>* Other names: STELARA;Drug: Ustekinumab 90 mg<br>* Participants will receive ustekinumab 90 mg SC at Week 8 and every 8 Weeks (q8w) through Week 72 in Group 1 and q8w Week 32 through Week 72 in Group 2.<br>* Other names: STELARA;Drug: Placebo IV<br>* Participants will receive IV dosing of placebo at Week 24 in Group 1 and at Week 0 in Group 2.<br>|
| Placebo Comparator: Group 2: Placebo + Ustekinumab<br>Participants will receive IV dosing of placebo at Week 0 followed by placebo SC administrations at Weeks 8,16 and 24. At Week 24, participants will receive body weight-range based IV dosing of approximately 6 mg/kg of ustekinumab, followed by ustekinumab 90 mg SC q8w administrations Week 32 through Week 72. | Drug: Ustekinumab 6 mg/kg<br>* Participants will receive body weight-range based IV dosing of 6 mg/kg of ustekinumab at Week 0 in Group 1 and at Week 24 in Group 2.<br>* Other names: STELARA;Drug: Ustekinumab 90 mg<br>* Participants will receive ustekinumab 90 mg SC at Week 8 and every 8 Weeks (q8w) through Week 72 in Group 1 and q8w Week 32 through Week 72 in Group 2.<br>* Other names: STELARA;Drug: Placebo IV<br>* Participants will receive IV dosing of placebo at Week 24 in Group 1 and at Week 0 in Group 2.<br>Drug: Placebo SC<br>* Participants will receive SC dosing of placebo at Weeks 8,16 and 24.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants who achieve Minimal Improvement in International Myositis Assessment and Clinical Studies Total Improvement Score (IMACS TIS) at Week 24 | Minimal improvement is defined as IMACS TIS greater than or equal to (>=)20 in participants with polymyositis (PM)/ dermatomyositis (DM). The criteria use the 6 IMACS core set measures: Global Activity-VAS, Patient Global Activity-VAS, MMT-8, Muscle Enzymes, Extramuscular Assessment (MDAAT), and Functional Assessment (HAQ-DI). The absolute percentage change in each measure with varying weights is combined to obtain a Total Improvement Score (TIS) on a scale of 0 to 100. Higher score indicates greater improvement. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Functional Index-2 (FI-2) Score at Week 24 | Change from baseline in functional Index-2 at Week 24 will be reported. The FI-2 is a functional outcome developed for participants with adult PM or DM to assess muscle endurance in 7 muscle groups. Each muscle group is scored as the number of correctly performed repetitions with 60 or 120 maximal number of repetitions depending on muscle group. The FI-2 is performed unilaterally, preferably on the participant's dominant side for muscle groups of shoulder, hip, and step test. The FI-2 has been validated as to content and construct validity and intra- and interrater reliability. The score ranges from 0-60 or 0-120 depending on the muscle group. Higher score indicates better muscle endurance. | Baseline and Week 24 | 
| Percentage of Participants who Experience Disease Worsening Through Week 24 Based on Consensus Criteria for Worsening | Percentage of participants who experience disease worsening through Week 24 based on consensus criteria for worsening will be reported. Criteria for disease worsening in a clinical trial were based on international consensus guideline developed by the IMACS. The worsening of disease is defined as 1 of the following criteria: Worsening of the Physician Global Activity by greater than or equal to (>=2) centimeter (cm) on a 10-cm VAS and worsening of findings of MMT-8 by >= 20 percent (%) from baseline; worsening of MDAAT-global extramuscular organ disease activity (a composite of constitutional, cutaneous, skeletal, gastrointestinal, pulmonary, and cardiac activity) by >=2 cm on a 10-cm VAS from baseline; worsening of any 3 of 6 IMACS core set activity measures by >= 30% from baseline. | Through Week 24 | 
| Change from Baseline in Manual Muscle Testing (MMT)-8 Score at Week 24 | Change from baseline in MMT-8 score at Week 24 will be reported. Manual Muscle Testing is a partially validated tool to assess muscle strength. MMT-8 score ranges from 0-80, where maximal score is sum of scores from 8 muscle groups and each muscle group is scored on a 0 to 10-point scale. Higher score indicates greater muscle strength, that is, less impairment of muscle. | Baseline and Week 24 | 
| Change from Baseline in Physician Global Activity (PhGA) at Week 24 | Change from baseline in physician global activity at Week 24 will be reported. Physician Global Activity is a partially validated tool to measure the global evaluation by the physician of the participant's overall disease activity at the time of assessment using a 10 cm VAS, where 0 cm= no evidence of disease activity and 10 cm= extremely active or severe disease activity. | Baseline and Week 24 | 
| Change from Baseline in Extramuscular Assessment (Myositis Disease Activity Assessment Tool [MDAAT]-Extramuscular Global Assessment) Score at Week 24 | Change from baseline in extramuscular assessment (myositis disease activity assessment tool [MDAAT]-Extramuscular Global Assessment) Score at Week 24 will be reported. MDAAT is scored on a 10 cm scale ranging from 0-10 cm where, 0 cm = absent and 10 cm = maximum disease activity. | Baseline and Week 24 | 
| Change from Baseline in Muscle Enzymes at Week 24 | Change from baseline in muscle enzyme like creatine kinase [CK], alanine aminotransferase [ALT], aspartate aminotransferase [AST], lactate dehydrogenase [LDH], and aldolase) at Week 24 measured as units/liter will be reported. | Baseline and Week 24 |