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Clinical Trial Results:
A Phase III, Multi-Center, Multi-National, Randomized Withdrawal Study to Evaluate the Safety and Efficacy of BMS-188667 in Children and Adolescents with Active Polyarticular Juvenile Rheumatoid Arthritis (JRA)

Summary
EudraCT number	2005-000443-28
Trial protocol	Outside EU/EEA
Global end of trial date	22 Nov 2011

Results information
Results version number	v1(current)
This version publication date	05 Jan 2017
First version publication date	05 Jan 2017
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

IM101-033

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Bristol-Myers Squibb International Corporation

Sponsor organisation address

Chausse de la Hulpe 185, Brussels, Belgium, 1170

Public contact

Bristol-Myers Squibb Study Director, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com

Scientific contact

Bristol-Myers Squibb Study Director, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-000118-PIP01-07

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

22 Nov 2011

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

22 Nov 2011

Was the trial ended prematurely?

Main objective of the trial

The primary purpose of the clinical research study is to assess the safety of treating children and juvenile subjects with BMS-188667 (Abatacept). In addition, the study will assess the effectiveness of BMS-188667 in reducing disease activity of Juvenile Rheumatoid Arthritis (JRA) or Juvenile Idiopathic Arthritis (JIA) as measured by the time to occurrence of disease flare.

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 subjects were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

05 Feb 2004

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 8

Country: Number of subjects enrolled

France: 28

Country: Number of subjects enrolled

United States: 31

Country: Number of subjects enrolled

Mexico: 41

Country: Number of subjects enrolled

Switzerland: 2

Country: Number of subjects enrolled

Peru: 19

Country: Number of subjects enrolled

Austria: 3

Country: Number of subjects enrolled

Spain: 8

Country: Number of subjects enrolled

Brazil: 48

Country: Number of subjects enrolled

Italy: 18

Country: Number of subjects enrolled

Portugal: 8

Worldwide total number of subjects

214

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

140

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study was conducted in 45 sites in 11 countries.

Screening details

214 enrolled; in Per A, 190 treated; 24 not treated due to screening failures.170 completed Per A, 123 responders qualified to enter Per B. One subject did not enter Per B; 122 responders were randomized, 60 abatacept and 62 placebo. 36 of 47 Per A non-responders re-entered at Per C. Protocol violation occurred; 5yr old participant.

Period 1 title

Open-Label Lead-In Phase (Period A)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Abatacept (All Participants in Period A)

Arm description

Abatacept: 10 milligram per kilogram body weight (mg/kg), limited to a maximum 1000 mg for participants weighing >100kg; solution infused intravenously (IV), over 90 minutes, once every 2 weeks for 3 doses.

Arm type

Experimental

Investigational medicinal product name

Abatacept

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Abatacept 10 milligram per kilogram body weight (mg/kg), limited to a maximum 1000 mg for participants weighing >100kg; solution infused intravenously (IV), over 90 minutes, once every 2 weeks for 3 doses.

Number of subjects in period 1 ^[1]	Abatacept (All Participants in Period A)
Started	190
Completed	170
Not completed	20
Consent withdrawn by subject	1
Adverse event, non-fatal	1
Not Specified	1
Lack of efficacy	17

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: 214 were enrolled but only were 190 treated; 24 not treated due to screening failures

Period 2 title

Double-Blind Phase (Period B)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Abatacept (Period B)

Arm description

Arm type

Experimental

Investigational medicinal product name

Abatacept

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Placebo (Period B)

Arm description

Placebo: Dextrose 5% in water (D5W) or normal saline (NS) IV infusion, once every 2 weeks for 3 doses, then monthly up to 6 months. Participants were seated or in supine position during infusion.

Arm type

Placebo

Investigational medicinal product name

Dextrose 5% in water

Investigational medicinal product code

Other name

D5W

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Dextrose 5% in water (D5W) IV infusion, once every 2 weeks for 3 doses, then monthly up to 6 months. Participants were seated or in supine position during infusion.

Investigational medicinal product name

Saline

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Normal saline (NS) IV infusion, once every 2 weeks for 3 doses, then monthly up to 6 months. Participants were seated or in supine position during infusion.

Number of subjects in period 2 ^[2]	Abatacept (Period B)	Placebo (Period B)
Started	60	62
Completed	49	31
Not completed	11	31
Consent withdrawn by subject	1	-
Lack of efficacy	10	31

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: 170 subjects completed Period A. Of those, 123 were responders who qualified to enter Period B. 122 subjects were randomized, 60 to Abatacept and 62 to placebo. One chose not to enter Period B.

Period 3 title

Open-Label Extension Phase (Period C)

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Abatacept (Period C)

Arm description

Arm type

Experimental

Investigational medicinal product name

Abatacept

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Placebo (Period B) to Abatacept (Period C)

Arm description

Participants from Period B Placebo group entering Period C. Abatacept: 10 milligram per kilogram body weight (mg/kg), limited to a maximum 1000 mg for participants weighing >100kg; solution infused intravenously (IV), over 90 minutes, once a month for up to 5 years.

Arm type

Experimental

Investigational medicinal product name

Abatacept

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Number of subjects in period 3	Abatacept (Period C)	Placebo (Period B) to Abatacept (Period C)
Started	47	33
Completed	29	27
Not completed	29	32
No Longer Meets Study Criteria	1	1
Adverse event, serious fatal	-	1
Consent withdrawn by subject	6	-
Poor/Non-Compliance	2	2
Adverse event, non-fatal	2	3
Pregnancy	2	3
Not Specified	6	8
Lost to follow-up	5	6
Lack of efficacy	5	8
Joined	11	26
Subjects who discontinued Per B rejoining at Per C	11	26

Baseline characteristics

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Reporting group title

Abatacept (All Participants in Period A)

Reporting group description

Reporting group values	Abatacept (All Participants in Period A)	Total
Number of subjects	190	190
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	63	63
Adolescents (12-17 years)	127	127
Adults (18-64 years)	0	0
From 65-84 years	0	0
85 years and over	0	0
Age Continuous
Units: years
median (full range (min-max))	13 (5 to 17)	-
Gender, Male/Female
Units: participants
Female	137	137
Male	53	53

Subject analysis set title

Abatacept (All participants in Period A)

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Abatacept (All Participants in Period C)

Subject analysis set type

Sub-group analysis

Subject analysis set description

All participants in Period C; composite of those who completed Period B plus those non-responders from Period A who re-entered at Period C.

Subject analysis set title

Placebo (Period B) to Abatacept (Period C)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Abatacept (Period A Non-Responders in Period C)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants not eligible to continue into Period B but re-entered in Period C. Abatacept: 10 milligram per kilogram body weight (mg/kg), limited to a maximum 1000 mg for participants weighing >100kg; solution infused intravenously (IV), over 90 minutes, once every two weeks for three doses (Period A) and once a month for up to 5 years (Period C).

Subject analysis sets values	Abatacept (All participants in Period A)	Abatacept (All Participants in Period C)	Placebo (Period B) to Abatacept (Period C)	Abatacept (Period A Non-Responders in Period C)
Number of subjects	190	153	59	36
Age categorical
Units: Subjects
In utero	0
Preterm newborn infants (gestational age < 37 wks)	0
Newborns (0-27 days)	0
Infants and toddlers (28 days-23 months)	0
Children (2-11 years)	63
Adolescents (12-17 years)	127
Adults (18-64 years)	0
From 65-84 years	0
85 years and over	0
Age Continuous
Units: years
median (full range (min-max))	13 (5 to 17)
Gender, Male/Female
Units: participants
Female	137
Male	53

End points

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Reporting group title

Abatacept (All Participants in Period A)

Reporting group description

Reporting group title

Abatacept (Period B)

Reporting group description

Reporting group title

Placebo (Period B)

Reporting group description

Placebo: Dextrose 5% in water (D5W) or normal saline (NS) IV infusion, once every 2 weeks for 3 doses, then monthly up to 6 months. Participants were seated or in supine position during infusion.

Reporting group title

Abatacept (Period C)

Reporting group description

Reporting group title

Placebo (Period B) to Abatacept (Period C)

Reporting group description

Subject analysis set title

Abatacept (All participants in Period A)

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Abatacept (All Participants in Period C)

Subject analysis set type

Sub-group analysis

Subject analysis set description

All participants in Period C; composite of those who completed Period B plus those non-responders from Period A who re-entered at Period C.

Subject analysis set title

Placebo (Period B) to Abatacept (Period C)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Abatacept (Period A Non-Responders in Period C)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Primary: Median Time to Occurrence of Juvenile Rheumatoid Arthritis/Juvenile Idiopathic Arthritis (JRA/JIA) Disease Flare During Double-Blind Phase (Period B)

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End point title

Median Time to Occurrence of Juvenile Rheumatoid Arthritis/Juvenile Idiopathic Arthritis (JRA/JIA) Disease Flare During Double-Blind Phase (Period B)

End point description

Time to flare is defined as the elapsed number of days between the first dose date in Period B and the study day that disease flare is confirmed. All of the following criteria must be met to be defined as a flare: • > 30% worsening in at least 3 of the 6 JRA/JIA core response variables • > 30% improvement in not more than 1 of the 6 JRA/JIA core set variables • ≥ 2 cm of worsening must be present if the Physician or Parent Global Assessment is used to define flare • worsening in ≥ 2 joints must be present if the number of active joints or joints with limitation of motion is used to define flare based on changes in the surrogate marker, erythrocyte sedimentation rate (ESR) The analysis population included all treated subjects. Here, 99999 signifies that the value was not estimated. Fewer than 50% of the participants in the abatacept group experienced a flare, therefore the median time to flare is known to exceed 6 months, but cannot be estimated.

End point type

Primary

End point timeframe

Period B (Day 113 to Day 282)

End point values	Abatacept (Period B)	Placebo (Period B)
Number of subjects analysed	60	62
Units: months
number (not applicable)	99999	6

Comparison of Abatacept to Placebo

Comparison groups

Abatacept (Period B) v Placebo (Period B)

Number of subjects included in analysis

122

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0002

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.31

Confidence interval

level

95%

sides

2-sided

lower limit

0.16

upper limit

0.59

Secondary: Number of Participants with a Juvenile Rheumatoid Arthritis/Juvenile Idiopathic Arthritis (JRA/JIA) Disease with a Flare During Double-Blind Phase (Period B)

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End point title

Number of Participants with a Juvenile Rheumatoid Arthritis/Juvenile Idiopathic Arthritis (JRA/JIA) Disease with a Flare During Double-Blind Phase (Period B)

End point description

All of the following criteria must be met to be defined as a flare: • > 30% worsening in at least 3 of the 6 JRA/JIA core response variables • > 30% improvement in not more than 1 of the 6 JRA/JIA core set variables • ≥ 2 cm of worsening must be present if the Physician or Parent Global Assessment is used to define flare • worsening in ≥ 2 joints must be present if the number of active joints or joints with limitation of motion is used to define flare based on changes in the surrogate marker, erythrocyte sedimentation rate (ESR) The analysis population included all treated subjects.

End point type

Secondary

End point timeframe

Period B (Day 113 to Day 282)

End point values	Abatacept (Period B)	Placebo (Period B)
Number of subjects analysed	60	62
Units: participants
number (not applicable)	12	33

Comparison of Abatacept to Placebo

Comparison groups

Abatacept (Period B) v Placebo (Period B)

Number of subjects included in analysis

122

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

Chi-squared

Confidence interval

Secondary: Number of Participants With Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs During Open-Label Lead-In Phase (Period A)

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End point title

Number of Participants With Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs During Open-Label Lead-In Phase (Period A)

End point description

AE=any new unfavorable symptom, sign or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity or drug dependency/abuse; is life-threatening, an important medical event or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible or missing relationship to study drug. Death=during the study and up to 28 days past study discontinuation. The select AEs were determined using the Medical Dictionary for Regulatory Activities (MedDRA, v14.1). The analysis population included all treated subjects in Period A.

End point type

Secondary

End point timeframe

Period A (Day 1 to Day 113)

End point values	Abatacept (All Participants in Period A)
Number of subjects analysed	190
Units: participants
number (not applicable)
SAE	6
Treatment-Related AE	0
All Deaths	0
Treatment-Related Deaths	0
Discontinuation of Study Drug due to AEs	1

No statistical analyses for this end point

Secondary: Number of Participants With Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs During Double-Blind Phase (Period B)

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End point title

Number of Participants With Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs During Double-Blind Phase (Period B)

End point description

End point type

Secondary

End point timeframe

Period B (Day 113 to Day 282)

End point values	Abatacept (Period B)	Placebo (Period B)
Number of subjects analysed	60	62
Units: participants
number (not applicable)
SAE	0	2
Treatment-Related AE	0	0
All Deaths	0	0
Treatment-Related Deaths	0	0
Discontinuation of Study Drug due to AEs	0	0

No statistical analyses for this end point

Secondary: Number of Participants With Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs During Open-Label Phase (Period C)

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End point title

Number of Participants With Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs During Open-Label Phase (Period C)

End point description

AE=any new unfavorable symptom, sign or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity or drug dependency/abuse; is life-threatening, an important medical event or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible or missing relationship to study drug. Death=during the study and up to 85 days past study discontinuation. The select AEs were determined using the Medical Dictionary for Regulatory Activities (MedDRA, v14.1). The analysis population included all treated subjects in Period C.

End point type

Secondary

End point timeframe

Period C (Day 282 to end of study)

End point values	Abatacept (Period C)	Placebo (Period B) to Abatacept (Period C)	Abatacept (Period A Non-Responders in Period C)
Number of subjects analysed	58	59	36
Units: participants
number (not applicable)
SAE	9	12	9
Treatment-Related AE	4	3	2
All Deaths	0	1	0
Treatment-Related Deaths	0	0	0
Discontinuation of Study Drug due to AEs	2	3	1

No statistical analyses for this end point

Secondary: Median Percent Change From Baseline in JRA/JIA Core Set Variables During Double-Blind Phase (Period B)

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End point title

Median Percent Change From Baseline in JRA/JIA Core Set Variables During Double-Blind Phase (Period B)

End point description

Percent change from baseline was calculated from the difference between post-baseline and baseline divided by baseline multiplied by 100 and reported as the range between 25th and 75th percentile, not full range; American College of Rheumatology (ACR) Pediatric 30 JRA/JIA core set variables include active joints, limited range of motion, physician's global assessment of disease severity, parent global assessment of overall well-being, change in physical function as measured by the Childhood Health Assessment Questionnaire (CHAQ), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). The analysis population included all treated subjects in Period B.

End point type

Secondary

End point timeframe

Period B (Day 113 to Day 282)

End point values	Abatacept (Period B)	Placebo (Period B)
Number of subjects analysed	60	62
Units: percentage change from baseline
median (inter-quartile range (Q1-Q3))
Active Joints	-20.9 (-92 to 17.86)	50 (0 to 100)
Joints with LOM	0 (-45.5 to 0)	50 (0 to 100)
Physical Global Assessment	-29.8 (-86.3 to 22.48)	55.95 (-31.3 to 250)
Parent Global Assessment	-11.2 (-56.8 to 28.41)	8.39 (-31.8 to 100)
CHAQ Disability Index	0 (-38.9 to 2.17)	0 (-13.3 to 55.56)
ESR	0 (-20.7 to 50)	20.5 (-14.3 to 92)
CRP	0 (-46.6 to 67)	6.25 (-33.3 to 150)

No statistical analyses for this end point

Secondary: Median Percent Change From Baseline in JRA/JIA Core Set Variables During Open-Label Phase (Period C)

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End point title

Median Percent Change From Baseline in JRA/JIA Core Set Variables During Open-Label Phase (Period C)

End point description

End point type

Secondary

End point timeframe

Period C (Day 282 to end of study)

End point values	Abatacept (Period C)	Placebo (Period B) to Abatacept (Period C)	Abatacept (Period A Non-Responders in Period C)
Number of subjects analysed	58	59	36
Units: percentage change from baseline
median (inter-quartile range (Q1-Q3))
Active Joints	-70.2 (-94.1 to -50)	-82.4 (-100 to -62.5)	-26.7 (-66.7 to 0)
Joints with Limited Range of Motion	-50 (-75 to -27.3)	-71.4 (-86.2 to -23.1)	0 (-33.3 to 36.67)
Physician's Global Assessment of Disease Severity	-75 (-91.3 to -52.3)	-81.8 (-91.4 to -64.3)	-31.9 (-50 to -9.33)
Parent Global Assessment of Overall Well-Being	-62.7 (-93.8 to -27.5)	-63.9 (-84.2 to -38.8)	1.96 (-19.6 to 26.67)
CHAQ Disability Index	-56.7 (-81.8 to -18.2)	-45.5 (-75 to -12.5)	14.14 (-16.7 to 100)
ESR	-27.3 (-54.8 to 20)	-24.2 (-50 to 0)	20.87 (-15.5 to 83.77)
CRP	-33.8 (-84.4 to 54.84)	-27.8 (-75 to 11.11)	0 (-31.6 to 43.68)

No statistical analyses for this end point

Secondary: Events of Special Interest During Open-Label Lead-In Phase (Period A), Including Infections, Peri-Infusional Adverse Events (AEs), Autoimmune Disorders and Malignancies

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End point title

Events of Special Interest During Open-Label Lead-In Phase (Period A), Including Infections, Peri-Infusional Adverse Events (AEs), Autoimmune Disorders and Malignancies

End point description

The sponsor prospectively identified categories of AEs that may be associated with the use of immunomodulatory drugs including infections, peri-infusional AEs, autoimmune disorders, malignancies. Peri-infusional AEs are defined as those AEs of special interest occurring during the first 24 hours after the start of study drug infusion. Malignancies definitions were based on events in the MedDRA Maintenance and Support Services Organization (MSSO) malignancies Structured MedDRA Query (SMQ).Autoimmune disorders are in alignment with the pre-specified MedDRA codes of autoimmune disorders events of interest. The analysis population included al treated subjects in Period A.

End point type

Secondary

End point timeframe

Period A (Day 1 to Day 113)

End point values	Abatacept (All Participants in Period A)
Number of subjects analysed	190
Units: participants
number (not applicable)
Infections and Infestations	68
Peri-Infusional AEs	30
Autoimmune Disorders	2
Malignancies	0

No statistical analyses for this end point

Secondary: Events of Special Interest During Double-Blind Phase (Period B), Including Infections, Peri-Infusional Adverse Events (AEs), Autoimmune Disorders and Malignancies

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End point title

Events of Special Interest During Double-Blind Phase (Period B), Including Infections, Peri-Infusional Adverse Events (AEs), Autoimmune Disorders and Malignancies

End point description

End point type

Secondary

End point timeframe

Period B (Day 113 to Day 282)

End point values	Abatacept (Period B)	Placebo (Period B)
Number of subjects analysed	60	62
Units: participants
number (not applicable)
Infections and Infestations	27	27
Peri-Infusional AEs	2	2
Autoimmune Disorders	0	0
Malignancies	0	0

No statistical analyses for this end point

Secondary: Events of Special Interest During Open-Label Phase (Period C), Including Infections, Peri-Infusional Adverse Events (AEs), Autoimmune Disorders and Malignancies

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End point title

Events of Special Interest During Open-Label Phase (Period C), Including Infections, Peri-Infusional Adverse Events (AEs), Autoimmune Disorders and Malignancies

End point description

End point type

Secondary

End point timeframe

Period C (Day 282 up to 56 days after the last dose of study medication)

End point values	Abatacept (All Participants in Period C)
Number of subjects analysed	153
Units: participants
number (not applicable)
Infections and Infestations	120
Peri-Infusional AEs	22
Autoimmune Disorders	7
Malignancies	1

No statistical analyses for this end point

Secondary: Percentage of Participants Achieving American College of Rheumatology (ACR) Pediatric 30 (ACRP30), ACR Pediatric 50, ACR Pediatric 70, ACR Pediatric 90, and Inactive Disease Status Erythrocyte Sedimentation Rate (ESR) Response Rate

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End point title

Percentage of Participants Achieving American College of Rheumatology (ACR) Pediatric 30 (ACRP30), ACR Pediatric 50, ACR Pediatric 70, ACR Pediatric 90, and Inactive Disease Status Erythrocyte Sedimentation Rate (ESR) Response Rate

End point description

The ACRP30 response criteria were defined as a ≥ 30% improvement over baseline in ESR. ACRP 50, 70, and 90 responses were defined similarly with 50%, 70%, and 90% improvements required, respectively. Here ‘99999’ signifies not estimable data and -99999 to 99999 signifies that no confidence interval is applicable. The analysis population included all treated subjects.

End point type

Secondary

End point timeframe

Day 113, Day 282, and Day 2047

End point values	Abatacept (Period C)	Placebo (Period B) to Abatacept (Period C)	Abatacept (Period A Non-Responders in Period C)
Number of subjects analysed	58	59	36
Units: percentage of participants
number (confidence interval 95%)
ACR Pediatric 30 (ESR) at Day 113	100 (-99999 to 99999)	100 (-99999 to 99999)	0 (-99999 to 99999)
ACR Pediatric 30 (ESR) at Day 282	84.5 (75.2 to 93.8)	67.8 (55.9 to 79.7)	99999 (-99999 to 99999)
ACR Pediatric 30 (ESR) at Day 2047	97 (91.1 to 100)	86.7 (74.5 to 98.8)	69.2 (44.1 to 94.3)
ACR Pediatric 50 (ESR) at Day 113	65.5 (53.3 to 77)	88.1 (79.9 to 96.4)	0 (-99999 to 99999)
ACR Pediatric 50 (ESR) at Day 282	79.3 (68.9 to 89.7)	52.5 (39.8 to 65.3)	99999 (-99999 to 99999)
ACR Pediatric 50 (ESR) at Day 2047	93.9 (85.8 to 100)	80 (65.7 to 94.3)	69.2 (44.1 to 94.3)
ACR Pediatric 70 (ESR) at Day 113	37.9 (25.4 to 50.4)	49.2 (36.4 to 61.9)	0 (-99999 to 99999)
ACR Pediatric 70 (ESR) at Day 282	55.2 (42.4 to 68)	30.5 (18.8 to 42.3)	99999 (-99999 to 99999)
ACR Pediatric 70 (ESR) at Day 2047	78.8 (64.89 to 92.7)	63.3 (46.1 to 80.6)	53.8 (26.7 to 80.9)
ACR Pediatric 90 (ESR) at Day 113	17.2 (7.5 to 27)	22 (11.5 to 32.6)	0 (-99999 to 99999)
ACR Pediatric 90 (ESR) at Day 282	41.4 (28.7 to 54.1)	15.3 (6.1 to 24.4)	99999 (-99999 to 99999)
ACR Pediatric 90 (ESR) at Day 2047	66.7 (50.6 to 82.8)	40 (22.5 to 57.5)	38.5 (12 to 64.9)

No statistical analyses for this end point

Secondary: Number of Treated Participants with Marked Laboratory Abnormalities During Open-Label Lead-In Phase (Period A)

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End point title

Number of Treated Participants with Marked Laboratory Abnormalities During Open-Label Lead-In Phase (Period A)

End point description

Marked abnormalities were pre-defined as changes after drug infusion reported relative to normal. Hemoglobin, 11.6-14.8 grams per deciliter (g/dL);Hematocrit, 36.0-50.0%;Erythrocytes, 3.80-5.10x10*6 cells per microliter (c/uL);Platelets, 140-44 cells per liter (c/L);Leukocytes,4.00-12.50 c/uL;Absolute Neutrophils + Bands, if <1.00x10^3 c/uL;Absolute Lymphocytes, if <0.72x10^3 or >7.50x10^3c/uL;Absolute Eosinophils, if >0.750X10^3 c/uL;Alanine Aminotransferase, 0-40 units per liter(U/L);G-Glutamyl Transferase, 0-60 U/L;Bilirubin, 0.1-1.2 milligrams per deciliter (mg/dL);Blood Urea Nitrogen, 5.9-26.0 mg/dL;Creatinine, 0.50-1.50 mg/dL;Serum Potassium, 3.5-5.5 milliequivalents per liter (mEq/L);Serum Glucose, 65-99 mg/dL;Fasting Serum Glucose, 65-99 mg/dL;Total Protein, 6.0-8.5 g/dL;Albumin, 3.5-5.5 g/dL;Urine Protein, >=4;Urine Glucose,>=4;Urine Blood, >=4;Urine Red Blood Cells >=4;Urine White Blood Cells, >=4. The analysis population included all treated and evaluated subjects in Per A.

End point type

Secondary

End point timeframe

Period A (Day 1 to Day 113)

End point values	Abatacept (All Participants in Period A)	Abatacept (All participants in Period A)
Number of subjects analysed	190	190
Units: participants
number (not applicable)
Hemoglobin (Low) n=189	2	2
Hematocrit (Low) n=189	2	2
Erythrocytes (Low) n=189	1	1
Platelets (Low) n=189	1	1
Platelet Count (High) n=189	2	2
Leukocytes (Low) n=189	9	9
Leukocytes (High) n=189	10	10
Absolute Neutrophils + Bands (Low) n=189	5	5
Absolute Lymphocytes (Low) n=189	9	9
Absolute Eosinophils (High) n=189	16	16
Alanine Aminotransferase (ALT, High) n=190	2	2
G-Glutamyl Transferase (GGT, High) n=190	1	1
Bilirubin (Total, High) n=190	1	1
Blood Urea Nitrogen (High) n=190	6	6
Creatinine (High) n=190	12	12
Potassium (High) n=190	4	4
Serum Glucose (Low) n=190	26	26
Serum Glucose (High) n=190	2	2
Fasting Serum Glucose (High) n=109	1	1
Total Protein (High) n=190	2	2
Albumin (Low) n=190	2	2
Urine Protein (High) n=190	12	12
Urine Glucose (High) n=190	1	1
Urine Blood (High) n=190	23	23
Urine White Blood Cells (High) n=75	9	9
Urine Red Blood Cells (High) n=75	25	25

No statistical analyses for this end point

Secondary: Number of Treated Participants with Marked Laboratory Abnormalities During Double-Blind Phase (Period B)

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End point title

Number of Treated Participants with Marked Laboratory Abnormalities During Double-Blind Phase (Period B)

End point description

Marked abnormalities were pre-defined as changes occurring after drug infusion and reported relative to normal. Hemoglobin, 11.6-14.8 grams per deciliter (g/dL);Hematocrit, 36.0-50.0 percent;Erythrocytes, 3.80-5.10x10*6 cells per microliter (c/uL);Platelets, 140-44 cells per liter (c/L);Leukocytes, 4.00-12.50 c/uL;Absolute Neutrophils + Bands, if <1.00x10^3 c/uL;Absolute Lymphocytes, if <0.72x10^3 or >7.50x10^3 c/uL;Absolute Eosinophils, if >0.750X10^3 c/uL;Aspartate Aminotransferase, 0-40 units per liter (U/L); Alanine Aminotransferase, 0-40 U/L;Blood Urea Nitrogen, 5.9-26.0 mg/dL;Serum Sodium, 135-148 milliequivalents per liter (mEq/L);Serum Potassium, 3.5-5.5 mEq/L;Serum Glucose, 65-99 mg/dL;Fasting Serum Glucose, 65-99 mg/dL;Urine Protein, >=4;Urine Blood, >=4;Urine Red Blood Cells >=4;Urine White Blood Cells, >=4. The analysis population included all treated and evaluated subjects in Period B.

End point type

Secondary

End point timeframe

Period B (Day 113 to Day 282)

End point values	Abatacept (Period B)	Placebo (Period B)
Number of subjects analysed	60	62
Units: participants
number (not applicable)
Hemoglobin (Low) n=60, 61	1	1
Hematocrit (Low) n=60, 61	1	1
Erythrocytes (Low) n=60, 61	0	1
Platelets (Low) n-60, 61	4	0
Platelets (High) n=189	0	1
Leukocytes (Low) n=60, 61	1	1
Leukocytes (High) n=60, 61	1	2
Absolute Neutrophils + Bands (Low) n=60, 62	0	1
Absolute Lymphocytes (Low) n=60, 62	2	3
Absolute Eosinophils (High) n=60, 62	6	4
Aspartate Aminotransferase (AST, High) n=60, 62	1	0
Alanine Aminotransferase (ALT, High) n=60, 62	1	0
Blood Urea Nitrogen (High) n=60, 62	1	1
Serum Sodium (Low) n=60, 62	0	1
Serum Potassium (High) n=60, 62	2	0
Serum Glucose (Low) n=60, 62	4	5
Serum Glucose (High) n=60, 62	0	1
Fasting Serum Glucose (High) n=60, 62	1	1
Urine Protein (High) n=62	2	2
Urine Blood (High) n=60, 62	12	6
Urine White Blood Cells (High) n=24, 20	5	2
Urine Red Blood Cells (High) n=24, 20	6	4

No statistical analyses for this end point

Secondary: Number of Treated Participants with Marked Laboratory Abnormalities During Open-Label Phase (Period C)

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End point title

Number of Treated Participants with Marked Laboratory Abnormalities During Open-Label Phase (Period C)

End point description

Marked abnormalities were pre-defined as changes after drug infusion relative to normal. Hemoglobin,11.6-14.8 g/dL;Hematocrit,36.0-50.0 percent;Erythrocytes,3.80-5.10x10*6 c/uL;Platelets,140-44 c/L;Leukocytes,4.00-12.50c/uL;Absolute(Abs)Neutrophils+Bands,<1.00x10^3 c/uL;Abs Lymphocytes,<0.72x10^3 or>7.50x10^3 c/uL;Abs Eosinophils,>0.750X10^3 c/uL;Alkaline Phosphatase,0-40 U/L;Aspartate Aminotransferase,0-40 U/L;Alanine Aminotransferase,0-40U/L;G-Glutamyl Transferase,0-60 U/L;Bilirubin, 0.1-1.2 mg/dL;Blood Urea Nitrogen,5.9-26.0 mg/dL;Creatinine, 0.50-1.50mg/dL;Inorganic Phosphorus,2.8-6.2 U/L;Serum Potassium,3.5-5.5 mEq/L;Serum Glucose,65-99 mg/dL;Fasting Serum Glucose,65-99 mg/dL;Total Protein, 6.0-8.5 g/dL;Albumin,3.5-5.5 g/dL;Urine Protein,>=4;Urine Glucose,>=4;Urine Blood,>=4;Urine Red Blood Cells>=4;Urine White Blood Cells,>=4. The analysis population included all treated and evaluated subjects in Period C.

End point type

Secondary

End point timeframe

Period C (Day 282 to end of study)

End point values	Abatacept (All Participants in Period C)
Number of subjects analysed	153
Units: participants
number (not applicable)
Hemoglobin (Low) n=153	12
Hematocrit (Low) n=153	8
Erythrocytes (Low) n=153	4
Platelet Count (Low) n=153	4
Platelet Count (High) n=153	5
Leukocytes (Low) n=153	20
Leukocytes (High) n=153	18
Absolute Neutrophils + Bands (Low)	14
Absolute Lymphocytes (Low) n=153	21
Absolute Lymphocytes (High) n=153	5
Absolute Eosinophils (High) n=153	50
Alkaline Phosphatase (ALP, High) n=153	2
Aspartate Aminotransferase (AST, High)	5
Alanine Aminotransferase (ALT, High) n=153	11
G-Glutamyl Transferase (GGT, High) n=153	6
Bilirubin (Total, High) n=153	3
Blood Urea Nitrogen (High) n=153	15
Creatinine (High) n=153	36
Potassium (High) n=153	10
Inorganic Phosphorus (High) n=153	4
Serum Glucose (Low) n=153	54
Serum Glucose (High) n=153	1
Fasting Serum Glucose (Low) n=100	11
Fasting Serum Glucose (High) n=100	7
Total Protein (Low) n=153	1
Total Protein (High) n=153	1
Albumin (Low) n=153	9
Urine Protein (High) n=153	35
Urine Glucose (High) n=153	1
Urine Blood (High) n=153	73
Urine White Blood Cells (High) n=117	49
Urine Red Blood Cells (High) n=117	86

No statistical analyses for this end point

Secondary: Number of Participants With Anti-Abatacept or Anti-CTLA4 Positive Responses Over Time During Open-Label Phase (Period C)

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End point title

Number of Participants With Anti-Abatacept or Anti-CTLA4 Positive Responses Over Time During Open-Label Phase (Period C)

End point description

During Period C, blood samples for immunogenicity assessments were obtained just prior to the start of the IV infusion of abatacept at 3-month intervals during the first 2 years of Period C, at 6-month intervals thereafter, and again 28, 56, and 85 days after the last infusion. Direct-format, enzyme-linked immunosorbent assays (ELISAs) were used to evaluate the cytotoxic T-lymphocyte antigen 4 (CTLA4) and the anti-CTLA4-T antibody. The analysis population included all treated subjects who were evaluated for immunogenicity during Period C.

End point type

Secondary

End point timeframe

Period C (Day 282 to 85 days after the last dose of study medication)

End point values	Abatacept (Period C)	Placebo (Period B) to Abatacept (Period C)	Abatacept (Period A Non-Responders in Period C)
Number of subjects analysed	57	58	33
Units: participants
number (not applicable)
Anti-Abatacept, Overall on Treatment (n=31,54,54)	5	2	1
Anti-Abatacept, Post-Treatment (n=25,41,38)	3	3	0
Anti-CTLA4-T, Overall on Treatment (n=33,57,58)	4	4	4
Anti-CTLA4-T, Overall Post-Treatment (n=27,46,42)	1	1	4

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first dose to last dose plus 56 days up to end of study (November 2011)

Adverse event reporting additional description

Study initiated: February 2004; Study completed: November 2011

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

14.1

Reporting group title

Abatacept (Only Period A)

Reporting group description

Participants treated in Period A but did not in Periods B or C. Abatacept: 10 milligram per kilogram body weight (mg/kg), limited to a maximum 1000 mg for participants weighing >100kg; solution infused intravenously (IV), over 90 minutes, once every 2 weeks for 3 doses.

Reporting group title

Abatacept (Period A/Period C)

Reporting group description

Participants treated in Period A, not eligible to continue into Period B, but re-entered in Period C. Abatacept: 10 milligram per kilogram body weight (mg/kg), limited to a maximum 1000 mg for participants weighing >100kg; solution infused intravenously (IV), over 90 minutes, once every two weeks for three doses (Period A) and once a month for up to 5 years (Period C).

Reporting group title

Abatacept (Period A/Period B)

Reporting group description

All participants treated with Abatacept in Periods A and B who may or may not have entered Period C. Abatacept: 10 milligram per kilogram body weight (mg/kg), limited to a maximum 1000 mg for participants weighing >100kg; solution infused intravenously (IV), over 90 minutes, once every 2 weeks for 3 doses, then once a month for 6 months. If participants entered Period C, treatment continued once a month for up to 5 years.

Reporting group title

Abatacept (Period A)/Placebo (Period B)

Reporting group description

All participants treated with Abatacept in Period A, placebo in Period B, who may or may not have entered Period C. Placebo: Dextrose 5% in water (D5W) or normal saline (NS) IV infusion, once every 2 weeks for 3 doses, then monthly up to 6 months. Participants were seated or in supine position during infusion. If participants entered Period C, they were treated with Abatacept,10 milligram per kilogram body weight (mg/kg), limited to a maximum 1000 mg for participants weighing >100kg; solution infused intravenously (IV), over 90 minutes, once a month for up to 5 years.

Serious adverse events	Abatacept (Only Period A)	Abatacept (Period A/Period C)	Abatacept (Period A/Period B)	Abatacept (Period A)/Placebo (Period B)
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 32 (12.50%)	10 / 36 (27.78%)	9 / 60 (15.00%)	14 / 62 (22.58%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events	0			0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Fibroadenoma of breast
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	0 / 36 (0.00%)	1 / 60 (1.67%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute lymphocytic leukaemia
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	1 / 32 (3.13%)	0 / 36 (0.00%)	0 / 60 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Haematoma
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	0 / 36 (0.00%)	0 / 60 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Fatigue
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	0 / 36 (0.00%)	0 / 60 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Condition aggravated
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	1 / 36 (2.78%)	0 / 60 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	0 / 36 (0.00%)	1 / 60 (1.67%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Food allergy
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	0 / 36 (0.00%)	0 / 60 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypersensitivity
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	0 / 36 (0.00%)	1 / 60 (1.67%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Ovarian cyst
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	1 / 32 (3.13%)	0 / 36 (0.00%)	0 / 60 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Suicide attempt
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	0 / 36 (0.00%)	0 / 60 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Joint dislocation
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	0 / 36 (0.00%)	0 / 60 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Overdose
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	0 / 36 (0.00%)	1 / 60 (1.67%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Multiple injuries
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	0 / 36 (0.00%)	0 / 60 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Encephalitis
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	0 / 36 (0.00%)	0 / 60 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Temporal lobe epilepsy
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	0 / 36 (0.00%)	0 / 60 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Multiple sclerosis
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	0 / 36 (0.00%)	0 / 60 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	0 / 36 (0.00%)	1 / 60 (1.67%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	0 / 36 (0.00%)	1 / 60 (1.67%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	0 / 36 (0.00%)	0 / 60 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Skin ulcer
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	1 / 36 (2.78%)	0 / 60 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthritis
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	3 / 36 (8.33%)	3 / 60 (5.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Foot deformity
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	0 / 36 (0.00%)	1 / 60 (1.67%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rheumatoid arthritis
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	2 / 32 (6.25%)	1 / 36 (2.78%)	0 / 60 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Torticollis
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	1 / 36 (2.78%)	0 / 60 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arthralgia
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	1 / 36 (2.78%)	1 / 60 (1.67%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arthropathy
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	0 / 36 (0.00%)	0 / 60 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Juvenile arthritis
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	1 / 36 (2.78%)	0 / 60 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Synovial cyst
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	0 / 36 (0.00%)	0 / 60 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Erysipelas
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	0 / 36 (0.00%)	0 / 60 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abscess limb
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	1 / 36 (2.78%)	0 / 60 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	0 / 36 (0.00%)	2 / 60 (3.33%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	0 / 36 (0.00%)	0 / 60 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Herpes zoster
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	1 / 36 (2.78%)	0 / 60 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Meningitis bacterial
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	1 / 36 (2.78%)	0 / 60 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tooth abscess
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	0 / 36 (0.00%)	1 / 60 (1.67%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis bacterial
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	1 / 36 (2.78%)	0 / 60 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dengue fever
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	1 / 36 (2.78%)	0 / 60 (0.00%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	1 / 36 (2.78%)	1 / 60 (1.67%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Varicella
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	1 / 36 (2.78%)	0 / 60 (0.00%)	1 / 62 (1.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Type 1 diabetes mellitus
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	0 / 36 (0.00%)	1 / 60 (1.67%)	0 / 62 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Abatacept (Only Period A)	Abatacept (Period A/Period C)	Abatacept (Period A/Period B)	Abatacept (Period A)/Placebo (Period B)
Total subjects affected by non serious adverse events
subjects affected / exposed	22 / 32 (68.75%)	32 / 36 (88.89%)	57 / 60 (95.00%)	54 / 62 (87.10%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	1 / 32 (3.13%)	0 / 36 (0.00%)	3 / 60 (5.00%)	4 / 62 (6.45%)
occurrences all number	1	0	3	4
Vascular disorders
Hypertension
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	2 / 36 (5.56%)	2 / 60 (3.33%)	0 / 62 (0.00%)
occurrences all number	0	2	2	0
Flushing
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	2 / 32 (6.25%)	0 / 36 (0.00%)	0 / 60 (0.00%)	0 / 62 (0.00%)
occurrences all number	2	0	0	0
General disorders and administration site conditions
Fatigue
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	2 / 32 (6.25%)	2 / 36 (5.56%)	0 / 60 (0.00%)	1 / 62 (1.61%)
occurrences all number	2	2	0	2
Chest pain
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	2 / 36 (5.56%)	2 / 60 (3.33%)	2 / 62 (3.23%)
occurrences all number	0	2	2	2
Pain
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	1 / 32 (3.13%)	2 / 36 (5.56%)	0 / 60 (0.00%)	2 / 62 (3.23%)
occurrences all number	1	2	0	2
Chills
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	0 / 36 (0.00%)	3 / 60 (5.00%)	1 / 62 (1.61%)
occurrences all number	0	0	3	1
Influenza like illness
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	0 / 36 (0.00%)	3 / 60 (5.00%)	4 / 62 (6.45%)
occurrences all number	0	0	3	4
Pyrexia
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	2 / 32 (6.25%)	8 / 36 (22.22%)	12 / 60 (20.00%)	12 / 62 (19.35%)
occurrences all number	4	12	17	15
Reproductive system and breast disorders
Vaginal discharge
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	2 / 36 (5.56%)	1 / 60 (1.67%)	1 / 62 (1.61%)
occurrences all number	0	2	1	1
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	4 / 32 (12.50%)	3 / 36 (8.33%)	8 / 60 (13.33%)	8 / 62 (12.90%)
occurrences all number	6	3	10	8
Rhinitis allergic
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	2 / 32 (6.25%)	1 / 36 (2.78%)	4 / 60 (6.67%)	2 / 62 (3.23%)
occurrences all number	2	1	4	2
Cough
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	4 / 32 (12.50%)	7 / 36 (19.44%)	10 / 60 (16.67%)	13 / 62 (20.97%)
occurrences all number	6	10	13	17
Epistaxis
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	2 / 32 (6.25%)	2 / 36 (5.56%)	0 / 60 (0.00%)	0 / 62 (0.00%)
occurrences all number	2	2	0	0
Nasal congestion
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	2 / 32 (6.25%)	0 / 36 (0.00%)	1 / 60 (1.67%)	1 / 62 (1.61%)
occurrences all number	2	0	1	1
Dyspnoea
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	2 / 36 (5.56%)	0 / 60 (0.00%)	0 / 62 (0.00%)
occurrences all number	0	2	0	0
Rhinorrhoea
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	2 / 36 (5.56%)	3 / 60 (5.00%)	2 / 62 (3.23%)
occurrences all number	0	2	3	2
Psychiatric disorders
Insomnia
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	2 / 32 (6.25%)	0 / 36 (0.00%)	0 / 60 (0.00%)	1 / 62 (1.61%)
occurrences all number	2	0	0	1
Investigations
Alanine aminotransferase increased
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	0 / 36 (0.00%)	5 / 60 (8.33%)	2 / 62 (3.23%)
occurrences all number	0	0	6	4
Transaminases increased
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	1 / 36 (2.78%)	3 / 60 (5.00%)	1 / 62 (1.61%)
occurrences all number	0	1	3	1
Aspartate aminotransferase increased
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	0 / 36 (0.00%)	3 / 60 (5.00%)	2 / 62 (3.23%)
occurrences all number	0	0	3	2
Injury, poisoning and procedural complications
Joint injury
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	1 / 36 (2.78%)	1 / 60 (1.67%)	5 / 62 (8.06%)
occurrences all number	0	1	1	5
Arthropod bite
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	2 / 36 (5.56%)	0 / 60 (0.00%)	2 / 62 (3.23%)
occurrences all number	0	2	0	2
Fall
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	0 / 36 (0.00%)	2 / 60 (3.33%)	5 / 62 (8.06%)
occurrences all number	0	0	2	6
Nervous system disorders
Dizziness
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	4 / 32 (12.50%)	3 / 36 (8.33%)	7 / 60 (11.67%)	4 / 62 (6.45%)
occurrences all number	6	4	10	6
Headache
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	7 / 32 (21.88%)	10 / 36 (27.78%)	14 / 60 (23.33%)	11 / 62 (17.74%)
occurrences all number	10	14	20	14
Blood and lymphatic system disorders
Anaemia
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	2 / 36 (5.56%)	3 / 60 (5.00%)	5 / 62 (8.06%)
occurrences all number	0	2	3	5
Leukopenia
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	3 / 36 (8.33%)	4 / 60 (6.67%)	3 / 62 (4.84%)
occurrences all number	0	3	4	3
Eosinophilia
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	4 / 36 (11.11%)	5 / 60 (8.33%)	6 / 62 (9.68%)
occurrences all number	0	6	8	6
Ear and labyrinth disorders
Ear pain
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	0 / 36 (0.00%)	1 / 60 (1.67%)	4 / 62 (6.45%)
occurrences all number	0	0	1	4
Eye disorders
Cataract
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	2 / 36 (5.56%)	1 / 60 (1.67%)	0 / 62 (0.00%)
occurrences all number	0	2	1	0
Conjunctivitis allergic
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	0 / 36 (0.00%)	4 / 60 (6.67%)	0 / 62 (0.00%)
occurrences all number	0	0	4	0
Conjunctivitis
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	4 / 36 (11.11%)	5 / 60 (8.33%)	4 / 62 (6.45%)
occurrences all number	0	4	5	4
Gastrointestinal disorders
Diarrhoea
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	2 / 32 (6.25%)	8 / 36 (22.22%)	11 / 60 (18.33%)	15 / 62 (24.19%)
occurrences all number	2	11	14	18
Mouth ulceration
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	2 / 32 (6.25%)	1 / 36 (2.78%)	3 / 60 (5.00%)	4 / 62 (6.45%)
occurrences all number	2	1	4	4
Abdominal discomfort
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	2 / 36 (5.56%)	2 / 60 (3.33%)	0 / 62 (0.00%)
occurrences all number	0	4	5	0
Abdominal pain
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	1 / 32 (3.13%)	6 / 36 (16.67%)	8 / 60 (13.33%)	8 / 62 (12.90%)
occurrences all number	1	6	8	8
Abdominal pain upper
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	5 / 36 (13.89%)	10 / 60 (16.67%)	10 / 62 (16.13%)
occurrences all number	0	5	10	10
Duodenitis
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	2 / 36 (5.56%)	0 / 60 (0.00%)	0 / 62 (0.00%)
occurrences all number	0	2	0	0
Gastritis
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	6 / 36 (16.67%)	6 / 60 (10.00%)	5 / 62 (8.06%)
occurrences all number	0	6	6	5
Vomiting
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	2 / 32 (6.25%)	7 / 36 (19.44%)	9 / 60 (15.00%)	13 / 62 (20.97%)
occurrences all number	4	8	11	15
Aphthous stomatitis
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	1 / 32 (3.13%)	3 / 36 (8.33%)	3 / 60 (5.00%)	2 / 62 (3.23%)
occurrences all number	1	3	3	3
Dyspepsia
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	1 / 36 (2.78%)	4 / 60 (6.67%)	3 / 62 (4.84%)
occurrences all number	0	1	4	3
Nausea
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	6 / 32 (18.75%)	5 / 36 (13.89%)	9 / 60 (15.00%)	12 / 62 (19.35%)
occurrences all number	6	5	12	15
Skin and subcutaneous tissue disorders
Pruritus
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	1 / 32 (3.13%)	2 / 36 (5.56%)	2 / 60 (3.33%)	1 / 62 (1.61%)
occurrences all number	1	2	2	1
Eczema
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	2 / 32 (6.25%)	0 / 36 (0.00%)	2 / 60 (3.33%)	4 / 62 (6.45%)
occurrences all number	2	0	2	4
Rash
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	1 / 36 (2.78%)	3 / 60 (5.00%)	5 / 62 (8.06%)
occurrences all number	0	1	3	5
Dermatitis
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	1 / 36 (2.78%)	3 / 60 (5.00%)	0 / 62 (0.00%)
occurrences all number	0	1	3	0
Renal and urinary disorders
Haematuria
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	2 / 36 (5.56%)	5 / 60 (8.33%)	4 / 62 (6.45%)
occurrences all number	0	2	6	4
Dysuria
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	0 / 36 (0.00%)	4 / 60 (6.67%)	4 / 62 (6.45%)
occurrences all number	0	0	4	4
Leukocyturia
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	2 / 36 (5.56%)	1 / 60 (1.67%)	0 / 62 (0.00%)
occurrences all number	0	2	1	0
Musculoskeletal and connective tissue disorders
Myalgia
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	0 / 36 (0.00%)	3 / 60 (5.00%)	4 / 62 (6.45%)
occurrences all number	0	0	4	5
Torticollis
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	2 / 36 (5.56%)	1 / 60 (1.67%)	0 / 62 (0.00%)
occurrences all number	0	2	2	0
Arthralgia
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	1 / 36 (2.78%)	1 / 60 (1.67%)	4 / 62 (6.45%)
occurrences all number	0	1	1	4
Back pain
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	3 / 36 (8.33%)	5 / 60 (8.33%)	2 / 62 (3.23%)
occurrences all number	0	3	5	2
Infections and infestations
Pneumonia
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	2 / 36 (5.56%)	0 / 60 (0.00%)	0 / 62 (0.00%)
occurrences all number	0	2	0	0
Bacteriuria
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	2 / 36 (5.56%)	6 / 60 (10.00%)	2 / 62 (3.23%)
occurrences all number	0	2	8	2
Pharyngitis streptococcal
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	2 / 32 (6.25%)	0 / 36 (0.00%)	0 / 60 (0.00%)	1 / 62 (1.61%)
occurrences all number	2	0	1	1
Pharyngotonsillitis
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	2 / 36 (5.56%)	3 / 60 (5.00%)	1 / 62 (1.61%)
occurrences all number	0	2	3	1
Vulvovaginitis
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	4 / 36 (11.11%)	1 / 60 (1.67%)	2 / 62 (3.23%)
occurrences all number	0	4	1	2
Fungal skin infection
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	3 / 36 (8.33%)	3 / 60 (5.00%)	2 / 62 (3.23%)
occurrences all number	0	3	3	2
Impetigo
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	3 / 36 (8.33%)	2 / 60 (3.33%)	2 / 62 (3.23%)
occurrences all number	0	3	2	2
Pneumonia primary atypical
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	2 / 36 (5.56%)	0 / 60 (0.00%)	0 / 62 (0.00%)
occurrences all number	0	2	0	0
Rhinitis
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	6 / 36 (16.67%)	8 / 60 (13.33%)	9 / 62 (14.52%)
occurrences all number	0	8	8	12
Gastroenteritis
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	1 / 32 (3.13%)	4 / 36 (11.11%)	6 / 60 (10.00%)	5 / 62 (8.06%)
occurrences all number	1	5	8	5
Tonsillitis
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	6 / 36 (16.67%)	7 / 60 (11.67%)	3 / 62 (4.84%)
occurrences all number	0	8	10	3
Upper respiratory tract infection
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	3 / 32 (9.38%)	12 / 36 (33.33%)	11 / 60 (18.33%)	12 / 62 (19.35%)
occurrences all number	3	12	11	12
Urinary tract infection
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	2 / 36 (5.56%)	10 / 60 (16.67%)	3 / 62 (4.84%)
occurrences all number	0	2	10	3
Lice infestation
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	2 / 36 (5.56%)	3 / 60 (5.00%)	0 / 62 (0.00%)
occurrences all number	0	2	3	0
Pharyngitis
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	3 / 36 (8.33%)	10 / 60 (16.67%)	13 / 62 (20.97%)
occurrences all number	0	3	12	15
Nasopharyngitis
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	3 / 32 (9.38%)	11 / 36 (30.56%)	20 / 60 (33.33%)	15 / 62 (24.19%)
occurrences all number	3	14	15	20
Sinusitis
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	1 / 32 (3.13%)	5 / 36 (13.89%)	12 / 60 (20.00%)	7 / 62 (11.29%)
occurrences all number	1	5	15	7
Paronychia
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	2 / 32 (6.25%)	3 / 36 (8.33%)	3 / 60 (5.00%)	2 / 62 (3.23%)
occurrences all number	2	3	3	2
Tinea versicolour
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	1 / 36 (2.78%)	3 / 60 (5.00%)	1 / 62 (1.61%)
occurrences all number	0	1	3	1
Varicella
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	1 / 36 (2.78%)	3 / 60 (5.00%)	3 / 62 (4.84%)
occurrences all number	0	1	3	3
Viral infection
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	3 / 32 (9.38%)	0 / 36 (0.00%)	2 / 60 (3.33%)	4 / 62 (6.45%)
occurrences all number	0	3	2	4
Bronchitis
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	2 / 36 (5.56%)	8 / 60 (13.33%)	4 / 62 (6.45%)
occurrences all number	0	2	10	4
Influenza
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	1 / 32 (3.13%)	6 / 36 (16.67%)	16 / 60 (26.67%)	12 / 62 (19.35%)
occurrences all number	1	8	20	12
Otitis media acute
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	2 / 36 (5.56%)	1 / 60 (1.67%)	3 / 62 (4.84%)
occurrences all number	0	2	1	3
Metabolism and nutrition disorders
Decreased appetite
alternative dictionary used: MedDRA 14.1
subjects affected / exposed	0 / 32 (0.00%)	2 / 36 (5.56%)	3 / 60 (5.00%)	0 / 62 (0.00%)
occurrences all number	0	2	3	0

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

01 Dec 2003

Clarified that Period C would continue for 2 years or until abatacept is approved for the indication of JRA/JIA in each local country.

08 Nov 2006

Decreased frequency of efficacy, safety and laboratory assessments beginning with study Day C701 to once every 6 months; removed requirement for male contraception use; stated that use of abatacept in combination with another biologic agent for RA was not recommended; minor editorial clarifications.

26 Apr 2010

Implemented collection of biomarkers typically associated with diabetes and hypothyroidism to examine the potential relationship between abatacept treatment and the development of immunogenicity in influencing the onset of autoimmune disorders.

30 Sep 2010

Terminated the study by December 2011 based on the fact that abatacept was commercially available to treat JRA in the IM101033 participating countries.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Phase III, Multi-Center, Multi-National, Randomized Withdrawal Study to Evaluate the Safety and Efficacy of BMS-188667 in Children and Adolescents with Active Polyarticular Juvenile Rheumatoid Arthritis (JRA)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Median Time to Occurrence of Juvenile Rheumatoid Arthritis/Juvenile Idiopathic Arthritis (JRA/JIA) Disease Flare During Double-Blind Phase (Period B)

Primary: Median Time to Occurrence of Juvenile Rheumatoid Arthritis/Juvenile Idiopathic Arthritis (JRA/JIA) Disease Flare During Double-Blind Phase (Period B)

Secondary: Number of Participants with a Juvenile Rheumatoid Arthritis/Juvenile Idiopathic Arthritis (JRA/JIA) Disease with a Flare During Double-Blind Phase (Period B)

Secondary: Number of Participants with a Juvenile Rheumatoid Arthritis/Juvenile Idiopathic Arthritis (JRA/JIA) Disease with a Flare During Double-Blind Phase (Period B)

Secondary: Number of Participants With Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs During Open-Label Lead-In Phase (Period A)

Secondary: Number of Participants With Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs During Open-Label Lead-In Phase (Period A)

Secondary: Number of Participants With Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs During Double-Blind Phase (Period B)

Secondary: Number of Participants With Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs During Double-Blind Phase (Period B)

Secondary: Number of Participants With Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs During Open-Label Phase (Period C)

Secondary: Number of Participants With Serious Adverse Events (SAEs), Treatment-Related AEs, Deaths, Discontinuation of Study Drug Due to AEs During Open-Label Phase (Period C)

Secondary: Median Percent Change From Baseline in JRA/JIA Core Set Variables During Double-Blind Phase (Period B)

Secondary: Median Percent Change From Baseline in JRA/JIA Core Set Variables During Double-Blind Phase (Period B)

Secondary: Median Percent Change From Baseline in JRA/JIA Core Set Variables During Open-Label Phase (Period C)

Secondary: Median Percent Change From Baseline in JRA/JIA Core Set Variables During Open-Label Phase (Period C)

Secondary: Events of Special Interest During Open-Label Lead-In Phase (Period A), Including Infections, Peri-Infusional Adverse Events (AEs), Autoimmune Disorders and Malignancies

Secondary: Events of Special Interest During Open-Label Lead-In Phase (Period A), Including Infections, Peri-Infusional Adverse Events (AEs), Autoimmune Disorders and Malignancies

Secondary: Events of Special Interest During Double-Blind Phase (Period B), Including Infections, Peri-Infusional Adverse Events (AEs), Autoimmune Disorders and Malignancies

Secondary: Events of Special Interest During Double-Blind Phase (Period B), Including Infections, Peri-Infusional Adverse Events (AEs), Autoimmune Disorders and Malignancies

Secondary: Events of Special Interest During Open-Label Phase (Period C), Including Infections, Peri-Infusional Adverse Events (AEs), Autoimmune Disorders and Malignancies

Secondary: Events of Special Interest During Open-Label Phase (Period C), Including Infections, Peri-Infusional Adverse Events (AEs), Autoimmune Disorders and Malignancies

Secondary: Percentage of Participants Achieving American College of Rheumatology (ACR) Pediatric 30 (ACRP30), ACR Pediatric 50, ACR Pediatric 70, ACR Pediatric 90, and Inactive Disease Status Erythrocyte Sedimentation Rate (ESR) Response Rate

Secondary: Percentage of Participants Achieving American College of Rheumatology (ACR) Pediatric 30 (ACRP30), ACR Pediatric 50, ACR Pediatric 70, ACR Pediatric 90, and Inactive Disease Status Erythrocyte Sedimentation Rate (ESR) Response Rate

Secondary: Number of Treated Participants with Marked Laboratory Abnormalities During Open-Label Lead-In Phase (Period A)

Secondary: Number of Treated Participants with Marked Laboratory Abnormalities During Open-Label Lead-In Phase (Period A)

Secondary: Number of Treated Participants with Marked Laboratory Abnormalities During Double-Blind Phase (Period B)

Secondary: Number of Treated Participants with Marked Laboratory Abnormalities During Double-Blind Phase (Period B)

Secondary: Number of Treated Participants with Marked Laboratory Abnormalities During Open-Label Phase (Period C)

Secondary: Number of Treated Participants with Marked Laboratory Abnormalities During Open-Label Phase (Period C)

Secondary: Number of Participants With Anti-Abatacept or Anti-CTLA4 Positive Responses Over Time During Open-Label Phase (Period C)

Secondary: Number of Participants With Anti-Abatacept or Anti-CTLA4 Positive Responses Over Time During Open-Label Phase (Period C)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Phase III, Multi-Center, Multi-National, Randomized Withdrawal Study to Evaluate the Safety and Efficacy of BMS-188667 in Children and Adolescents with Active Polyarticular Juvenile Rheumatoid Arthritis (JRA)