Trial to Evaluate the Efficacy and Safety of Abatacept in Combination With Standard Therapy Compared to Standard Therapy Alone in Improving Disease Activity in Adults With Active Idiopathic Inflammatory Myopathy

Study Overview
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Brief Summary
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Trial to Evaluate the Efficacy and Safety of Abatacept subcutaneous (SC) in Combination With Standard Therapy Compared to Standard Therapy Alone in Improving Disease Activity in Adults With Active Idiopathic Inflammatory Myopathy

Official Title
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A Phase 3, Randomized, Double-Blind Clinical Trial to Evaluate the Efficacy and Safety of Abatacept SC With Standard Treatment Compared to Standard Treatment Alone in Improving Disease Activity in Adults With Active Idiopathic Inflammatory Myopathy (IIM)

Conditions
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Polymyositis, Dermatomyositis, Autoimmune Necrotizing Myopathy, Overlap Myositis, Juvenile Myositis Above the Age of 18

Intervention / Treatment
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* Drug: Abatacept subcutaneous
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: -Diagnosis of IIM based on the Bohan and Peter classification criteria: i) Subjects with dermatomyositis (DM) must also have a confirmed myositis-associated rash (Gottron's papules or a heliotrope rash preferably confirmed by skin biopsy) and 2 or more of the remaining 4 criteria. ii) Subjects with a diagnosis of IIM other than DM include PM, autoimmune necrotizing myopathy, myositis in association with another connective tissue disease (overlap myositis) and juvenile myositis subjects above the age of 18. These subjects must have a prior muscle biopsy diagnostic for IIM or a positive test for at least one myositis-specific autoantibody (anti-aminoacyl-tRNA synthetases (Jo-1, PL-7, PL-12, EJ, OJ, KS, Zo, YRS), anti-Mi-2, anti-SRP, anti-TIF1-g, anti-NXP-2, anti-MDA5, anti-SAE, anti-HMGCR). For subjects with overlap myositis, the myositis must be the principal clinically active manifestation of their disease. Where applicable, documentation of prior skin biopsy, muscle biopsy, and autoantibody results must be obtained and retained by the site. Demonstrable muscle weakness measured by the MMT-8 of ≤ 135 units and any 3 of the following: i) MMT-8 ≤ 125 units; ii) Physician's global assessment (PGA) visual analog scale (VAS) ≥2 cm; iii) Subject's global assessment (SGA) VAS ≥2 cm; iv) HAQ-DI ≥ 0.5; v) One or more muscle enzyme (CK, aldolase, LDH, AST, ALT) ³ 1.3 times upper limit of normal (ULN); vi) MDAAT Extramuscular Global Activity VAS ≥2 cm Demonstration of currently active IIM will be determined by an adjudication committee unless the subject has any one of the following: i) an active myositis-associated rash (Gottron's papules or heliotrope rash), or ii) a recent (within 3 months prior to signing informed consent) biopsy, magnetic resonance imaging (MRI), or electromyogram (EMG) demonstrating active disease, or iii) an elevated CK > 5 times the upper limit of normal Active disease despite prior treatment with corticosteroids, immunosuppressants, or biologics as determined by the investigator The subject must be on background standard treatment for IIM. The standard treatments that are allowed as background treatment for IIM includes: i) Corticosteroids alone, or ii) One of the following immunosuppressants: methotrexate, azathioprine, mycophenolate mofetil, tacrolimus, or cyclosporine (combinations of these treatments are not allowed), or iii) A combination of corticosteroids and one of the above immunosuppressants. The subject must have been on the same medication(s) for IIM for 12 weeks prior to randomization and the dose must have been stable for 4 weeks prior to randomization. If using azathioprine, the subject must have been on azathioprine for at least 24 weeks with a stable dose for at least 12 weeks prior to randomization. Exclusion Criteria: Subjects with Inclusion Body Myositis (IBM), or myositis other than IIM, eg, drug-induced myositis and PM associated with HIV Subjects treated with penicillamine or zidovudine in the past 3 months Subjects treated with rituximab in the 6 months prior to randomization (there must be laboratory results indicating the presence of circulating B cells [CD19+]). Any other biologic treatment in the past 3 months or immune globulin (intravenous [IVIG] or subcutaneous [SCIG]) in the past 3 months prior to randomization Subjects with uncontrolled or rapidly progressive interstitial lung disease Subjects with severe muscle damage (Myositis Damage Index > 7/10), permanent weakness due to a non-IIM cause, or myositis with cardiac involvement Cancer-associated myositis (myositis diagnosed within 2 years of a diagnosis of cancer Subjects who are known to be positive for the anti-TIF-1 (p155/140) autoantibody prior to randomization who were diagnosed with IIM < 1 year prior to randomization. Subjects at risk for tuberculosis Subjects with recent acute infection requiring antibiotics Subjects with history of chronic or recurrent bacterial, viral or systemic fungal infections Subjects who have a present malignancy or have had a previous malignancy within the last 5 years prior to screening (except for a documented history of cured non-metastatic squamous or basal cell skin carcinoma or cervical carcinoma in situ). Other protocol-defined inclusion/exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 18 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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Abatacept subcutaneous + Standard Treatment<br>Abatacept subcutaneous weekly in addition to the subject's current standard treatment for 24 weeks followed by a 28 week open-label period of abatacept treatment plus the subject's current standard treatment. | Drug: Abatacept subcutaneous<br>* Specified dose of Abatacept subcutaneous on specified days<br>|
| Placebo Comparator: Placebo of Abatacept subcutaneous + Standard Treatment<br>Placebo of Abatacept subcutaneous weekly in addition to the subject's current standard treatment for 24 weeks followed by a 28 week open-label period of abatacept treatment plus the subject's current standard treatment. | Drug: Placebo<br>* Placebo of Abatacept subcutaneous<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Achieving International Myositis Assessment and Clinical Studies Definition of Improvement (IMACS DOI) at Week 24 Without Rescue | The number of participants who achieve IMACS DOI (International Myositis Assessment and Clinical Studies definition of improvement) without rescue medication at week 24. The IMACS DOI is: An improvement of >/= 20% from baseline in 3 IMACS core measures, no more than 2 IMACS core measure scores worsen by >/= 25% from baseline, and no more than 2 IMACS core measure scores worsen by >/= 25% from baseline. IMACS core measures are: Physician Global Assessment of Disease Activity (PGA), Patient (Subject) Global Assessment of Disease Activity (SGA), Manual Muscle Test (MMT-8), Health Assessment Questionnaire-Disability Index (HAQ-DI), Muscle Enzyme levels, Myositis Disease Activity Assessment Tool (MDAAT) Extramuscular Global Activity. | From first dose to 24 weeks after first dose. (Approximately 169 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in Health Assessment Questionnaire-Disability Index (HAQ-DI) From Baseline to Week 24 | The adjusted mean change from baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI). HAQ-DI is a patient-reported outcome measuring disability by asking a total of 20 questions in eight categories of function: dressing, arising, eating, walking, hygiene, reach, grip, and activities. If an aid or device is used or if help is required from another individual, then the minimum score for that section is 2. The highest component score in each category determines the score for the category and scores are averaged to give the disability index. The HAQ scale ranges from 0 (no difficulties) to 3 (unable to do). | From first dose to 24 weeks after first dose. (Approximately 169 days) | 
| Mean Change in Muscle Endurance Using the Myositis Function Index (FI-2) From Baseline to Week 24 | The adjusted mean change from baseline in Myositis FI-2 scores is assessing muscle endurance impairment by testing specific muscle groups. The 3 Score average includes shoulder flexion, hip flexion, and head lift. Each muscle group is scored as the number of correctly performed repetitions with 60 maximal number of repetitions. The total score is based on hip flexion, shoulder flexion (R/L) and neck divided by 3 (range 0-60 repetitions). | From first dose to 24 weeks after first dose. (Approximately 169 days) | 
| Mean Change in Myositis Disease Activity Assessment Tool (MDAAT) Assessment of Extra-muscular From Baseline to Week 24 | The adjusted mean change from baseline in the Myositis Disease Activity Assessment Tool (MDAAT) assessment of extra-muscular uses a 100 mm Visual Analog Scale (VAS) scale. This VAS assesses the overall extra-muscular clinical features based upon: 1) The presence of clinical features or symptoms within the previous 4 weeks that are due to active disease. 2) The judgment that the feature is due to the myositis disease process. 3) The concept that disease activity is defined as a potentially reversible finding. 4) A clinical, functional, and laboratory assessments. The scoring is performed by the investigator and ranges from 0 (absent extra-muscular disease activity) to 100 (maximum extra-muscular disease activity). | From first dose to 24 weeks after first dose. (Approximately 169 days) | 
| Myositis Response Criteria (MRC) Total Improvement Score From Baseline to Week 24 | The Myositis Response Criteria (MRC) is a continuous total improvement score from baseline (range 0-100) based on the sum of the absolute percent change in the 6 core domains (weighted) used in the IMACS DOI (International Myositis Assessment and Clinical Studies definition of improvement) IMACS core measures are: Physician Global Assessment of Disease Activity (PGA), Patient (Subject) Global Assessment of Disease Activity (SGA), Manual Muscle Test (MMT-8), Health Assessment Questionnaire-Disability Index (HAQ-DI), Muscle Enzyme levels, Myositis Disease Activity Assessment Tool (MDAAT) Extramuscular Global Activity. The total improvement score ranges between 0 and 100 percent corresponds to the degree of improvement, with higher scores corresponding to a greater degree of improvement ( >/= 20 represents minimal improvement, a score of >/= 40 represents moderate improvement, and a score of >/= 60 represents major improvement). | From first dose to 24 weeks after first dose. (Approximately 169 days) | 
| Number of Participants Experiencing Adverse Events (AE) in the Double-Blind Period | The number of treated participants experiencing an adverse event. An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in participants administered a study drug and that does not necessarily have a causal relationship with the treatment. | From first dose up to approximately 56 days post last dose date in double-blind period or first dose in open-label period. (Up to approximately 274 days) | 
| Number of Participants Experiencing Serious Adverse Events (SAE) in the Double-Blind Period | The number of treated participants experiencing a Serious Adverse Event (SAE). A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event. | From first dose up to approximately 56 days post last dose date in double-blind period or first dose in open-label period. (Up to approximately 274 days) | 
| Number of Participants Experiencing Adverse Events (AE) of Special Interest in the Double-Blind Period | The number of treated participants experiencing adverse events of special interest: infections, malignancies, autoimmune events, local injection site reactions, and systemic injection reactions. | From first dose up to approximately 56 days post last dose date in double-blind period or first dose in open-label period. (Up to approximately 274 days) | 
| Number of Participants Experiencing Laboratory Test Abnormalities in the Double-Blind Period | The number of participants experiencing laboratory test abnormalities. Laboratory analysis was performed on the following: hematology, liver and kidney function, electrolytes, other chemistry testing (glucose, protein, cardiac), and urine chemistry. Only tests with participants experiencing abnormalities were reported. | From first dose up to approximately 56 days post last dose date in double-blind period or first dose in open-label period. (Up to approximately 274 days) | 
| Number of Participants Experiencing Adverse Events (AE) in the Cumulative Abatacept Period | The number of treated participants experiencing an adverse event. An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in participants administered a study drug and that does not necessarily have a causal relationship with the treatment. | From first dose up to approximately 56 days post last dose (up to approximately 54 months) | 
| Number of Participants Experiencing Serious Adverse Events (SAE) in the Cumulative Abatacept Period | The number of treated participants experiencing a Serious Adverse Event (SAE). A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event. | From first dose up to approximately 56 days post last dose (up to approximately 54 months) | 
| Number of Participants Experiencing Adverse Events (AE) of Special Interest in the Cumulative Abatacept Period | The number of treated participants experiencing adverse events of special interest: infections, malignancies, autoimmune events, local injection site reactions, and systemic injection reactions. | From first dose up to approximately 56 days post last dose (up to approximately 54 months) | 
| Number of Participants Experiencing Laboratory Test Abnormalities in the Open-Label Period | The number of participants experiencing laboratory test abnormalities. Laboratory analysis was performed on the following: hematology, liver and kidney function, electrolytes, other chemistry testing (glucose, protein, cardiac), and urine chemistry. Only tests with participants experiencing abnormalities were reported. For participants who enter the Japan open-label extension period or long-term extension period, assessments after the first dose in the open-label period and before the first dose date in the subsequent period are included. For participants who prematurely discontinue the open-label period or complete the open-label period but do not enter the Japan open-label extension period or long-term term extension period, assessments after the first dose in the open-label period and up to 56 days post last dose are included. | From first dose in open label period to first dose date in the subsequent period or up to 56 days post last dose (up to approximately 666 days) | 
| Number of Participants Experiencing Laboratory Test Abnormalities in the Long-Term Open Label Period | The number of participants experiencing laboratory test abnormalities. Laboratory analysis was performed on the following: hematology, liver and kidney function, electrolytes, other chemistry testing (glucose, protein, cardiac), and urine chemistry. Only tests with participants experiencing abnormalities were reported. For participants who completed/discontinued the Long-Term Extension Period, assessments after the first dose in the Long-Term Extension Period and up to 56 days post last dose in the Long-Term Extension Period are included. | From first dose in the Long-Term Open Label Period up to 56 days post last dose in the Long-Term Open Label Period (up to approximately 958 days) |