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    Clinical Trial Results:
    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)

    Summary
    EudraCT number
    		 2016-002269-77
    Trial protocol
    		 DE   CZ   SE   FR   IT  
    Global end of trial date
    02 Aug 2022

    Results information
    Results version number
    		 v2(current)
    This version publication date
    01 Oct 2023
    First version publication date
    17 Aug 2023
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    IM101-611
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussée de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Dec 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Aug 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective for this study is to compare the clinical efficacy of weekly abatacept in combination with standard treatment to standard treatment alone by assessing the percentage of subjects who achieve the IMACS DOI by Week 24 compared to baseline, defined as: - An improvement of >/= 20% in 3 IMACS core measures, AND - No more than 2 IMACS core measure scores worsen by >/= 25%, AND - Manual Muscle Test (MMT-8) may not decrease by >/= 25%
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial participants were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 May 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Brazil: 24
    Country: Number of subjects enrolled
    Czechia: 7
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Japan: 21
    Country: Number of subjects enrolled
    Korea, Republic of: 15
    Country: Number of subjects enrolled
    Mexico: 20
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    United States: 48
    Worldwide total number of subjects
    148
    EEA total number of subjects
    20
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    133
    From 65 to 84 years
    15
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 148 were randomized and treated

    Period 1
    Period 1 title
    Double-Blind Period (24 weeks)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Abatacept + Standard Treatment
    Arm description
    		 Participants receive subcutaneous abatacept (125 mg weekly) in combination with standard treatment for the first 24 weeks (6 months) during the double-blind period. Participants continue to receive abatacept in the Open-Label and Long-Term Open Label Periods.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Abatacept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Abatacept SC 125 mg in 1 ml pre-filled syringes

    Arm title
    		 Placebo + Standard Treatment
    Arm description
    		 Participants receive placebo (to match subcutaneous abatacept) in combination with standard treatment for the first 24 weeks (6 months) during the double-blind period. Participants then switch from placebo to abatacept in the Open-Label and Long-Term Open Label Periods.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo to match abatacept SC in 1 ml pre-filled syringes

    Number of subjects in period 1
    		Abatacept + Standard Treatment Placebo + Standard Treatment
    Started
    75
    73
    Completed
    69
    65
    Not completed
    6
    8
         Poor/Non-Compliance
    -
    1
         Participant withdrew consent
    1
    1
         Adverse event, non-fatal
    -
    2
         Participant no longer meets study criteria
    1
    -
         Other reasons
    -
    1
         Lost to follow-up
    1
    -
         Participant request to discontinue study treatment
    1
    1
         Lack of efficacy
    2
    2
    Period 2
    Period 2 title
    Open-Label (OL) Period
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Abatacept + Standard Treatment
    Arm description
    		 Participants receive subcutaneous abatacept (125 mg weekly) in combination with standard treatment for the first 24 weeks (6 months) during the double-blind period. Participants continue to receive abatacept in the Open-Label and Long-Term Open Label Periods.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Abatacept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Abatacept SC 125 mg in 1 ml pre-filled syringes

    Arm title
    		 Placebo + Standard Treatment
    Arm description
    		 Participants receive placebo (to match subcutaneous abatacept) in combination with standard treatment for the first 24 weeks (6 months) during the double-blind period. Participants then switch from placebo to abatacept in the Open-Label and Long-Term Open Label Periods.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Abatacept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Abatacept SC 125 mg in 1 ml pre-filled syringes

    Number of subjects in period 2 [1]
    		Abatacept + Standard Treatment Placebo + Standard Treatment
    Started
    69
    63
    Completed
    65
    61
    Not completed
    4
    2
         Lost to follow-up
    1
    -
         Participants withdrew consent
    -
    2
         Participant request to discontinue study treatment
    1
    -
         Lack of efficacy
    2
    -
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Not all participants who completed the preceding period moved onto the next period.
    Period 3
    Period 3 title
    Long-Term Open Label
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Abatacept + Standard Treatment
    Arm description
    		 Participants receive subcutaneous abatacept (125 mg weekly) in combination with standard treatment for the first 24 weeks (6 months) during the double-blind period. Participants continue to receive abatacept in the Open-Label and Long-Term Open Label Periods.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Abatacept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Abatacept SC 125 mg in 1 ml pre-filled syringes

    Arm title
    		 Placebo + Standard Treatment
    Arm description
    		 Participants receive placebo (to match subcutaneous abatacept) in combination with standard treatment for the first 24 weeks (6 months) during the double-blind period. Participants then switch from placebo to abatacept in the Open-Label and Long-Term Open Label Periods.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Abatacept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Abatacept SC 125 mg in 1 ml pre-filled syringes

    Number of subjects in period 3 [2]
    		Abatacept + Standard Treatment Placebo + Standard Treatment
    Started
    25
    21
    Completed
    1
    0
    Not completed
    24
    21
         Participant withdrew consent
    1
    -
         Adverse event, non-fatal
    1
    2
         Administrative reason by sponsor
    20
    17
         Participant request to discontinue study treatment
    1
    1
         Lack of efficacy
    1
    1
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Not all participants who completed the preceding period moved onto the next period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Abatacept + Standard Treatment
    Reporting group description
    		 Participants receive subcutaneous abatacept (125 mg weekly) in combination with standard treatment for the first 24 weeks (6 months) during the double-blind period. Participants continue to receive abatacept in the Open-Label and Long-Term Open Label Periods.

    Reporting group title
    Placebo + Standard Treatment
    Reporting group description
    		 Participants receive placebo (to match subcutaneous abatacept) in combination with standard treatment for the first 24 weeks (6 months) during the double-blind period. Participants then switch from placebo to abatacept in the Open-Label and Long-Term Open Label Periods.

    Reporting group values
    		 Abatacept + Standard Treatment Placebo + Standard Treatment Total
    Number of subjects
    		 75 73 148
    Age Categorical
    Units: Participants
        16-29 years old
    		 9 9 18
        30-39 years old
    		 8 14 22
        40-49 years old
    		 14 14 28
        50-59 years old
    		 31 19 50
        >/= 60 years old
    		 13 17 30
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 49.3 ( 14.41 ) 48.1 ( 14.09 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 52 54 106
        Male
    		 23 19 42
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 7 3 10
        Not Hispanic or Latino
    		 19 19 38
        Unknown or Not Reported
    		 49 51 100
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 3 3 6
        Asian
    		 10 6 16
        Black or African American
    		 9 8 17
        White
    		 42 42 84
        Japanese
    		 11 10 21
        Other
    		 0 3 3
        Unknown
    		 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Abatacept + Standard Treatment
    Reporting group description
    		 Participants receive subcutaneous abatacept (125 mg weekly) in combination with standard treatment for the first 24 weeks (6 months) during the double-blind period. Participants continue to receive abatacept in the Open-Label and Long-Term Open Label Periods.

    Reporting group title
    Placebo + Standard Treatment
    Reporting group description
    		 Participants receive placebo (to match subcutaneous abatacept) in combination with standard treatment for the first 24 weeks (6 months) during the double-blind period. Participants then switch from placebo to abatacept in the Open-Label and Long-Term Open Label Periods.
    Reporting group title
    Abatacept + Standard Treatment
    Reporting group description
    		 Participants receive subcutaneous abatacept (125 mg weekly) in combination with standard treatment for the first 24 weeks (6 months) during the double-blind period. Participants continue to receive abatacept in the Open-Label and Long-Term Open Label Periods.

    Reporting group title
    Placebo + Standard Treatment
    Reporting group description
    		 Participants receive placebo (to match subcutaneous abatacept) in combination with standard treatment for the first 24 weeks (6 months) during the double-blind period. Participants then switch from placebo to abatacept in the Open-Label and Long-Term Open Label Periods.
    Reporting group title
    Abatacept + Standard Treatment
    Reporting group description
    		 Participants receive subcutaneous abatacept (125 mg weekly) in combination with standard treatment for the first 24 weeks (6 months) during the double-blind period. Participants continue to receive abatacept in the Open-Label and Long-Term Open Label Periods.

    Reporting group title
    Placebo + Standard Treatment
    Reporting group description
    		 Participants receive placebo (to match subcutaneous abatacept) in combination with standard treatment for the first 24 weeks (6 months) during the double-blind period. Participants then switch from placebo to abatacept in the Open-Label and Long-Term Open Label Periods.

    Primary: Number of Participants Achieving International Myositis Assessment and Clinical Studies Definition of Improvement (IMACS DOI) at Week 24 Without Rescue

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    End point title
    		 Number of Participants Achieving International Myositis Assessment and Clinical Studies Definition of Improvement (IMACS DOI) at Week 24 Without Rescue
    End point description
    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.
    End point type
    Primary
    End point timeframe
    From first dose to 24 weeks after first dose. (Approximately 169 days)
    End point values
    		 Abatacept + Standard Treatment Placebo + Standard Treatment
    Number of subjects analysed
    75
    73
    Units: Participants
    42
    31
    Statistical analysis title
    		 IMACs DOI at week 24
    Comparison groups
    Abatacept + Standard Treatment v Placebo + Standard Treatment
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.083
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 3.5

    Secondary: Mean change in Health Assessment Questionnaire-Disability Index (HAQ-DI) from baseline to Week 24

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    End point title
    		 Mean change in Health Assessment Questionnaire-Disability Index (HAQ-DI) from baseline to Week 24
    End point description
    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).
    End point type
    Secondary
    End point timeframe
    From first dose to 24 weeks after first dose. (Approximately 169 days)
    End point values
    		 Abatacept + Standard Treatment Placebo + Standard Treatment
    Number of subjects analysed
    66
    62
    Units: Score on a scale
        arithmetic mean (standard error)
    -0.31 ( 0.067 )
    -0.20 ( 0.069 )
    No statistical analyses for this end point

    Secondary: Mean Change in Muscle Endurance Using the Myositis Function Index (FI-2) from Baseline to Week 24

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    End point title
    		 Mean Change in Muscle Endurance Using the Myositis Function Index (FI-2) from Baseline to Week 24
    End point description
    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).
    End point type
    Secondary
    End point timeframe
    From first dose to 24 weeks after first dose. (Approximately 169 days)
    End point values
    		 Abatacept + Standard Treatment Placebo + Standard Treatment
    Number of subjects analysed
    59
    58
    Units: Number of repetitions
        arithmetic mean (standard error)
    4.1 ( 1.33 )
    1.2 ( 1.38 )
    No statistical analyses for this end point

    Secondary: Mean change in Myositis Disease Activity Assessment Tool (MDAAT) assessment of extra-muscular from baseline to Week 24

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    End point title
    		 Mean change in Myositis Disease Activity Assessment Tool (MDAAT) assessment of extra-muscular from baseline to Week 24
    End point description
    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).
    End point type
    Secondary
    End point timeframe
    From first dose to 24 weeks after first dose. (Approximately 169 days)
    End point values
    		 Abatacept + Standard Treatment Placebo + Standard Treatment
    Number of subjects analysed
    63
    60
    Units: Score on a scale
        arithmetic mean (standard error)
    -1.56 ( 0.202 )
    -1.40 ( 0.208 )
    No statistical analyses for this end point

    Secondary: Number of Participants Experiencing Adverse Events (AE) in the Double-Blind Period

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    End point title
    		 Number of Participants Experiencing Adverse Events (AE) in the Double-Blind Period
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    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)
    End point values
    		 Abatacept + Standard Treatment Placebo + Standard Treatment
    Number of subjects analysed
    75
    73
    Units: Participants
    52
    55
    No statistical analyses for this end point

    Secondary: Myositis Response Criteria (MRC) Total Improvement Score From Baseline to Week 24

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    End point title
    		 Myositis Response Criteria (MRC) Total Improvement Score From Baseline to Week 24
    End point description
    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).
    End point type
    Secondary
    End point timeframe
    From first dose to 24 weeks after first dose. (Approximately 169 days)
    End point values
    		 Abatacept + Standard Treatment Placebo + Standard Treatment
    Number of subjects analysed
    62
    58
    Units: Score on a scale
        arithmetic mean (standard error)
    40.83 ( 2.873 )
    37.22 ( 2.963 )
    No statistical analyses for this end point

    Secondary: Number of Participants Experiencing Serious Adverse Events (SAE) in the Double-Blind Period

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    End point title
    		 Number of Participants Experiencing Serious Adverse Events (SAE) in the Double-Blind Period
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    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)
    End point values
    		 Abatacept + Standard Treatment Placebo + Standard Treatment
    Number of subjects analysed
    75
    73
    Units: Participants
    4
    4
    No statistical analyses for this end point

    Secondary:  Number of Participants Experiencing Adverse Events (AE) of Special Interest in the Double-Blind Period

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    End point title
    		  Number of Participants Experiencing Adverse Events (AE) of Special Interest in the Double-Blind Period
    End point description
    The number of treated participants experiencing adverse events of special interest: infections, malignancies, autoimmune events, local injection site reactions, and systemic injection reactions.
    End point type
    Secondary
    End point timeframe
    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)
    End point values
    		 Abatacept + Standard Treatment Placebo + Standard Treatment
    Number of subjects analysed
    75
    73
    Units: Participants
        Infections
    19
    31
        Malignancies
    0
    0
        Autoimmune Disorders
    2
    3
        Systemic Injection Reactions
    4
    5
        Local Injection Site Reactions
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Participants Experiencing Laboratory Test Abnormalities in the Double-Blind Period

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    End point title
    		 Number of Participants Experiencing Laboratory Test Abnormalities in the Double-Blind Period
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    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)
    End point values
    		 Abatacept + Standard Treatment Placebo + Standard Treatment
    Number of subjects analysed
    75
    73
    Units: Participants
        LOW LEUKOCYTES
    1
    0
        HIGH LEUKOCYTES
    2
    4
        HIGH EOSINOPHILS (ABSOLUTE)
    3
    2
        LOW LYMPHOCYTES (ABSOLUTE)
    17
    14
        LOW NEUTROPHILS + BANDS (ABSOLUTE)
    1
    0
        HIGH ALANINE AMINOTRANSFERASE (ALT)
    1
    1
        HIGH ASPARTATE AMINOTRANSFERASE (AST)
    0
    1
        HIGH G-GLUTAMYL TRANSFERASE (GGT)
    4
    1
        HIGH BLOOD UREA NITROGEN
    0
    1
        HIGH CREATININE
    3
    3
        HIGH CALCIUM, TOTAL
    1
    0
        LOW PHOSPHORUS, INORGANIC
    0
    1
        HIGH PHOSPHORUS, INORGANIC
    1
    0
        HIGH SODIUM, SERUM
    0
    1
        LOW GLUCOSE, SERUM
    4
    3
        HIGH GLUCOSE, SERUM
    8
    8
        HIGH PROTEIN, TOTAL
    0
    1
        HIGH CREATINE KINASE (CK)
    0
    4
        HIGH LACTATE DEHYDROGENASE (LD)
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Participants Experiencing Adverse Events (AE) in the Cumulative Abatacept Period

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    End point title
    		 Number of Participants Experiencing Adverse Events (AE) in the Cumulative Abatacept Period
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    From first dose up to approximately 56 days post last dose (up to approximately 54 months)
    End point values
    		 Abatacept + Standard Treatment Placebo + Standard Treatment
    Number of subjects analysed
    75
    63
    Units: Participants
    64
    39
    No statistical analyses for this end point

    Secondary: Number of Participants Experiencing Serious Adverse Events (SAE) in the Cumulative Abatacept Period

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    End point title
    		 Number of Participants Experiencing Serious Adverse Events (SAE) in the Cumulative Abatacept Period
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    From first dose up to approximately 56 days post last dose (up to approximately 54 months)
    End point values
    		 Abatacept + Standard Treatment Placebo + Standard Treatment
    Number of subjects analysed
    75
    63
    Units: Participants
    14
    8
    No statistical analyses for this end point

    Secondary:  Number of Participants Experiencing Adverse Events (AE) of Special Interest in the Cumulative Abatacept Period

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    End point title
    		  Number of Participants Experiencing Adverse Events (AE) of Special Interest in the Cumulative Abatacept Period
    End point description
    The number of treated participants experiencing adverse events of special interest: infections, malignancies, autoimmune events, local injection site reactions, and systemic injection reactions.
    End point type
    Secondary
    End point timeframe
    From first dose up to approximately 56 days post last dose (up to approximately 54 months)
    End point values
    		 Abatacept + Standard Treatment Placebo + Standard Treatment
    Number of subjects analysed
    75
    63
    Units: Participants
        Infections and infestations
    34
    19
        Malignancies
    0
    0
        Autoimmune Disorders
    5
    4
        Systemic Injection Reactions
    5
    3
        Local Injection Site Reactions
    2
    2
    No statistical analyses for this end point

    Secondary: Number of Participants Experiencing Laboratory Test Abnormalities in the Open-Label Period

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    End point title
    		 Number of Participants Experiencing Laboratory Test Abnormalities in the Open-Label Period
    End point description
    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. 99999 = N/A - no participants had laboratory reports for this analyte.
    End point type
    Secondary
    End point timeframe
    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)
    End point values
    		 Abatacept + Standard Treatment Placebo + Standard Treatment
    Number of subjects analysed
    69
    63
    Units: Participants
        LOW HEMOGLOBIN
    0
    1
        LOW LEUKOCYTES
    2
    1
        HIGH LEUKOCYTES
    2
    0
        HIGH EOSINOPHILS (ABSOLUTE)
    2
    0
        LOW LYMPHOCYTES (ABSOLUTE)
    15
    8
        HIGH LYMPHOCYTES (ABSOLUTE)
    1
    0
        LOW NEUTROPHILS + BANDS (ABSOLUTE)
    2
    0
        HIGH ALANINE AMINOTRANSFERASE (ALT)
    1
    0
        HIGH ALKALINE PHOSPHATASE (ALP)
    0
    2
        HIGH ASPARTATE AMINOTRANSFERASE (AST)
    0
    1
        HIGH G-GLUTAMYL TRANSFERASE (GGT)
    2
    1
        HIGH BLOOD UREA NITROGEN
    2
    1
        HIGH CREATININE
    6
    2
        HIGH POTASSIUM, SERUM
    1
    0
        LOW GLUCOSE, SERUM
    1
    1
        HIGH GLUCOSE, SERUM
    3
    3
        LOW ALBUMIN
    0
    1
        HIGH CREATINE KINASE (CK)
    3
    5
        HIGH LACTATE DEHYDROGENASE (LD)
    0
    1
        HIGH BLOOD, URINE Abatacept Arm- n=2
    2
    99999
        HIGH WBC, URINE Abatacept Arm n=1
    1
    99999
    No statistical analyses for this end point

    Secondary: Number of Participants Experiencing Laboratory Test Abnormalities in the Long-Term Open Label Period

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    End point title
    		 Number of Participants Experiencing Laboratory Test Abnormalities in the Long-Term Open Label Period
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    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)
    End point values
    		 Abatacept + Standard Treatment Placebo + Standard Treatment
    Number of subjects analysed
    22
    21
    Units: Participants
        LOW HEMOGLOBIN
    1
    0
        LOW LYMPHOCYTES (ABSOLUTE)
    1
    4
        HIGH BLOOD UREA NITROGEN
    2
    0
        HIGH CREATININE
    2
    1
        HIGH GLUCOSE, SERUM
    1
    0
        HIGH CREATINE KINASE (CK)
    1
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-cause mortality was assessed from participants first dose to their study completion (up to approximately 55 months) SAEs and Other AEs were assessed from first dose to 100 days following last dose (up to approximately 55 months)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Abatacept + Standard Treatment
    Reporting group description
    		 Participants receive subcutaneous abatacept (125 mg weekly) in combination with standard treatment during the cumulative abatacept period.

    Reporting group title
    Placebo + Standard Treatment
    Reporting group description
    		 Participants receive placebo (to match subcutaneous abatacept) in combination with standard treatment during the double-blind period.

    Serious adverse events
    		 Abatacept + Standard Treatment Placebo + Standard Treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    22 / 138 (15.94%)
    5 / 73 (6.85%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lymphoproliferative disorder
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Obsessive-compulsive disorder
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Spinal compression fracture
         subjects affected / exposed
    2 / 138 (1.45%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Comminuted fracture
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Coronary artery disease
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Glaucoma
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Large intestine polyp
         subjects affected / exposed
    2 / 138 (1.45%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatomyositis
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Myositis
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polymyositis
         subjects affected / exposed
    2 / 138 (1.45%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 138 (0.72%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    3 / 138 (2.17%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 138 (1.45%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 138 (0.72%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Abatacept + Standard Treatment Placebo + Standard Treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    31 / 138 (22.46%)
    23 / 73 (31.51%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    4 / 138 (2.90%)
    4 / 73 (5.48%)
         occurrences all number
    5
    5
    Vascular disorders
    Hypertension
         subjects affected / exposed
    7 / 138 (5.07%)
    1 / 73 (1.37%)
         occurrences all number
    7
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 138 (5.80%)
    7 / 73 (9.59%)
         occurrences all number
    12
    7
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    7 / 138 (5.07%)
    2 / 73 (2.74%)
         occurrences all number
    7
    2
    Infections and infestations
    Influenza
         subjects affected / exposed
    3 / 138 (2.17%)
    6 / 73 (8.22%)
         occurrences all number
    3
    6
    Nasopharyngitis
         subjects affected / exposed
    9 / 138 (6.52%)
    8 / 73 (10.96%)
         occurrences all number
    14
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Mar 2017
    Clarifies the target population (Inclusion/Exclusion criteria), randomization stratification criteria, exploratory endpoints, study procedures and sub-studies, training requirements for site staff, the process for adjudication, the duration of samples retention for additional research and the duration of post drug follow-up.
    09 May 2018
    Clarifies language and allowable concomitant medication and adjusts criteria to improve subject selection.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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