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Clinical Trial Results:
A Phase IIIB Multicenter, Randomized, Double-Blind, Double-Dummy Study to Compare the Efficacy and Safety of Abatacept Administered Subcutaneously and Intravenously in Subjects with Rheumatoid Arthritis, Receiving Background Methotrexate, and Experiencing an Inadequate Response to Methotrexate.

Summary
EudraCT number	2007-005434-37
Trial protocol	FR IE HU GB BE DE NL IT AT GR
Global end of trial date	12 Sep 2014

Results information
Results version number	v1(current)
This version publication date	18 May 2016
First version publication date	18 May 2016
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

IM101-174

ISRCTN number

US NCT number

NCT00559585

WHO universal trial number (UTN)

Sponsor organisation name

Bristol Myers Squibb

Sponsor organisation address

Chaussee de la Hulpe 185, Brussels, Belgium,

Public contact

Bristol Myers Squibb Study Director, Bristol Myers Squibb, clinical.trials@bms.com

Scientific contact

Bristol Myers Squibb Study Director, Bristol Myers Squibb, clinical.trials@bms.com

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

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?

Analysis stage

Final

Date of interim/final analysis

12 Sep 2014

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

12 Sep 2014

Was the trial ended prematurely?

Main objective of the trial

The primary objective for this study is to demonstrate that subcutaneous (SC) injections of abatacept are non-inferior to intravenous (IV) infusions of abatacept in ACR 20 responses after 6 months of treatment in subjects who have active RA, are receiving methotrexate and experiencing an inadequate response to methotrexate. The main objective of the long-term (LT) period was to assess the safety and long-term tolerability of SC injections of abatacept as well as the maintenance of efficacy responses in subjects who completed the initial 6-month short-term (ST) period.

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

17 Jan 2008

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

6 Months

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 290

Country: Number of subjects enrolled

Australia: 38

Country: Number of subjects enrolled

Belgium: 29

Country: Number of subjects enrolled

Brazil: 163

Country: Number of subjects enrolled

Canada: 60

Country: Number of subjects enrolled

Chile: 79

Country: Number of subjects enrolled

France: 29

Country: Number of subjects enrolled

Germany: 24

Country: Number of subjects enrolled

Greece: 6

Country: Number of subjects enrolled

Hungary: 27

Country: Number of subjects enrolled

India: 75

Country: Number of subjects enrolled

Ireland: 3

Country: Number of subjects enrolled

Italy: 20

Country: Number of subjects enrolled

Korea, Republic of: 76

Country: Number of subjects enrolled

Mexico: 433

Country: Number of subjects enrolled

Netherlands: 6

Country: Number of subjects enrolled

Peru: 201

Country: Number of subjects enrolled

Poland: 200

Country: Number of subjects enrolled

Russian Federation: 68

Country: Number of subjects enrolled

South Africa: 122

Country: Number of subjects enrolled

Taiwan: 51

Country: Number of subjects enrolled

Turkey: 9

Country: Number of subjects enrolled

United Kingdom: 16

Country: Number of subjects enrolled

United States: 468

Worldwide total number of subjects

2493

EEA total number of subjects

360

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)

Adults (18-64 years)

2163

From 65 to 84 years

329

85 years and over

Subject disposition

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Recruitment details

The study was conducted at 222 centers in 24 countries.

Screening details

2493 subjects were enrolled in the study: Enrolled for Double blind short term period - 2473; randomised - 1464; randomised and treated - 1457. 20 enrolled in Anti-TNF sub-study: randomized in substudy - 18.

Period 1 title

Short Term Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Blinding implementation details

Both subject and investigator were blinded in the study.

Are arms mutually exclusive

Yes

Subcutaneous (SC) Abatacept

Arm description

Subjects received weekly injections of 125 mg SC abatacept for 6 months (with a loading dose of IV abatacept on Day 1, based on weight). A double-dummy design was used to protect the blind, thus, Subjects also received IV injections of placebo (IV placebo) with the exception that on Day 1, a loading dose of IV abatacept replaced the IV placebo treatment.

Arm type

Experimental

Investigational medicinal product name

Abatacept

Investigational medicinal product code

BMS-188667

Other name

Orencia

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Abatacept 125-mg/mL was administered as subcutaneous injection once weekly.

Investigational medicinal product name

Abatacept

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Abatacept was administered as intravenous infusion on day 1 based on weight of the subject: 500 mg for subjects <60 kg, 750 mg for subjects in between 60 to 100 kg, and 1 gram for subjects >100 kg.

Investigational medicinal product name

Abatacept matching placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Abatacept matching placebo was administered as intravenous infusion on Day 15, Day 29, and every 28 days thereafter through day 141.

Intravenous (IV) Abatacept

Arm description

Subjects received IV abatacept infusions on Days 1, 15, and 29 and every 28 days thereafter. A double-dummy design was used to protect the blind, thus, Subjects also received subcutaneous injections of placebo (subcutaneous placebo).

Arm type

Active comparator

Investigational medicinal product name

Abatacept matching placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Abatacept matching placebo was administered as subcutaneous injection on Day 8 and weekly thereafter.

Investigational medicinal product name

Abatacept

Investigational medicinal product code

BMS-188667

Other name

Orencia

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Abatacept was administered as intravenous infusion based on the weight of the subject: 500 mg for subjects <60 kg, 750 mg for subjects in between 60 to 100 kg, and 1 gram for subjects >100 kg.

Subcutaneous (SC) Abatacept (Anti-TNF Sub-Study)

Arm description

Subjects who had failed one anti-TNF therapy received abatacept 125 mg subcutaneous injections once weekly for 6 months (with an IV abatacept loading dose on Day 1, based on weight: 500 mg for subjects <60 kg, 750 mg for subjects in between 60 to 100 kg, and 1 gram for subjects >100 kg). A double-dummy design was used to protect the blind, thus, subjects also received IV injections of placebo (IV Placebo) with the exception that on Day 1 a loading dose of IV abatacept replaced the IV Placebo treatment.

Arm type

Experimental

Investigational medicinal product name

Abatacept

Investigational medicinal product code

BMS-188667

Other name

Orencia

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Abatacept 125-mg/mL was administered as subcutaneous injection once weekly.

Investigational medicinal product name

Abatacept matching placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Abatacept matching placebo was administered as intravenous infusion on Day 15, Day 29, and every 28 days thereafter through day 141.

Investigational medicinal product name

Abatacept

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Abatacept was administered as intravenous infusion on day 1 based on weight of the subject: 500 mg for subjects <60 kg, 750 mg for subjects in between 60 to 100 kg, and 1 gram for subjects >100 kg.

Intravenous (IV) Abatacept (Anti-TNF Sub-Study)

Arm description

Subjects who had failed one anti-TNF therapy received IV abatacept infusions on Days 1, 15, 29, and every 28 days, thereafter for 6 months. A double-dummy design was used to protect the blind, thus, subjects also received SC injections of placebo (SC Placebo).

Arm type

Active comparator

Investigational medicinal product name

Abatacept matching placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Abatacept matching placebo was administered as subcutaneous injection on Day 8 and weekly thereafter.

Investigational medicinal product name

Abatacept

Investigational medicinal product code

BMS-188667

Other name

Orencia

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Abatacept was administered as intravenous infusion based on the weight of the subject: 500 mg for subjects <60 kg, 750 mg for subjects in between 60 to 100 kg, and 1 gram for subjects >100 kg.

Number of subjects in period 1 ^[1]	Subcutaneous (SC) Abatacept	Intravenous (IV) Abatacept	Subcutaneous (SC) Abatacept (Anti-TNF Sub-Study)	Intravenous (IV) Abatacept (Anti-TNF Sub-Study)
Started	736	721	8	10
Completed	693	676	7	9
Not completed	43	45	1	1
Physician decision	-	1	-	-
Missed doses	-	1	-	-
Subject no longer meets study criteria	2	1	-	-
Suspended drug due to surgery	-	1	-	-
Subject Withdrew-Recurrent Infection	-	1	-	-
Consent withdrawn by subject	11	5	-	-
Subject gain weight	1	-	-	-
Adverse event, non-fatal	17	25	-	-
Death	1	1	-	-
Poor compliance/noncompliance	3	-	-	-
Ongoing Infection Risk	1	-	-	-
Incomplete breast exam	-	1	-	-
Lost to follow-up	-	6	-	-
Early discontinuation	-	1	-	-
Lack of efficacy	6	1	1	1
Administrative reason by sponsor	1	-	-	-

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: 2493 subjects were enrolled in the study: 2473 were enrolled for Double blind short term period; 1464 were randomised; 1457 were randomised and treated. Reasons for enrolled but not randomised were: withdrew consent - 61, lost to follow-up - 7, subject no longer meet study criteria - 918, other reasons - 23. 20 enrolled in Anti-TNF sub-study; 2 not randomised as no longer met criteria; 18 randomized in substudy.

Period 2 title

Open Label LT Period Main + Sub-Study

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Subcutaneous (SC) Abatacept

Arm description

Subjects could either continue with or switch to 125 mg weekly SC abatacept injections until the SC formulation became commercially available on a country basis or the Sponsor terminated the study. The Anti-TNF Sub-study terminated due to low recruitment and Subjects were permitted to roll into the LT Open Label Period.

Arm type

Experimental

Investigational medicinal product name

Abatacept

Investigational medicinal product code

BMS-188667

Other name

Orencia

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Abatacept 125-mg/mL was administered as subcutaneous injection once weekly.

Investigational medicinal product name

Abatacept matching placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Abatacept matching placebo was administered as intravenous infusion on Day 15, Day 29, and every 28 days thereafter through day 141.

Investigational medicinal product name

Abatacept

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Abatacept was administered as intravenous infusion on day 1 based on weight of the subject: 500 mg for subjects <60 kg, 750 mg for subjects in between 60 to 100 kg, and 1 gram for subjects >100 kg.

Number of subjects in period 2 ^[2]	Subcutaneous (SC) Abatacept
Started	1373
Completed	945
Not completed	428
Consent withdrawn by subject	81
Adverse event, non-fatal	100
Death	20
Poor compliance/noncompliance	8
no end of study status page	1
Pregnancy	16
non-specified	71
Lost to follow-up	32
No longer met criteria	1
Administrative reason by sponsor	9
Lack of efficacy	89

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: Out of 1385 subjects who completed the short term double blind period, 1373 entered into long term period.

Baseline characteristics

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Reporting group title

Subcutaneous (SC) Abatacept

Reporting group description

Reporting group title

Intravenous (IV) Abatacept

Reporting group description

Reporting group title

Subcutaneous (SC) Abatacept (Anti-TNF Sub-Study)

Reporting group description

Reporting group title

Intravenous (IV) Abatacept (Anti-TNF Sub-Study)

Reporting group description

Reporting group values	Subcutaneous (SC) Abatacept	Intravenous (IV) Abatacept	Subcutaneous (SC) Abatacept (Anti-TNF Sub-Study)	Intravenous (IV) Abatacept (Anti-TNF Sub-Study)	Total
Number of subjects	736	721	8	10	1475
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	49.9 ( 13.2 )	50.1 ( 12.6 )	43 ( 16.6 )	47.4 ( 11.9 )	-
Gender categorical
Units: Subjects
Female	621	580	8	9	1218
Male	115	141	0	1	257
Weight category
Units: Subjects
<60 kg	186	179	2	2	369
60-100 kg	492	489	5	6	992
>100 kg	58	53	1	2	114
Race
Units: Subjects
White	550	537	7	9	1103
Black/African American	29	27	1	0	57
American Indian/Alaska Native	5	1	0	0	6
Asian	64	73	0	1	138
Native Hawaiian/other Pacific Islander	0	0	0	0	0
Other	88	83	0	0	171
Region
Units: Subjects
North America	142	128	7	7	284
South America	359	349	0	0	708
Europe	127	128	1	3	259
Rest of World	108	116	0	0	224
Duration of disease category
Units: Subjects
<= 2 years	240	221	5	4	470
2 - <= 5 years	155	150	2	0	307
5- <= 10 years	142	164	0	2	308
> 10 years	199	186	1	4	390
Rheumatoid Factor Status
Rheumatoid factor (RF or RhF) is an autoantibody (antibody directed against an organism's own tissues) most relevant in rheumatoid arthritis. It is an antibody against the Fc portion of Immunoglobulin (Ig)G, which is itself an antibody. RF and IgG join to form immune complexes which contribute to the disease process. A positive value for RF was >20 IU/mL; a negative value for RF was ≤ 20 IU/mL.
Units: Subjects
Negative	110	100	4	4	218
Positive	614	611	4	6	1235
Unknown	12	10	0	0	22
Weight
Units: kilogram(s)
arithmetic mean (standard deviation)	72 ( 18 )	71.8 ( 17.6 )	72.9 ( 21.5 )	85.8 ( 18.9 )	-
Duration of disease
Units: year
arithmetic mean (standard deviation)	7.6 ( 8.1 )	7.7 ( 7.8 )	4.6 ( 7.5 )	12.4 ( 13.3 )	-
Number of Tender Joints
Units: tender joints
arithmetic mean (standard deviation)	30.1 ( 14.1 )	29.1 ( 13.3 )	29.4 ( 15.2 )	24.4 ( 16.3 )	-
Number of Swollen Joints
Units: swollen joints
arithmetic mean (standard deviation)	20.4 ( 9.6 )	19.4 ( 8.6 )	20.4 ( 11.8 )	17.7 ( 15.1 )	-
Subject Pain Assessment
The subject self-reported pain assessment is a core component of the ACR scoring system where increasing score indicates increasing level of severity as indicated on a 100 mm Visual Analog Scale (VAS) with 0 mm representing no pain and 100 mm representing the most pain possible. For each post-baseline visit in the DB, time-matched baseline Subject Pain Assessment values were presented and represent the mean baseline value for only that cohort of subjects with assessments available at that visit.
Units: units on a scale
arithmetic mean (standard deviation)	67.8 ( 20.1 )	66.8 ( 20.5 )	76 ( 18.2 )	57.5 ( 23.9 )	-
Physical Function (Health Assessment Questionnaire Disability Index [HAQ-DI])
The disability section of the full HAQ includes 20 questions to assess physical The HAQ-DI includes 20 questions to assess physical function in 8 domains: dressing, arising, eating, walking, hygiene, reach, grip, and common activities. The domain questions are evaluated on a 4-point scale: 0=without any difficulty, 1=with some difficulty, 2=with much difficulty, 3=unable to do. HAQ-DI=sum of worst scores in each domain divided by the number of domains answered. HAQ-DI overall score ranges from a minimum of 0 to a maximum of 3.0.
Units: units on a scale
arithmetic mean (standard deviation)	1.72 ( 0.68 )	1.67 ( 0.67 )	1.97 ( 0.44 )	1.64 ( 0.62 )	-
Subject Global Assessment
Subjects used a horizontal VAS of 100 mm for overall assessment of rheumatoid arthritis. Scale ranged from 0 (very well) to 100 (very poor). Subjects were instructed to draw a vertical through a horizontal line to indicate state of rheumatoid arthritis. Distance from the "very well" end of the horizontal line to the vertical line drawn by the subject was the global disease assessment score on a scale of 1-10, where 1=controlled or equivocal rheumatoid arthritis activity, 1.1-4=mild activity, 4-8=moderate activity, and 8.1-10=high activity.
Units: units on a scale
arithmetic mean (standard deviation)	66.8 ( 20.4 )	64.9 ( 20 )	70.9 ( 23.6 )	60.7 ( 19.4 )	-
Physician Global Assessment
Physician global rheumatoid arthritis assessment core component of the ACR scoring system where increasing score indicates increasing level of severity as indicated on a 100 mm Visual Analog Scale, with 0 mm representing no pain and 100 mm representing the most pain possible.
Units: units on a scale
arithmetic mean (standard deviation)	64.3 ( 16.5 )	63.1 ( 16.6 )	66.5 ( 17.3 )	55.4 ( 20 )	-
High Sensitivity C-Reactive Protein (hsCRP) Level
Hs-CRP is an acute phase reactant protein that is a clinical marker for Rheumatoid Arthritis (RA). Levels of hs-CRP can be used to determine Disease Activity Score (DAS28).
Units: mg/dL
arithmetic mean (standard deviation)	2.62 ( 2.9 )	2.71 ( 2.94 )	2.98 ( 3.14 )	4.77 ( 5.18 )	-
Disease Activity Score (CRP)
The DAS28 (CRP) is a continuous disease measure which is a composite of 4 variables: the 28 tender joint count, the 28 swollen joint count, CRP levels, and subject assessment of disease activity measure on a visual analogue scale. The DAS28 has numeric thresholds that define high disease activity (>5.1), low disease activity (<3.2) and remission (<2.6). A clinically significant response= decrease in DAS28 score of >1.2 from baseline.
Units: units on a scale
arithmetic mean (standard deviation)	6.23 ( 0.85 )	6.2 ( 0.84 )	6.31 ( 0.81 )	5.76 ( 1.2 )	-
Baseline Methotrexate (MTX) Dose
Units: mg/wk
arithmetic mean (standard deviation)	16.3 ( 3.6 )	16.5 ( 3.8 )	14.4 ( 3.5 )	15.3 ( 4.3 )	-

End points

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Reporting group title

Subcutaneous (SC) Abatacept

Reporting group description

Reporting group title

Intravenous (IV) Abatacept

Reporting group description

Reporting group title

Subcutaneous (SC) Abatacept (Anti-TNF Sub-Study)

Reporting group description

Reporting group title

Intravenous (IV) Abatacept (Anti-TNF Sub-Study)

Reporting group description

Reporting group title

Subcutaneous (SC) Abatacept

Reporting group description

Primary: Double-blind Period: Number of Subjects Achieving American College of Rheumatology (ACR) 20 Response

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End point title

Double-blind Period: Number of Subjects Achieving American College of Rheumatology (ACR) 20 Response ^[1] ^[2]

End point description

The ACR 20 definition of improvement is a 20% improvement from baseline in the number of tender and swollen joints, and a 20% improvement from baseline in 3 of the remaining 5 core set measures: subject global assessment of pain, subject global assessment of disease activity, physician global assessment of disease activity, subject assessment of physical function and acute phase reactant value (C-reactive protein). The analysis was performed in Per protocol (PP) population, defined as subjects who are compliant with the study criteria.

End point type

Primary

End point timeframe

Day 169

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive summary statistics were planned for this outcome measure.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate for the specified arm only.

End point values	Subcutaneous (SC) Abatacept	Intravenous (IV) Abatacept
Number of subjects analysed	693	678
Units: Subjects	527	514

No statistical analyses for this end point

Primary: Anti-TNF Failure Sub-study Double-blind Period: Number of Subjects With Positive Anti-abatacept or Anti-Cytotoxic T Lymphocyte Antigen 4-T Cell (CTLA4-T) Response in Anti-TNF Failure Population

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End point title

Anti-TNF Failure Sub-study Double-blind Period: Number of Subjects With Positive Anti-abatacept or Anti-Cytotoxic T Lymphocyte Antigen 4-T Cell (CTLA4-T) Response in Anti-TNF Failure Population ^[3] ^[4]

End point description

Serum samples from all treated adult subjects with active rheumatoid arthritis who were from the Anti-TNF failure population (Subjects who had failed one anti-TNF therapy) were screened for the presence of drug-specific antibodies using Enzyme Linked Immunoabsorbant Assay (ELISA). The analysis was performed in all randomised subjects in the Anti-TNF Failure Sub-study who received at least 1 dose of study medication. n=Number of subjects with at least 1 assessment available.

End point type

Primary

End point timeframe

Days 1, 85, and 169 and postvisits on Days 28, 56, and 85

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive summary statistics were planned for this outcome measure.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate for the specified arm only.

End point values	Subcutaneous (SC) Abatacept (Anti-TNF Sub-Study)	Intravenous (IV) Abatacept (Anti-TNF Sub-Study)
Number of subjects analysed	8	10
Units: Subjects
Day 85 Anti-abatacept (n=8,10)	0	0
Day 85 Anti-CTLA4-T (n=8,10)	0	0
Day 169 Anti-abatacept (n=6,9)	0	0
Day 169 Anti-CTLA4-T(n=6,9)	1	0
Overall Treatment Anti-abatacept (n=8,10)	0	0
Overall on Treatment Anti-CTLA4-T(n=8,10)	1	0
28 days post Anti-abatacept (n=1,1)	0	0
28 days post Anti-CTLA4-T (n=1,1)	0	0
56 days post Anti-abatacept (n=0,1)	0	0
56 days post Anti-CTLA4-T (n=0,1)	0	0
85 days post Anti-abatacept (n=0,1)	0	0
85 days post Anti-CTLA4-T (n=0,1)	0	0

No statistical analyses for this end point

Primary: Anti-TNF Failure Sub-study Double-blind Period: Number of Subjects Achieving American College of Rheumatology (ACR) 20 Response

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End point title

Anti-TNF Failure Sub-study Double-blind Period: Number of Subjects Achieving American College of Rheumatology (ACR) 20 Response ^[5] ^[6]

End point description

The ACR 20 definition of improvement is a 20% improvement from baseline in the number of tender and swollen joints, and a 20% improvement from baseline in 3 of the remaining 5 core set measures: subject global assessment of pain, subject global assessment of disease activity, physician global assessment of disease activity, subject assessment of physical function and acute phase reactant value (C-reactive protein). Subjects who had failed one anti-TNF therapy were included in the sub-studyThe analysis was performed in all randomised subjects in the Anti-TNF Failure Sub-study who received at least 1 dose of study medication.

End point type

Primary

End point timeframe

Day 169

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive summary statistics were planned for this outcome measure.
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate for the specified arm only.

End point values	Subcutaneous (SC) Abatacept (Anti-TNF Sub-Study)	Intravenous (IV) Abatacept (Anti-TNF Sub-Study)
Number of subjects analysed	8	10
Units: Subjects	5	6

No statistical analyses for this end point

Secondary: Double-blind Period: Number of Subjects Achieving ACR 50 and ACR 70 Responses

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End point title

Double-blind Period: Number of Subjects Achieving ACR 50 and ACR 70 Responses ^[7]

End point description

The ACR 50 definition of improvement is a 50% improvement from baseline in the number of tender and swollen joint counts, and a 50% improvement from baseline in 3 of the remaining 5 core set measures: Subject global assessment of pain, Subject global assessment of disease activity, physician global assessment of disease activity, Subject assessment of physical function and acute phase reactant value (C-reactive protein). ACR 70 is defined similarly with 70% improvements from baseline for tender and swollen joint counts and 3 out of 5 core measures. Analysis was performed in Per-Protocol population, defined as subjects who are compliant with the study criteria.

End point type

Secondary

End point timeframe

Day 169

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate for the specified arm only.

End point values	Subcutaneous (SC) Abatacept	Intravenous (IV) Abatacept
Number of subjects analysed	693	678
Units: Subjects
ACR 50	357	341
ACR 70	183	170

No statistical analyses for this end point

Secondary: Double-blind Period: Mean Baseline Health Assessment Questionnaire Disability Index (HAQ-DI) for Subjects With Assessments

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End point title

Double-blind Period: Mean Baseline Health Assessment Questionnaire Disability Index (HAQ-DI) for Subjects With Assessments ^[8]

End point description

The disability section of the full HAQ-DI includes 20 questions to assess physical functions in 8 domains: dressing, arising, eating, walking, hygiene, reach, grip and common activities. The questions are evaluated on a 4-point scale: 0=without any difficulty, 1=with some difficulty, 2=with much difficulty, and 3=unable to do. Higher scores=greater dysfunction. A disability index was calculated by summing the worst scores in each domain and dividing by the number of domains answered. Analysis was performed on all subjects who received at least 1 dose of study medication at any time and had HAD-QI scores available.

End point type

Secondary

End point timeframe

Day 169

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate for the specified arm only.

End point values	Subcutaneous (SC) Abatacept	Intravenous (IV) Abatacept
Number of subjects analysed	729	711
Units: Units on a scale
arithmetic mean (standard deviation)	1.72 ( 0.68 )	1.67 ( 0.67 )

No statistical analyses for this end point

Secondary: Double-blind Period: Adjusted Mean Change From Baseline to Day 169 in HAQ-DI

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End point title

Double-blind Period: Adjusted Mean Change From Baseline to Day 169 in HAQ-DI ^[9]

End point description

The HAQ-DI includes 20 questions to assess physical function in 8 domains: dressing, arising, eating, walking, hygiene, reach, grip, and common activities. The domain questions are evaluated on a 4-point scale: 0=without any difficulty, 1=with some difficulty, 2=with much difficulty, 3=unable to do. HAQ-DI=sum of worst scores in each domain divided by the number of domains answered. HAQ-DI ranges from 0 to a maximum overall score of 3.0. Analysis was performed on all subjects who received at least 1 dose of study medication at any time and had HAD-QI scores available.

End point type

Secondary

End point timeframe

Baseline to Day 169

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate for the specified arm only.

End point values	Subcutaneous (SC) Abatacept	Intravenous (IV) Abatacept
Number of subjects analysed	729	711
Units: Units on a scale
arithmetic mean (standard error)	-0.69 ( 0.02 )	-0.7 ( 0.02 )

No statistical analyses for this end point

Secondary: Double-blind Period: Number of Subjects Achieving Clinically Meaningful HAQ-DI Response at Day 169

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End point title

Double-blind Period: Number of Subjects Achieving Clinically Meaningful HAQ-DI Response at Day 169 ^[10]

End point description

The disability section of the full HAQ-DI includes 20 questions to assess physical functions in 8 domains: dressing, arising, eating, walking, hygiene, reach, grip and common activities. The questions are evaluated on a 4-point scale: 0=without any difficulty, 1= with some difficulty, 2= with much difficulty, and 3=unable to do. Higher scores=greater dysfunction. A disability index was calculated by summing the worst scores in each domain and dividing by the number of domains answered. Clinically meaningful HAQ-DI response=an improvement of at least 0.3 units from baseline in HAQ-DI. Analysis was performed in all the subjects who received at least 1 dose of study medication at any time and had HAD-QI scores available.

End point type

Secondary

End point timeframe

Day 169

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate for the specified arm only.

End point values	Subcutaneous (SC) Abatacept	Intravenous (IV) Abatacept
Number of subjects analysed	729	711
Units: Subjects	483	442

No statistical analyses for this end point

Secondary: Double-blind Period: Number of Subjects With Death As Outcome, Serious Adverse Events (SAEs), Treatment- related SAEs, SAEs Leading to Discontinuation, Adverse Events (AEs), Treatment-related AEs, or AEs Leading to Discontinuation

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End point title

Double-blind Period: Number of Subjects With Death As Outcome, Serious Adverse Events (SAEs), Treatment- related SAEs, SAEs Leading to Discontinuation, Adverse Events (AEs), Treatment-related AEs, or AEs Leading to Discontinuation ^[11]

End point description

AE=any new untoward medical event or worsening of a preexisting medical condition that does not necessarily have a causal relationship with this treatment. SAE=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, results in development of drug dependency or drug abuse, is an important medical event. Treatment-related SAE=possibly, probably, or certainly related to study drug. All randomised subjects who received at least 1 dose of study medication were analysed.

End point type

Secondary

End point timeframe

Day 1 to 56 days after last dose in short-term or first dose in the long-term, whichever occurs first.

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate for the specified arm only.

End point values	Subcutaneous (SC) Abatacept	Intravenous (IV) Abatacept
Number of subjects analysed	736	721
Units: Subjects
Deaths	2	5
SAEs	31	35
Treatment-related SAEs	5	12
SAEs Leading to Discontinuation	8	14
AEs	493	470
Treatment-related AEs	204	210
AEs Leading to Discontinuation	15	25

No statistical analyses for this end point

Secondary: Anti-TNF Failure Sub-study Double-blind Period: Number of Subjects With SAEs, AEs Leading to Discontinuation or Who Died

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End point title

Anti-TNF Failure Sub-study Double-blind Period: Number of Subjects With SAEs, AEs Leading to Discontinuation or Who Died ^[12]

End point description

AE=any new untoward medical event or worsening of a preexisting medical condition that does not necessarily have a causal relationship with this treatment. SAE=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, results in development of drug dependency or drug abuse, is an important medical event. Subjects who had failed one anti-TNF therapy were included in the sub-study. All randomised subjects who received at least 1 dose of study medication were analysed.

End point type

Secondary

End point timeframe

Day 1 to 56 days after last dose in short-term or first dose in the long-term, whichever occurs first.

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate for the specified arm only.

End point values	Subcutaneous (SC) Abatacept (Anti-TNF Sub-Study)	Intravenous (IV) Abatacept (Anti-TNF Sub-Study)
Number of subjects analysed	8	10
Units: Subjects
Deaths	0	0
SAEs	0	0
AEs Leading to Discontinuation	0	0

No statistical analyses for this end point

Secondary: Double-blind Period: Number of Subjects With AEs of Special Interest

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End point title

Double-blind Period: Number of Subjects With AEs of Special Interest ^[13]

End point description

AE=any new untoward medical occurrence or worsening of a preexisting medical condition that does not necessarily have a causal relationship with this treatment. AEs of special interest are those AEs that may be associated with the use of immunomodulatory drugs: all infections,serious infections,and opportunistic infections; autoimmune disorders; malignancies; acute infusional AEs (prespecified AEs occurring within 1 hr of start of infusion), peri-infusional AEs (prespecified AEs occurring within 24 hrs of the start of infusion), system injection reactions, and local injection site reactions. All randomised subjects who received at least 1 dose of study medication were analysed.

End point type

Secondary

End point timeframe

Day 1 up to 56 days post last dose in short- term period or first dose in the long -term period, whichever occurs first.

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate for the specified arm only.

End point values	Subcutaneous (SC) Abatacept	Intravenous (IV) Abatacept
Number of subjects analysed	736	721
Units: Subjects
Infections	234	221
Malignancies	3	5
Autoimmune Disorders	7	6
Acute Infusional AEs	20	16
Peri-infusional AEs	59	59
Local Injection Site Reactions	19	18
Systemic Injection Reactions	56	56

No statistical analyses for this end point

Secondary: Double-blind Period: Number of Subjects With Clinically Significant Abnormalities in Vital Sign Measurements

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End point title

Double-blind Period: Number of Subjects With Clinically Significant Abnormalities in Vital Sign Measurements ^[14]

End point description

Vital sign measurements were performed for subjects before and after infusion/subcutaneous injection of study medication at each visit and included seated systolic blood pressure, seated diastolic blood pressure, temperature, and heart rate. Abnormalities were determined to be clinically significant by the investigator. All randomised subjects who received at least 1 dose of study medication were analysed.

End point type

Secondary

End point timeframe

Day 1 through end of short-term period (Day 169)

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate for the specified arm only.

End point values	Subcutaneous (SC) Abatacept	Intravenous (IV) Abatacept
Number of subjects analysed	736	721
Units: Subjects	0	0

No statistical analyses for this end point

Secondary: Double-blind Period: Number of Subjects With Hematology Laboratory Test Results Meeting the Criteria for Marked Abnormality

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End point title

Double-blind Period: Number of Subjects With Hematology Laboratory Test Results Meeting the Criteria for Marked Abnormality ^[15]

End point description

ULN=upper limit of normal; LLN=lower limit of normal; BL= baseline. Marked abnormality criteria: Hemoglobin: >3 g/dL decrease from BL; hematocrit: <0.75*BL; erythrocytes: <0.75*BL; platelets: <0.67*LLN/>1.5*ULN, or if BL<LLN, use <0.5*BL and <100,000 mm^3; leukocytes: <0.75*LLN/>1.25*ULN, or if BL<LLN use <0.8*BL or >ULN, or if BL>ULN, use >1.2*BL or <LLN; neutrophils+bands: <1.0*10^3 c/uL; eosinophils: >0.750*10^3 c/uL; basophils: >400 mm^3; monocytes: >2000 mm^3; lymphocytes: <0.750*10^3 c/uL/>7.50*10^3 c/uL. The analysis was performed in all the randomised subjects who received at least 1 dose of study medication. Here "n" = Number of subjects with assessments available.

End point type

Secondary

End point timeframe

Day 1 through end of short-term period (Day 169)

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate for the specified arm only.

End point values	Subcutaneous (SC) Abatacept	Intravenous (IV) Abatacept
Number of subjects analysed	736	721
Units: Subjects
Low hemoglobin (LLN=11.5 g/dL); n=729, 713	2	5
Low hematocrit (LLN=34%); n=726, 713	2	4
Low erythrocytes(LLN=3.8 x10*6c/uL);n=729, 713	2	3
Low platelets (LLN=140*10^9 c/L); n=725, 709	1	0
High platelets (ULN=450*10^9 c/L); n=725, 709	0	0
Low leukocytes (LLN= 3.8*10^3 c/uL); n=729, 713	6	2
High eosinophils (ULN= 7*10^3 c/uL); n=730, 712	22	16
High basophils (ULN= 0.2*10^3 c/uL); n=730, 712	0	0
High monocytes (ULN=1*10^3 c/uL); n=730, 712	0	1
Low lymphocytes (LLN= 0.7*10^3 c/uL);n=730,712	40	42
Low neutrophils+bands(LLN=1.8*10^3 c/uL);n=730,713	0	0
High leukocytes (ULN = 10.6*10^3 c/uL);n=729, 713	25	18
High lymphocytes (ULN=4.5*10^3 c/uL); n=730,712	40	42

No statistical analyses for this end point

Secondary: Double-blind Period: Number of Subjects With Liver Function Laboratory Test Results Meeting the Criteria for Marked Abnormality

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End point title

Double-blind Period: Number of Subjects With Liver Function Laboratory Test Results Meeting the Criteria for Marked Abnormality ^[16]

End point description

Marked abnormality criteria: Alkaline phosphatase (ALP): >2*ULN, or if BL>ULN, use >3*BL; aspartate aminotransferase (AST): >3*ULN, or if BL>ULN, use >4*BL; alanine aminotransferase (ALT): >3*ULN, or if BL>ULN, use >4*BL; G-glutamyl transferase (GGT): >2* ULN, or if BL>ULN, use >3*BL; bilirubin: >2* ULN, or if BL>ULN, use >4*BL; blood urea nitrogen: >2* BL; creatinine: >1.5*BL. The analysis was performed in all the randomised subjects who received at least 1 dose of study medication. Here "n" = Number of subjects with assessments available.

End point type

Secondary

End point timeframe

Day 1 through end of short-term period (Day 169)

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate for the specified arm only.

End point values	Subcutaneous (SC) Abatacept	Intravenous (IV) Abatacept
Number of subjects analysed	736	721
Units: Subjects
High ALP (ULN=400 U/L); n=730, 713	1	3
High AST (ULN=44 U/L); n=729, 713	5	5
High ALT (ULN=55 U/L);n=729, 713	12	16
High GGT (ULN=65 U/L); n=730, 713	8	14
High bilirubin (ULN=1.2 mg/dL); n=730, 713	1	0
High blood urea nitrogen (26 mg/dL); n=730, 713	21	27
High creatinine (ULN=1.5 mg/dL); n=730, 713	19	30

No statistical analyses for this end point

Secondary: Double-blind Period: Number of Subjects With Electrolyte Laboratory Test Results Meeting the Criteria for Marked Abnormality

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End point title

Double-blind Period: Number of Subjects With Electrolyte Laboratory Test Results Meeting the Criteria for Marked Abnormality ^[17]

End point description

Marked abnormality criteria: Sodium: <0.95*LLN/>1.05*ULN, or if BL<LLN, use <0.95* BL or >ULN, or if BL>ULN, use>1.05* BL or <LLN; potassium: <0.9* LLN/>1.1*ULN, or if BL<LLN then use <0.9* BL or >ULN, or if BL>ULN, use>1.1* BL or <LLN; chlorine: <0.9*LLN/>1.1* ULN, or if BL<LLN, use <0.9*BL or >ULN, or if BL>ULN, use>1.1*BL or <LLN; calcium: <0.8* LLN/>1.2* ULN, or if BL<LLN, use <0.75*BL or >ULN, or if BL>ULN, use>1.25* BL or <LLN; phosphorous: <0.75* LLN/>1.25*ULN, or if BL<LLN, use 0.67*BL or >ULN, or if BL>ULN, use>1.33* BL or <LLN. The analysis was performed in all the randomised subjects who received at least 1 dose of study medication. Here "N" = number of subjects with assessments available.

End point type

Secondary

End point timeframe

Day 1 through end of short-term period (Day 169)

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate for the specified arm only.

End point values	Subcutaneous (SC) Abatacept	Intravenous (IV) Abatacept
Number of subjects analysed	736	721
Units: Subjects
Low sodium (LLN=135 mEq/L)	2	0
High sodium (ULN=148 mEq/L)	0	0
Low potassium (LLN=3.5 mEq/L)	9	9
High potassium (ULN=5.5 mEq/L)	1	0
Low chlorine (LLN= 96 mEq/L)	0	0
High chlorine (ULN=109 mEq/L)	0	0
Low calcium (LLN=8.4 mg/dL)	1	0
High calcium (ULN=10.6 mg/dL)	1	0
Low phosphorous (LLN=0.8 mg/dL)	1	2
High phosphorous (ULN=5.6 mg/dL)	0	1

No statistical analyses for this end point

Secondary: Double-blind Period: Minimum Observed Serum Concentration of Abatacept

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End point title

Double-blind Period: Minimum Observed Serum Concentration of Abatacept ^[18]

End point description

A sensitive, validated immunoassay method will be used to measure concentrations of abatacept in serum. Subjects who received at least 1 dose of study medication and from whom at least 1 pharmacokinetic (PK) sample was collected and reported (N). Only subjects with adequate PK profiles were included in the summary statistics and statistical analysis (n). PK values were not sampled for IV abatacept group on Day 120, 127, 134. Here, ‘99999’ represents not estimable data for specified categories in respective arms.

End point type

Secondary

End point timeframe

Days 57, 85, 113, 120, 127, 134, 141, and 169

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate for the specified arm only.

End point values	Subcutaneous (SC) Abatacept	Intravenous (IV) Abatacept
Number of subjects analysed	736	721
Units: μg/mL
geometric mean (standard deviation)
Day 57 (n=25, n=16)	31.6 ( 21.483 )	23.14 ( 14.008 )
Day 85 (n=630, n=649)	28.3 ( 21.692 )	20 ( 13.441 )
Day 113 (n=44, n=29)	26.49 ( 16.569 )	18.76 ( 16.322 )
Day 120 (n=27)	25.1 ( 14.933 )	99999 ( 99999 )
Day 127 (n=28)	29.16 ( 14.78 )	99999 ( 99999 )
Day 134 (n=27)	25.1 ( 15.753 )	99999 ( 99999 )
Day 141 (n=26, n=26)	25.79 ( 14.264 )	18.1 ( 17.717 )
Day 169 (n=530, n=521)	24.91 ( 14.989 )	18.1 ( 17.94 )

No statistical analyses for this end point

Secondary: Anti-TNF Failure Sub-study Double-blind Period: Minimum Observed Serum Concentration (Cmin) of Abatacept

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End point title

Anti-TNF Failure Sub-study Double-blind Period: Minimum Observed Serum Concentration (Cmin) of Abatacept ^[19]

End point description

Serum concentrations of abatacept were analyzed using a validated ELISA. Steady-state trough observed concentration in serum (Cminss) was measured in μg/mL. Samples were obtained on Days 57, 85, 113, 120, 127, 134, 141, and 169. Subjects who had failed one anti-TNF therapy were included in the sub-study. Subjects who received at least 1 dose of study medication and who had adequate PK profiles were analyzed. n= number of subjects available at each specific time point. PK values were not sampled for IV abatacept group on Day 120, 127, 134. Here, ‘99999’ represents not estimable data for specified categories in respective arms.

End point type

Secondary

End point timeframe

Days 57, 85, 113, 120, 127, 134, 141, and 169 (ST Period)

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate for the specified arm only.

End point values	Subcutaneous (SC) Abatacept (Anti-TNF Sub-Study)	Intravenous (IV) Abatacept (Anti-TNF Sub-Study)
Number of subjects analysed	8	10
Units: μg/mL
geometric mean (geometric coefficient of variation)
Day 57 (n=3, 4)	25.53 ( 16 )	15.51 ( 25 )
Day 85 (n=6, 9)	21.51 ( 26 )	12.5 ( 48 )
Day 113 (n=6, 6)	23.14 ( 27 )	11.1 ( 31 )
Day 120 (n=4, 0)	25.75 ( 17 )	99999 ( 99999 )
Day 127 (n=3, 0)	25.42 ( 9 )	99999 ( 99999 )
Day 134 (n=3, 0)	25.55 ( 13 )	99999 ( 99999 )
Day 141 (n=4, 6)	20.85 ( 24 )	8.34 ( 44 )
Day 169 (n=5, 7)	19.66 ( 25 )	9 ( 53 )

No statistical analyses for this end point

Secondary: Double-blind Period: Maximum Observed Serum Concentration of Abatacept

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End point title

Double-blind Period: Maximum Observed Serum Concentration of Abatacept ^[20]

End point description

Subjects who received at least 1 dose of study medication and who had adequate PK profiles for analysis were evaluated for this outcome measure. Here, 'Number of Subjects Analysed' signifies the subjects evaluable for this outcome measure.

End point type

Secondary

End point timeframe

End of infusion on Days 1 and 113 for IV infusion and in the dosing interval of Days 113 to 120 for subcutaneous

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate for the specified arm only.

End point values	Subcutaneous (SC) Abatacept	Intravenous (IV) Abatacept
Number of subjects analysed	39	30
Units: μg/mL
geometric mean (standard deviation)	40.39 ( 30.148 )	222.35 ( 71.92 )

No statistical analyses for this end point

Secondary: Anti-TNF Failure Substudy Double Blind Period: Geometric Mean Maximum Observed Serum Concentration of Abatacept

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End point title

Anti-TNF Failure Substudy Double Blind Period: Geometric Mean Maximum Observed Serum Concentration of Abatacept ^[21]

End point description

Serum concentrations of abatacept were analyzed using a validated enzyme-linked immunosorbent assay. Samples were obtained on Days 57, 85, 113, 120, 127, 134, 141, and 169. Cmax was measured in micrograms per milliliter (μg/mL). Subjects who had failed one anti-TNF therapy were included in the sub-study. Subjects in the Sub-study who received at least 1 dose of study medication and who had adequate pharmacokinetic profiles were analysed. Here, 'Number of Subjects Analysed' signifies the subjects evaluable for this outcome measure.

End point type

Secondary

End point timeframe

End of infusion on Days 1 and 113 for IV infusion and in the dosing interval of Days 113 to 120 for subcutaneous

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate for the specified arm only.

End point values	Subcutaneous (SC) Abatacept (Anti-TNF Sub-Study)	Intravenous (IV) Abatacept (Anti-TNF Sub-Study)
Number of subjects analysed	5	5
Units: μg/mL
geometric mean (geometric coefficient of variation)	35.84 ( 24 )	229.88 ( 26 )

No statistical analyses for this end point

Secondary: Double-blind Period: Area Under The Curve In A Dose Interval (AUC TAU) of Abatacept

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End point title

Double-blind Period: Area Under The Curve In A Dose Interval (AUC TAU) of Abatacept ^[22]

End point description

A sensitive, validated immunoassay method was used to measure concentrations of abatacept in serum. The analysis was performed in all the subjects who received at least 1 dose of study medication and who had adequate PK profiles for analysis. Here, 'Number of Subjects Analysed' signifies the subjects evaluable for this outcome measure.

End point type

Secondary

End point timeframe

Dosing interval between Days 113 and 141 (TAU=28 days)

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate for the specified arm only.

End point values	Subcutaneous (SC) Abatacept	Intravenous (IV) Abatacept
Number of subjects analysed	39	33
Units: μg*h/mL
geometric mean (standard deviation)	5182.37 ( 2854.136 )	39587.08 ( 15444.74 )

No statistical analyses for this end point

Secondary: Anti-TNF Failure Sub-study Double Blind Period: Area Under The Curve In A Dose Interval (AUC TAU) of Abatacept

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End point title

Anti-TNF Failure Sub-study Double Blind Period: Area Under The Curve In A Dose Interval (AUC TAU) of Abatacept ^[23]

End point description

Serum concentrations of abatacept were analyzed using a validated ELISA. AUC(TAU) was measured as μg*h/mL. Samples were obtained on Days 113, 120, 127, 134, 141, and 169. Subjects who had failed one anti-TNF therapy were included in the sub-study. The analysis was performed in all subjects in the sub-study who received at least 1 dose of study medication and who had adequate PK profiles for analysis. Here, 'Number of Subjects Analysed' signifies the subjects evaluable for this outcome measure.

End point type

Secondary

End point timeframe

Dosing Interval between Days 113 and 141 (TAU=28 days)

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate for the specified arm only.

End point values	Subcutaneous (SC) Abatacept (Anti-TNF Sub-Study)	Intravenous (IV) Abatacept (Anti-TNF Sub-Study)
Number of subjects analysed	5	6
Units: μg*h/mL
geometric mean (geometric coefficient of variation)	4384.3 ( 17 )	34260.55 ( 35 )

No statistical analyses for this end point

Secondary: Double-blind Period: Number of Subjects With Positive Anti-abatacept or Anti-Cytotoxic T Lymphocyte Antigen 4-T Cell (CTLA4-T) Responses Over Time by Enzyme Linked Immunoabsorbant Assay (ELISA)

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End point title

Double-blind Period: Number of Subjects With Positive Anti-abatacept or Anti-Cytotoxic T Lymphocyte Antigen 4-T Cell (CTLA4-T) Responses Over Time by Enzyme Linked Immunoabsorbant Assay (ELISA) ^[24]

End point description

Serum samples from all treated adult subjects with active rheumatoid arthritis were screened for the presence of drug-specific antibodies using ELISA. Immunogenicity was defined as the presence of a positive anti-abatacept (anti-ABA) or anti-CTLA4 antibody (anti-CTLA4). The analysis was performed in all the randomised subjects who received at least 1 dose of study medication. Here "n" = Number of subjects with at least 1 assessment available.

End point type

Secondary

End point timeframe

Days 1, 85, and 169 and post-visits on Days 28, 56, and 85

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate for the specified arm only.

End point values	Subcutaneous (SC) Abatacept	Intravenous (IV) Abatacept
Number of subjects analysed	736	721
Units: Subjects
Day 85 anti-ABA (n=700, n=682)	0	2
Day 85 anti-CTLA4 (n=705, n=689)	0	0
Day 85 total (n=706, n=689)	0	2
Day 169 anti-ABA (n=671, n=648)	3	4
Day 169 anti-CTLA4 (n=681, n=658)	2	4
Day 169 total (n=681, n=658)	5	8
Overall on-treatment visits anti-ABA (n=707, 691)	3	5
Overall on-treatment visits anti-CTLA4 (n=716,702)	2	4
Overall on-treatment visits total (n=716, 702)	5	9
28 days post last dose anti-ABA (n=18, n=25)	0	0
28 days post last dose anti-CTLA4 (n=20, n=27)	0	2
28 days post last dose total (n=20, n=27)	0	2
56 days post last dose anti-ABA (n=19, n=22)	0	0
56 days post last dose anti-CTLA4 (n=19, n=23)	1	1
56 days post last dose total (n=19, n=23)	1	1
85 days post last dose anti-ABA (n=12, n=15)	0	0
85 days post last dose anti-CTLA4 (n=13, n=15)	2	5
85 days post last dose total (n=13, n=15)	2	5
Overall post visits anti-ABA (n=26, n=29)	0	0
Overall post visits anti-CTLA4 (n=28, n=31)	3	7
Overall post visits total (n=28, n=31)	3	7
Overall anti-ABA (n=714, n=698)	3	5
Overall anti-CTLA4 (n=725, n=710)	5	11
Overall total (n=725, n=710)	8	16

No statistical analyses for this end point

Secondary: Double-blind Period: Time-matched Median Percent Change From Baseline in Levels of Serum C-reactive Protein Over the Short-term Period

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End point title

Double-blind Period: Time-matched Median Percent Change From Baseline in Levels of Serum C-reactive Protein Over the Short-term Period ^[25]

End point description

C-reactive protein is an acute phase reactant protein that is a clinical marker for rheumatoid arthritis. Time-matched median percent change from baseline= (time-matched baseline value - Post-baseline value)/time-matched baseline value*100, where the time-matched baseline value represents the median baseline value for only that cohort of subjects with measurements available at that visit. The analysis was performed in all the randomised subjects who received at least 1 dose of study medication. Here "n" = Number of subjects with at least 1 assessment available.

End point type

Secondary

End point timeframe

Baseline to Days 15, 29, 57, 85, 113, 141, and 169

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate for the specified arm only.

End point values	Subcutaneous (SC) Abatacept	Intravenous (IV) Abatacept
Number of subjects analysed	736	721
Units: Percentage change
median (inter-quartile range (Q1-Q3))
Day 15 (n=720, n=703)	34.16 (-11.11 to 58.8)	33.74 (-6.24 to 58.41)
Day 29 (n=727, n=711)	39.74 (3.83 to 66.99)	42.52 (0.42 to 68.66)
Day 57 (n=727, n=711)	47.88 (6.84 to 73.53)	51.42 (7.53 to 74.95)
Day 85 (n=727, n=711)	52.9 (8.7 to 78.25)	53.65 (11.05 to 79.42)
Day 113 (n=727, n=711)	53.33 (7.09 to 80.29)	58.12 (11.21 to 81.26)
Day 141 (n=727, n=711)	56.12 (5.28 to 83.24)	58.39 (16.14 to 81.52)
Day 169 (n=727, n=711)	57.18 (11.18 to 83.28)	56.81 (17.92 to 82.7)

No statistical analyses for this end point

Secondary: Double-blind Period: Number of Subjects With Positive Anti-abatacept Responses Over Time by Electrochemiluminescence Immunoassay

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End point title

Double-blind Period: Number of Subjects With Positive Anti-abatacept Responses Over Time by Electrochemiluminescence Immunoassay ^[26]

End point description

An electro-chemiluminescence immunoassay screened sera for drug-specific antibodies, immuno-competition was used to identify specific anti-abatacept reactivity. CTLA4 and Possibly Ig category=reactivity against extracellular domain of human CTLA4, constant regions of human IgG1, or both (CTLA4Ig; abatacept molecule). Ig and/or Junction (JNCT) category=reactivity against constant regions and/or hinge region of human IgG1. Drug-induced seropositivity was defined as a post-baseline titer higher than Baseline, or any post-baseline positivity if baseline value was missing. Trt=treatment. The analysis was performed in all the subjects who received at least 1 dose of abatacept and had at least 1 immunogenicity result reported during the short-term period.

End point type

Secondary

End point timeframe

Days 85, and 169 and post-visits on Days 28, 56, and 85

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate for the specified arm only.

End point values	Subcutaneous (SC) Abatacept	Intravenous (IV) Abatacept
Number of subjects analysed	736	721
Units: Subjects
Day 85 CTLA4 + possibly Ig (n=78, n=67)	0	0
Day 85 Ig +/- JNCT (n=78, n=67)	0	0
Day 85 total (n=78, n=67)	0	0
Day 169 CTLA4 + possibly Ig (n=75, n=67)	0	1
Day 169 Ig +/- JNCT (n=75, n=67)	0	0
Day 169 total (n=75, n=67)	0	1
Overall on-TRT CTLA4 + possibly Ig (n=79, 70)	0	1
Overall on-TRT Ig +/- JNCT (n=79, 70)	0	0
Overall on-TRT total (n=79, 70)	0	1
28 days post last dose CTLA4+possibly Ig (n=2,n=2)	0	0
28 days post last dose Ig +/- JNCT (n=2, n=2)	0	0
28 days post last dose Total (n=2, n=2)	0	0
56 days post last dose CTLA4+possibly Ig (n=2,n=2)	0	0
56 days post last dose Ig +/- JNCT (n=2, n=2)	0	0
56 days post last dose total (n=2, n=2)	0	0
85 days post last dose CTLA4+possibly Ig (n=1,n=1)	0	0
85 days post last dose Ig +/- JNCT (n=1, n=1)	0	0
85 days post last dose total (n=1, n=1)	0	0
Overall post visits CTLA4+possibly Ig (n=3, n=2)	0	0
Overall post visits Ig +/- JNCT (n=3, n=2)	0	0
Overall post visits total (n=3, n=2)	0	0
Overall CTLA4+possibly Ig (n=82, n=71)	0	1
Overall Ig +/- JNCT (n=82, n=71)	0	0
Overall total (n=82, n=71)	0	1

No statistical analyses for this end point

Secondary: Double-blind Period: Number of Subjects Seroconverting by Day 169 According to Status (Negative or Positive) at Baseline

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End point title

Double-blind Period: Number of Subjects Seroconverting by Day 169 According to Status (Negative or Positive) at Baseline ^[27]

End point description

Rheumatoid factor (RF) is an autoantibody (antibody directed against an organism's own tissues) most relevant in rheumatoid arthritis. It is an antibody against the Fc portion of Immunoglobulin (Ig)G, which is itself an antibody. RF and IgG join to form immune complexes which contribute to the disease process. The analysis was performed in all the randomised subjects who received at least 1 dose of study medication. Here "n" = Number of subjectsts with at least 1 assessment available.

End point type

Secondary

End point timeframe

Baseline to Day 169

Notes
[27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate for the specified arm only.

End point values	Subcutaneous (SC) Abatacept	Intravenous (IV) Abatacept
Number of subjects analysed	736	721
Units: Subjects
Baseline RF negative	106	93
Baseline RF negative; Day 169 RF positive	2	3
Baseline RF positive	586	582
Baseline RF positive ; Day 169 RF negative	33	40

No statistical analyses for this end point

Secondary: Open-Label LT Period: Number of Subjects Achieving ACR 20 Response at Days 169, 729, 1261, and 1821

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End point title

Open-Label LT Period: Number of Subjects Achieving ACR 20 Response at Days 169, 729, 1261, and 1821

End point description

The ACR 20 definition of improvement is a 20% improvement from baseline in the number of tender and swollen joints, and a 20% improvement from baseline in 3 of the remaining 5 core set measures: subject global assessment of pain, subject global assessment of disease activity, physician global assessment of disease activity, subject assessment of physical function and acute phase reactant value (C-reactive protein). The analysis was performed in all the subjects who entered the LT period and received at least 1 dose of study drug during the LT period.

End point type

Secondary

End point timeframe

Days 169, 729, 1261, 1821

End point values	Subcutaneous (SC) Abatacept
Number of subjects analysed	1365
Units: Subjects
Day 169 (n=1357)	1087
Day 729 (n=1187)	973
Day 1261 (n=1068)	904
Day 1821 (n=421)	356

No statistical analyses for this end point

Secondary: Open-Label LT Period: Number of Subjects Achieving ACR 50 and ACR 70 Responses at Days 169, 729, 1261, 1821

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End point title

Open-Label LT Period: Number of Subjects Achieving ACR 50 and ACR 70 Responses at Days 169, 729, 1261, 1821

End point description

The ACR 50 definition of improvement is a 50% improvement from baseline in the number of tender and swollen joint counts, and a 50% improvement from baseline in 3 of the remaining 5 core set measures: subject global assessment of pain, subject global assessment of disease activity, physician global assessment of disease activity, subject assessment of physical function and acute phase reactant value (C-reactive protein). ACR 70 is defined similarly with 70% improvements from baseline for tender and swollen joint counts and 3 out of 5 core measures. All subjects who entered the LT period and received at least 1 dose of study drug during the LT period were summarized.

End point type

Secondary

End point timeframe

Days 169, 729, 1261, 1821

End point values	Subcutaneous (SC) Abatacept
Number of subjects analysed	1365
Units: Subjects
Day 169 ACR 50 (n=1362)	724
Day 729 ACR 50 (n=1185)	720
Day 1261 ACR 50(n=1069)	672
Day 1821 ACR 50 (n=423)	277
Day 169 ACR 70 (n=1362)	371
Day 729 ACR 70 (n=1186)	443
Day 1261 ACR 70 (n=1070)	438
Day 1821 ACR 70 (n=425)	191

No statistical analyses for this end point

Secondary: Open-Label LT Period: Mean Change From Baseline in Disease Activity Score in 28 Joints (DAS28) Using C-reactive Protein (CRP) at Days 169, 729, 1261, 1821

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End point title

Open-Label LT Period: Mean Change From Baseline in Disease Activity Score in 28 Joints (DAS28) Using C-reactive Protein (CRP) at Days 169, 729, 1261, 1821

End point description

The DAS28 index measures disease activity in rheumatoid arthritis and is a composite derived from the number of swollen/tender joints, laboratory tests of inflammation (C-reactive protein measured in mg/L), and subject assessment of global health (by marking a visual analog scale 100 mm line from "very good" to "very bad"). A higher DAS28 score indicates worse control of disease. High disease activity is > 5.1, low disease activity is < 3.2 and remission is < 2.6. A clinically significant response= decrease in DAS28 score of >1.2 from baseline. All subjects who entered the LT period and received at least 1 dose of study drug during the LT period were summarized.

End point type

Secondary

End point timeframe

Days 169, 729, 1261, 1821

End point values	Subcutaneous (SC) Abatacept
Number of subjects analysed	1365
Units: units on a scale
arithmetic mean (confidence interval 95%)
Day 169 (n=1353)	-2.65 (-2.71 to -2.58)
Day 729 (n=1181)	-2.94 (-3.01 to -2.86)
Day 1261 (n=1063)	-3.09 (-3.17 to -3)
Day 1821 (n=413)	-3.24 (-3.38 to -3.11)

No statistical analyses for this end point

Secondary: Open-Label LT Period: Number of Subjects Achieving DAS 28 Remission at Days 169, 729, 1261, 1821

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End point title

Open-Label LT Period: Number of Subjects Achieving DAS 28 Remission at Days 169, 729, 1261, 1821

End point description

The DAS28 index measures disease activity in rheumatoid arthritis and is a composite derived from the number of swollen/tender joints, laboratory tests of inflammation (C-reactive protein measured in mg/L), and subject assessment of global health (by marking a visual analog scale 100 mm line from "very good" to "very bad"). A higher DAS28 score indicates worse control of disease. High disease activity is > 5.1, low disease activity is < 3.2 and remission is < 2.6. All subjects who entered the LT period and received at least 1 dose of study drug during the LT period were summarised.

End point type

Secondary

End point timeframe

Days 169, 729, 1261, 1821

End point values	Subcutaneous (SC) Abatacept
Number of subjects analysed	1365
Units: Subjects
Day 169 (n=1355)	334
Day 729 (n=1183)	411
Day 1261 (n=1064)	425
Day 1821 (n=413)	169

No statistical analyses for this end point

Secondary: Open-Label LT Period: Number of Subjects Achieving DAS 28 Low Disease Activity (LDA) at Days 169, 729, 1261, 1821

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End point title

Open-Label LT Period: Number of Subjects Achieving DAS 28 Low Disease Activity (LDA) at Days 169, 729, 1261, 1821

End point description

The DAS28 index measures disease activity in rheumatoid arthritis and is a composite derived from the number of swollen/tender joints, laboratory tests of inflammation (C-reactive protein measured in mg/L), and subject assessment of global health (by marking a visual analog scale 100 mm line from "very good" to "very bad"). A higher DAS28 score indicates worse control of disease. High disease activity is > 5.1, low disease activity is < 3.2 and remission is < 2.6. All Subjects who entered the LT period and received at least 1 dose of study drug during the LT period were summarised.

End point type

Secondary

End point timeframe

Days 169, 729, 1261, 1821

End point values	Subcutaneous (SC) Abatacept
Number of subjects analysed	1365
Units: Subjects
Day 169 (n=1355)	553
Day 729 (n=1183)	600
Day 1261 (n=1064)	585
Day 1821 (n=413)	238

No statistical analyses for this end point

Secondary: Open-Label LT Period: Number of Subjects With HAQ-DI Response at Days 169, 729, 1261, 1821

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End point title

Open-Label LT Period: Number of Subjects With HAQ-DI Response at Days 169, 729, 1261, 1821

End point description

The disability section of the full HAQ includes 20 questions to assess physical function in 8 domains: dressing, arising, eating, walking, hygiene, reach, grip, and common activities. The domain questions are evaluated on a 4-point scale: 0=without any difficulty, 1=with some difficulty, 2=with much difficulty, 3=unable to do. HAQ-DI=sum of worst scores in each domain divided by the number of domains answered. HAQ-DI overall score ranges from a minimum of 0 to a maximum of 3.0. HAQ response was defined as an improvement (reduction) from baseline (Day 1) of at least 0.3 units in the HAQ score. All subjects who entered the LT period, received at least 1 dose of study drug during the LT period, and had HAD-QI scores at baseline and at specified days were summarised.

End point type

Secondary

End point timeframe

Days 169, 729, 1261, 1821

End point values	Subcutaneous (SC) Abatacept
Number of subjects analysed	1365
Units: Subjects
Day 169 (n=1364)	962
Day 729 (n=1190)	853
Day 1261 (n=1068)	780
Day 1821 (n=427)	315

No statistical analyses for this end point

Secondary: Open-Label LT Period: Number of Subjects With Death As Outcome, Serious Adverse Events (SAEs), Treatment-related SAEs, SAEs Leading to Discontinuation, Adverse Events (AEs), Treatment-related AEs, or AEs Leading to Discontinuation

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End point title

Open-Label LT Period: Number of Subjects With Death As Outcome, Serious Adverse Events (SAEs), Treatment-related SAEs, SAEs Leading to Discontinuation, Adverse Events (AEs), Treatment-related AEs, or AEs Leading to Discontinuation

End point description

AE=any new untoward medical event or worsening of a preexisting medical condition that does not necessarily have a causal relationship with this treatment. SAE=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, results in development of drug dependency or drug abuse, is an important medical event. Treatment-related SAE=possibly, probably, or certainly related to study drug. The analysis was performed in all the subjects who entered the LT Period and received at least 1 dose of study drug during the LT Period.

End point type

Secondary

End point timeframe

End of ST Period (Day 169) to last dose plus 85 days, up to 5 years (September 2014)

End point values	Subcutaneous (SC) Abatacept
Number of subjects analysed	1373
Units: Subjects
Death	41
SAE	353
Treatment-related SAE	88
SAEs leading to Discontinuation	73
Treatment-related AEs	632
AEs leading to Discontinuation	97

No statistical analyses for this end point

Secondary: Open-Label LT Period: Number of Subjects With Adverse Events (AEs) of Special Interest

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End point title

Open-Label LT Period: Number of Subjects With Adverse Events (AEs) of Special Interest

End point description

AE=any new untoward medical occurrence or worsening of a preexisting medical condition that does not necessarily have a causal relationship with this treatment. AEs of special interest are those AEs that may be associated with the use of immunomodulatory drugs: all infections, serious infections, and opportunistic infections; autoimmune disorders; malignancies; system injection reactions, and local injection site reactions. The analysis was performed in all the subjects who entered the LT Period and received at least 1 dose of study drug during the LT Period.

End point type

Secondary

End point timeframe

End of ST Period (Day 169) to last dose plus 85 days, up to 5 years (September 2014)

End point values	Subcutaneous (SC) Abatacept
Number of subjects analysed	1373
Units: Subjects
All Infections	962
Serious Infections	85
Infections leading to Discontinuation	25
Serious Infections leading to Discontinuation	16
Malignancies	56
Autoimmune Disorders	67
Local Injection Site Reactions	33
Systemic Injection Reactions	161

No statistical analyses for this end point

Secondary: Open-Label LT Period: Number of Subjects With Clinically Significant Abnormalities in Vital Sign Measurements

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End point title

Open-Label LT Period: Number of Subjects With Clinically Significant Abnormalities in Vital Sign Measurements

End point description

Vital sign assessments were performed in the LT period at 12-week intervals and at a yearly visit (at 16-week intervals) and, for subjects who withdrew from the study prematurely, 7 days after the last dose of SC abatacept. Vital signs included seated systolic blood pressure, seated diastolic blood pressure, temperature, and heart rate. Abnormalities were determined to be clinically significant by the investigator. The analysis was performed in all the subjects who entered the LT Period and received at least 1 dose of study drug during the LT Period.

End point type

Secondary

End point timeframe

End of ST Period (Day 169) to last dose plus 7 days, up to 5 years (September 2014)

End point values	Subcutaneous (SC) Abatacept
Number of subjects analysed	1373
Units: Subjects	0

No statistical analyses for this end point

Secondary: Open-Label LT Period: Number of Subjects With Clinically Significant Laboratory Abnormalities

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End point title

Open-Label LT Period: Number of Subjects With Clinically Significant Laboratory Abnormalities

End point description

Laboratory assessments were performed in the LT period at 12-week intervals and at a yearly visit and, for subjects who withdrew from the study prematurely, 7 days after the last dose of SC abatacept. Abnormalities were determined to be clinically significant by the investigator. The analysis was performed in all the subjects who entered the LT Period and received at least 1 dose of study drug during the LT Period.

End point type

Secondary

End point timeframe

End of ST Period (Day 169) to last dose plus 7 days, up to 5 years (September 2014)

End point values	Subcutaneous (SC) Abatacept
Number of subjects analysed	1373
Units: Subjects	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

First dose (Day 1) in ST period to last dose in LT period plus 85 days, up to 5 years (September 2014)

Adverse event reporting additional description

Population includes both Main Study and Anti-TNF Failure Sub-study. Sub-study was terminated early and subjects could enter LT Period of Main study.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.1

Reporting group title

IV Abatacept

Reporting group description

During the Main study Double Blind ST Period, subjects received IV abatacept infusions on Days 1, 15, 29, and every 28 days, thereafter for 6 months. A double-dummy design was used to protect the blind, thus, subjects also received SC injections of placebo (SC Placebo). An Anti-TNF Failure Sub-study was initiated (recruited separately from Main study) using the same treatment as the Main study in order to assess the immunogenicity and safety in the Anti-TNF Failure population. The Sub-study terminated due to low recruitment and subjects were permitted to roll into the LT Open Label Period. During the Open Label LT Period, subjects in both the Main Study and the Anti-TNF Failure Sub-study could switch to SC abatacept until the SC formulation became commercially available on a country basis or the Sponsor terminated the study.

Reporting group title

SC Abatacept

Reporting group description

During the Main Study Double Blind ST Period, subjects received 125 mg weekly SC abatacept injections for 6 months (with an IV abatacept loading dose on Day 1, based on weight). A double-dummy design was used to protect the blind, thus, subjects also received IV injections of placebo (IV Placebo) with the exception that on Day 1 a loading dose of IV abatacept replaced the IV Placebo treatment. An Anti-TNF Failure Sub-study was initiated (recruited separately from Main study) using the same treatment as the Main study in order to assess the immunogenicity and safety in the Anti-TNF Failure population. The Sub-study terminated due to low recruitment and subjects were permitted to roll into the LT Open Label Period. During the Open Label LT Period, subjects in both the Main Study and the Anti-TNF Failure Sub-study could continue SC abatacept until the SC formulation became commercially available on a country basis or the Sponsor terminated the study.

Serious adverse events	IV Abatacept	SC Abatacept
Total subjects affected by serious adverse events
subjects affected / exposed	206 / 731 (28.18%)	199 / 744 (26.75%)
number of deaths (all causes)	22	19
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cervix carcinoma stage 0
subjects affected / exposed	2 / 731 (0.27%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Colon cancer metastatic
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intraductal proliferative breast lesion
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Invasive ductal breast carcinoma
subjects affected / exposed	2 / 731 (0.27%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Lung neoplasm malignant
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metastases to peritoneum
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Ovarian epithelial cancer
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	2 / 731 (0.27%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Anal cancer
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Breast cancer
subjects affected / exposed	1 / 731 (0.14%)	3 / 744 (0.40%)
occurrences causally related to treatment / all	1 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Renal cell carcinoma
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Small cell lung cancer
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
B-cell lymphoma
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fibrous histiocytoma
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Invasive lobular breast carcinoma
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lung adenocarcinoma
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Non-Hodgkin's lymphoma
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	7 / 731 (0.96%)	2 / 744 (0.27%)
occurrences causally related to treatment / all	0 / 7	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cervix carcinoma
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fibroadenoma of breast
subjects affected / exposed	0 / 731 (0.00%)	2 / 744 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Mucoepidermoid carcinoma of salivary gland
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Non-small cell lung cancer
subjects affected / exposed	2 / 731 (0.27%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatic carcinoma
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Uterine leiomyoma
subjects affected / exposed	2 / 731 (0.27%)	4 / 744 (0.54%)
occurrences causally related to treatment / all	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Biliary cancer metastatic
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Chronic myelomonocytic leukaemia
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thyroid neoplasm
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Adenosquamous cell lung cancer
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bladder cancer
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Colon cancer
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diffuse large B-cell lymphoma
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neuroma
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gallbladder cancer metastatic
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Papillary thyroid cancer
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	2 / 731 (0.27%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal cancer
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Squamous cell carcinoma of skin
subjects affected / exposed	2 / 731 (0.27%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Uterine cancer
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Hypertensive crisis
subjects affected / exposed	2 / 731 (0.27%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertensive emergency
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Iliac artery occlusion
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertension
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Angiopathy
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	1 / 731 (0.14%)	3 / 744 (0.40%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Venous thrombosis
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Aortic aneurysm
subjects affected / exposed	2 / 731 (0.27%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vasculitis
subjects affected / exposed	2 / 731 (0.27%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Circulatory collapse
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Surgical and medical procedures
Mammoplasty
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (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
Chest pain
subjects affected / exposed	6 / 731 (0.82%)	4 / 744 (0.54%)
occurrences causally related to treatment / all	1 / 7	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Adhesion
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chest discomfort
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Embedded device
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Asthenia
subjects affected / exposed	1 / 731 (0.14%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sudden death
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Device failure
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Device malfunction
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Incarcerated hernia
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Multi-organ failure
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Pyrexia
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pacemaker generated arrhythmia
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sudden cardiac death
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	1 / 731 (0.14%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Pelvic haematoma
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Adenomyosis
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Endometriosis
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metrorrhagia
subjects affected / exposed	2 / 731 (0.27%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rectocele
subjects affected / exposed	1 / 731 (0.14%)	2 / 744 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Uterine prolapse
subjects affected / exposed	1 / 731 (0.14%)	2 / 744 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Endometrial hyperplasia
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Menorrhagia
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ovarian mass
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cervical dysplasia
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vaginal prolapse
subjects affected / exposed	2 / 731 (0.27%)	2 / 744 (0.27%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cystocele
subjects affected / exposed	2 / 731 (0.27%)	3 / 744 (0.40%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Ovarian cyst
subjects affected / exposed	1 / 731 (0.14%)	2 / 744 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary toxicity
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Acute respiratory failure
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary bulla
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	2 / 731 (0.27%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 731 (0.00%)	2 / 744 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 2
Haemoptysis
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary fibrosis
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Asthma
subjects affected / exposed	2 / 731 (0.27%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Aspiration
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Dyspnoea
subjects affected / exposed	2 / 731 (0.27%)	6 / 744 (0.81%)
occurrences causally related to treatment / all	1 / 2	2 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	1 / 731 (0.14%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis chronic
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemothorax
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Lung disorder
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oropharyngeal pain
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Tracheal stenosis
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Mental status changes
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Drug abuse
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Anxiety
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Schizophrenia
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Suicidal ideation
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Enterococcus test positive
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic enzyme increased
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Ankle fracture
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cervical vertebral fracture
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Contusion
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fall
subjects affected / exposed	1 / 731 (0.14%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	1 / 731 (0.14%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Joint injury
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Wound
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dislocation of vertebra
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Joint dislocation
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Laceration
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Limb traumatic amputation
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lumbar vertebral fracture
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Stress fracture
subjects affected / exposed	1 / 731 (0.14%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Median nerve injury
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Overdose
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	3 / 731 (0.41%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0
Multiple injuries
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural pain
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pubis fracture
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tibia fracture
subjects affected / exposed	0 / 731 (0.00%)	2 / 744 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Post-traumatic neck syndrome
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Thoracic vertebral fracture
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	2 / 731 (0.27%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	3 / 731 (0.41%)	2 / 744 (0.27%)
occurrences causally related to treatment / all	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	1 / 731 (0.14%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Foot fracture
subjects affected / exposed	1 / 731 (0.14%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Alcohol poisoning
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Limb injury
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	2 / 731 (0.27%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ulna fracture
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Animal bite
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac function disturbance postoperative
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Incisional hernia
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal fracture
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Wrist fracture
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Congenital, familial and genetic disorders
Metatarsus primus varus
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial septal defect
subjects affected / exposed	2 / 731 (0.27%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	1 / 731 (0.14%)	2 / 744 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	2 / 731 (0.27%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Ventricular tachycardia
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 731 (0.14%)	3 / 744 (0.40%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	1 / 731 (0.14%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	2 / 731 (0.27%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	1 / 731 (0.14%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sinus tachycardia
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	2 / 731 (0.27%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Coronary artery occlusion
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Acute left ventricular failure
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Cardiac failure
subjects affected / exposed	0 / 731 (0.00%)	2 / 744 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 2
Cardiopulmonary failure
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	1 / 731 (0.14%)	5 / 744 (0.67%)
occurrences causally related to treatment / all	0 / 1	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 2
Myocardial infarction
subjects affected / exposed	5 / 731 (0.68%)	11 / 744 (1.48%)
occurrences causally related to treatment / all	0 / 6	0 / 12
deaths causally related to treatment / all	0 / 2	0 / 0
Myocardial ischaemia
subjects affected / exposed	1 / 731 (0.14%)	3 / 744 (0.40%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	1 / 731 (0.14%)	2 / 744 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Brain stem stroke
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Multiple sclerosis
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sciatica
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	2 / 731 (0.27%)	4 / 744 (0.54%)
occurrences causally related to treatment / all	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Basilar migraine
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Coma
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoxic-ischaemic encephalopathy
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subarachnoid haemorrhage
subjects affected / exposed	2 / 731 (0.27%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Cerebral artery embolism
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebrovascular disorder
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Quadriparesis
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Syncope
subjects affected / exposed	2 / 731 (0.27%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Carotid artery aneurysm
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Demyelinating polyneuropathy
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Headache
subjects affected / exposed	3 / 731 (0.41%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Polyneuropathy
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	2 / 731 (0.27%)	2 / 744 (0.27%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral ischaemia
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	1 / 731 (0.14%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hydrocephalus
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoaesthesia
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Radiculitis lumbosacral
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Amyotrophic lateral sclerosis
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cervical cord compression
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Convulsion
subjects affected / exposed	1 / 731 (0.14%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Hypersplenism
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Splenomegaly
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anaemia
subjects affected / exposed	2 / 731 (0.27%)	3 / 744 (0.40%)
occurrences causally related to treatment / all	2 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Necrotising granulomatous lymphadenitis
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Autoimmune haemolytic anaemia
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Iron deficiency anaemia
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	2 / 731 (0.27%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Ear and labyrinth disorders
Deafness
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vertigo
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Meniere's disease
subjects affected / exposed	2 / 731 (0.27%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Keratitis
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Macular fibrosis
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blindness
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Uveitis
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Retinal infarction
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cataract
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	2 / 731 (0.27%)	4 / 744 (0.54%)
occurrences causally related to treatment / all	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric ulcer haemorrhage
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatic cyst
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis ischaemic
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Incarcerated inguinal hernia
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Large intestine perforation
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	1 / 731 (0.14%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Upper gastrointestinal haemorrhage
subjects affected / exposed	1 / 731 (0.14%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal distension
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric ulcer
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastritis
subjects affected / exposed	2 / 731 (0.27%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal ischaemia
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhoids
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	2 / 731 (0.27%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal angiodysplasia haemorrhagic
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mouth ulceration
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haematochezia
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	0 / 731 (0.00%)	3 / 744 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	2 / 731 (0.27%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Acute abdomen
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Aphthous stomatitis
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Crohn's disease
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	1 / 731 (0.14%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Enterocele
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis ulcerative
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hernial eventration
subjects affected / exposed	1 / 731 (0.14%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal infarction
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Pancreatitis
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Jaundice hepatocellular
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	3 / 731 (0.41%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis chronic
subjects affected / exposed	1 / 731 (0.14%)	4 / 744 (0.54%)
occurrences causally related to treatment / all	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic steatosis
subjects affected / exposed	1 / 731 (0.14%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Drug-induced liver injury
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Biliary colic
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	4 / 731 (0.55%)	2 / 744 (0.27%)
occurrences causally related to treatment / all	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	2 / 731 (0.27%)	2 / 744 (0.27%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Skin wrinkling
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psoriasis
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urticaria
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Hydronephrosis
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	3 / 731 (0.41%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal injury
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure acute
subjects affected / exposed	3 / 731 (0.41%)	2 / 744 (0.27%)
occurrences causally related to treatment / all	1 / 3	1 / 2
deaths causally related to treatment / all	1 / 1	0 / 1
Stress urinary incontinence
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bladder prolapse
subjects affected / exposed	1 / 731 (0.14%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Calculus bladder
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal impairment
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Facet joint syndrome
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Ligament disorder
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Joint contracture
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal osteoarthritis
subjects affected / exposed	1 / 731 (0.14%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	2 / 731 (0.27%)	2 / 744 (0.27%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Lumbar spinal stenosis
subjects affected / exposed	1 / 731 (0.14%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Osteoporotic fracture
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal column stenosis
subjects affected / exposed	1 / 731 (0.14%)	2 / 744 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Costochondritis
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arthralgia
subjects affected / exposed	1 / 731 (0.14%)	2 / 744 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Foot deformity
subjects affected / exposed	3 / 731 (0.41%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	12 / 731 (1.64%)	16 / 744 (2.15%)
occurrences causally related to treatment / all	0 / 15	0 / 17
deaths causally related to treatment / all	0 / 0	0 / 0
Pathological fracture
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Synovitis
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arthritis
subjects affected / exposed	1 / 731 (0.14%)	3 / 744 (0.40%)
occurrences causally related to treatment / all	1 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Joint range of motion decreased
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neck pain
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rotator cuff syndrome
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Back pain
subjects affected / exposed	2 / 731 (0.27%)	3 / 744 (0.40%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	2 / 731 (0.27%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rheumatoid arthritis
subjects affected / exposed	12 / 731 (1.64%)	14 / 744 (1.88%)
occurrences causally related to treatment / all	0 / 12	0 / 16
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Appendicitis perforated
subjects affected / exposed	1 / 731 (0.14%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arthritis infective
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Breast abscess
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	1 / 731 (0.14%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infective tenosynovitis
subjects affected / exposed	2 / 731 (0.27%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pelvic inflammatory disease
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Salpingitis
subjects affected / exposed	0 / 731 (0.00%)	2 / 744 (0.27%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal sepsis
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Urosepsis
subjects affected / exposed	1 / 731 (0.14%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Encephalitis
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Localised infection
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peritoneal tuberculosis
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	3 / 731 (0.41%)	3 / 744 (0.40%)
occurrences causally related to treatment / all	0 / 3	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	1 / 731 (0.14%)	2 / 744 (0.27%)
occurrences causally related to treatment / all	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	3 / 731 (0.41%)	2 / 744 (0.27%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
H1N1 influenza
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lobar pneumonia
subjects affected / exposed	0 / 731 (0.00%)	2 / 744 (0.27%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Mastitis
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tuberculosis
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Varicella
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal sepsis
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Abscess oral
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arthritis bacterial
subjects affected / exposed	2 / 731 (0.27%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	2 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Atypical pneumonia
subjects affected / exposed	1 / 731 (0.14%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchopneumonia
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infectious pleural effusion
subjects affected / exposed	0 / 731 (0.00%)	2 / 744 (0.27%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Ludwig angina
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oral candidiasis
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Septic shock
subjects affected / exposed	1 / 731 (0.14%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Viral hepatitis carrier
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	12 / 731 (1.64%)	8 / 744 (1.08%)
occurrences causally related to treatment / all	9 / 13	4 / 8
deaths causally related to treatment / all	1 / 3	2 / 3
Pneumonia staphylococcal
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Sinusitis
subjects affected / exposed	0 / 731 (0.00%)	2 / 744 (0.27%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Wound infection
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	2 / 731 (0.27%)	3 / 744 (0.40%)
occurrences causally related to treatment / all	3 / 3	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal infection
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Herpes zoster
subjects affected / exposed	2 / 731 (0.27%)	2 / 744 (0.27%)
occurrences causally related to treatment / all	2 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	1 / 731 (0.14%)	2 / 744 (0.27%)
occurrences causally related to treatment / all	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Sinusitis fungal
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Soft tissue infection
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Staphylococcal infection
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	7 / 731 (0.96%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	7 / 9	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic sinusitis
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary tuberculosis
subjects affected / exposed	0 / 731 (0.00%)	3 / 744 (0.40%)
occurrences causally related to treatment / all	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	1 / 1
Sepsis
subjects affected / exposed	1 / 731 (0.14%)	3 / 744 (0.40%)
occurrences causally related to treatment / all	1 / 1	1 / 3
deaths causally related to treatment / all	1 / 1	0 / 0
Osteomyelitis
subjects affected / exposed	1 / 731 (0.14%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pelvic abscess
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	2 / 731 (0.27%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	1 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Subcutaneous abscess
subjects affected / exposed	1 / 731 (0.14%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tetanus
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Viral infection
subjects affected / exposed	1 / 731 (0.14%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Diabetic ketoacidosis
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Obesity
subjects affected / exposed	2 / 731 (0.27%)	0 / 744 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dehydration
subjects affected / exposed	1 / 731 (0.14%)	2 / 744 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolic acidosis
subjects affected / exposed	0 / 731 (0.00%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Diabetes mellitus
subjects affected / exposed	1 / 731 (0.14%)	1 / 744 (0.13%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	IV Abatacept	SC Abatacept
Total subjects affected by non serious adverse events
subjects affected / exposed	544 / 731 (74.42%)	567 / 744 (76.21%)
Vascular disorders
Hypertension
subjects affected / exposed	85 / 731 (11.63%)	96 / 744 (12.90%)
occurrences all number	103	114
Nervous system disorders
Dizziness
subjects affected / exposed	40 / 731 (5.47%)	37 / 744 (4.97%)
occurrences all number	52	43
Headache
subjects affected / exposed	88 / 731 (12.04%)	86 / 744 (11.56%)
occurrences all number	156	120
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	26 / 731 (3.56%)	55 / 744 (7.39%)
occurrences all number	65	32
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	27 / 731 (3.69%)	39 / 744 (5.24%)
occurrences all number	37	46
Abdominal pain upper
subjects affected / exposed	47 / 731 (6.43%)	43 / 744 (5.78%)
occurrences all number	53	45
Diarrhoea
subjects affected / exposed	89 / 731 (12.18%)	96 / 744 (12.90%)
occurrences all number	128	129
Gastritis
subjects affected / exposed	30 / 731 (4.10%)	40 / 744 (5.38%)
occurrences all number	36	43
Nausea
subjects affected / exposed	53 / 731 (7.25%)	79 / 744 (10.62%)
occurrences all number	74	96
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	74 / 731 (10.12%)	72 / 744 (9.68%)
occurrences all number	108	91
Psychiatric disorders
Depression
subjects affected / exposed	40 / 731 (5.47%)	37 / 744 (4.97%)
occurrences all number	42	40
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	76 / 731 (10.40%)	76 / 744 (10.22%)
occurrences all number	99	95
Infections and infestations
Bronchitis
subjects affected / exposed	120 / 731 (16.42%)	109 / 744 (14.65%)
occurrences all number	182	183
Gastroenteritis
subjects affected / exposed	48 / 731 (6.57%)	60 / 744 (8.06%)
occurrences all number	57	72
Influenza
subjects affected / exposed	55 / 731 (7.52%)	51 / 744 (6.85%)
occurrences all number	82	74
Nasopharyngitis
subjects affected / exposed	143 / 731 (19.56%)	149 / 744 (20.03%)
occurrences all number	250	248
Pharyngitis
subjects affected / exposed	80 / 731 (10.94%)	74 / 744 (9.95%)
occurrences all number	127	109
Sinusitis
subjects affected / exposed	50 / 731 (6.84%)	69 / 744 (9.27%)
occurrences all number	77	122
Upper respiratory tract infection
subjects affected / exposed	131 / 731 (17.92%)	130 / 744 (17.47%)
occurrences all number	205	228
Urinary tract infection
subjects affected / exposed	133 / 731 (18.19%)	150 / 744 (20.16%)
occurrences all number	210	243

More information

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Were there any global substantial amendments to the protocol? Yes

19 Dec 2007

The target percentage for subcutaneous abatacept was increased to preserve the intravenous abatacept benefit over placebo to 70%. In accordance, the following revisions were made: • non-inferiority margin reduced to -7.5 • total sample size increased to 1440 • randomization ratio changed to 1:1.

25 Apr 2008

The purpose of this amendment was further clarification on target population to be methotrexate inadequate responders, introducing a limit of subjects with prior exposure to anti-TNF therapy to 10% of the study population, implementing stratification by weight and shifting the collection interval for Pharmacokinetic (PK) samples of the Full PK Profile.

25 Sep 2008

Incorporates changes in the main protocol that result from the implementation of the anti-TNF failure substudy at selected sites, like the increase of the total sample size. In addition, some minor clarifications and updates on the protocol document were added.

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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Double-blind Period: Number of Subjects Achieving American College of Rheumatology (ACR) 20 Response

Primary: Double-blind Period: Number of Subjects Achieving American College of Rheumatology (ACR) 20 Response

Primary: Anti-TNF Failure Sub-study Double-blind Period: Number of Subjects With Positive Anti-abatacept or Anti-Cytotoxic T Lymphocyte Antigen 4-T Cell (CTLA4-T) Response in Anti-TNF Failure Population

Primary: Anti-TNF Failure Sub-study Double-blind Period: Number of Subjects With Positive Anti-abatacept or Anti-Cytotoxic T Lymphocyte Antigen 4-T Cell (CTLA4-T) Response in Anti-TNF Failure Population

Primary: Anti-TNF Failure Sub-study Double-blind Period: Number of Subjects Achieving American College of Rheumatology (ACR) 20 Response

Primary: Anti-TNF Failure Sub-study Double-blind Period: Number of Subjects Achieving American College of Rheumatology (ACR) 20 Response

Secondary: Double-blind Period: Number of Subjects Achieving ACR 50 and ACR 70 Responses

Secondary: Double-blind Period: Number of Subjects Achieving ACR 50 and ACR 70 Responses

Secondary: Double-blind Period: Mean Baseline Health Assessment Questionnaire Disability Index (HAQ-DI) for Subjects With Assessments

Secondary: Double-blind Period: Mean Baseline Health Assessment Questionnaire Disability Index (HAQ-DI) for Subjects With Assessments

Secondary: Double-blind Period: Adjusted Mean Change From Baseline to Day 169 in HAQ-DI

Secondary: Double-blind Period: Adjusted Mean Change From Baseline to Day 169 in HAQ-DI

Secondary: Double-blind Period: Number of Subjects Achieving Clinically Meaningful HAQ-DI Response at Day 169

Secondary: Double-blind Period: Number of Subjects Achieving Clinically Meaningful HAQ-DI Response at Day 169

Secondary: Double-blind Period: Number of Subjects With Death As Outcome, Serious Adverse Events (SAEs), Treatment- related SAEs, SAEs Leading to Discontinuation, Adverse Events (AEs), Treatment-related AEs, or AEs Leading to Discontinuation

Secondary: Double-blind Period: Number of Subjects With Death As Outcome, Serious Adverse Events (SAEs), Treatment- related SAEs, SAEs Leading to Discontinuation, Adverse Events (AEs), Treatment-related AEs, or AEs Leading to Discontinuation

Secondary: Anti-TNF Failure Sub-study Double-blind Period: Number of Subjects With SAEs, AEs Leading to Discontinuation or Who Died

Secondary: Anti-TNF Failure Sub-study Double-blind Period: Number of Subjects With SAEs, AEs Leading to Discontinuation or Who Died

Secondary: Double-blind Period: Number of Subjects With AEs of Special Interest

Secondary: Double-blind Period: Number of Subjects With AEs of Special Interest

Secondary: Double-blind Period: Number of Subjects With Clinically Significant Abnormalities in Vital Sign Measurements

Secondary: Double-blind Period: Number of Subjects With Clinically Significant Abnormalities in Vital Sign Measurements

Secondary: Double-blind Period: Number of Subjects With Hematology Laboratory Test Results Meeting the Criteria for Marked Abnormality

Secondary: Double-blind Period: Number of Subjects With Hematology Laboratory Test Results Meeting the Criteria for Marked Abnormality

Secondary: Double-blind Period: Number of Subjects With Liver Function Laboratory Test Results Meeting the Criteria for Marked Abnormality

Secondary: Double-blind Period: Number of Subjects With Liver Function Laboratory Test Results Meeting the Criteria for Marked Abnormality

Secondary: Double-blind Period: Number of Subjects With Electrolyte Laboratory Test Results Meeting the Criteria for Marked Abnormality

Secondary: Double-blind Period: Number of Subjects With Electrolyte Laboratory Test Results Meeting the Criteria for Marked Abnormality

Secondary: Double-blind Period: Minimum Observed Serum Concentration of Abatacept

Secondary: Double-blind Period: Minimum Observed Serum Concentration of Abatacept

Secondary: Anti-TNF Failure Sub-study Double-blind Period: Minimum Observed Serum Concentration (Cmin) of Abatacept

Secondary: Anti-TNF Failure Sub-study Double-blind Period: Minimum Observed Serum Concentration (Cmin) of Abatacept

Secondary: Double-blind Period: Maximum Observed Serum Concentration of Abatacept

Secondary: Double-blind Period: Maximum Observed Serum Concentration of Abatacept

Secondary: Anti-TNF Failure Substudy Double Blind Period: Geometric Mean Maximum Observed Serum Concentration of Abatacept

Secondary: Anti-TNF Failure Substudy Double Blind Period: Geometric Mean Maximum Observed Serum Concentration of Abatacept

Secondary: Double-blind Period: Area Under The Curve In A Dose Interval (AUC TAU) of Abatacept

Secondary: Double-blind Period: Area Under The Curve In A Dose Interval (AUC TAU) of Abatacept

Secondary: Anti-TNF Failure Sub-study Double Blind Period: Area Under The Curve In A Dose Interval (AUC TAU) of Abatacept

Secondary: Anti-TNF Failure Sub-study Double Blind Period: Area Under The Curve In A Dose Interval (AUC TAU) of Abatacept

Secondary: Double-blind Period: Number of Subjects With Positive Anti-abatacept or Anti-Cytotoxic T Lymphocyte Antigen 4-T Cell (CTLA4-T) Responses Over Time by Enzyme Linked Immunoabsorbant Assay (ELISA)

Secondary: Double-blind Period: Number of Subjects With Positive Anti-abatacept or Anti-Cytotoxic T Lymphocyte Antigen 4-T Cell (CTLA4-T) Responses Over Time by Enzyme Linked Immunoabsorbant Assay (ELISA)

Secondary: Double-blind Period: Time-matched Median Percent Change From Baseline in Levels of Serum C-reactive Protein Over the Short-term Period

Secondary: Double-blind Period: Time-matched Median Percent Change From Baseline in Levels of Serum C-reactive Protein Over the Short-term Period

Secondary: Double-blind Period: Number of Subjects With Positive Anti-abatacept Responses Over Time by Electrochemiluminescence Immunoassay

Secondary: Double-blind Period: Number of Subjects With Positive Anti-abatacept Responses Over Time by Electrochemiluminescence Immunoassay

Secondary: Double-blind Period: Number of Subjects Seroconverting by Day 169 According to Status (Negative or Positive) at Baseline

Secondary: Double-blind Period: Number of Subjects Seroconverting by Day 169 According to Status (Negative or Positive) at Baseline

Secondary: Open-Label LT Period: Number of Subjects Achieving ACR 20 Response at Days 169, 729, 1261, and 1821

Secondary: Open-Label LT Period: Number of Subjects Achieving ACR 20 Response at Days 169, 729, 1261, and 1821

Secondary: Open-Label LT Period: Number of Subjects Achieving ACR 50 and ACR 70 Responses at Days 169, 729, 1261, 1821

Secondary: Open-Label LT Period: Number of Subjects Achieving ACR 50 and ACR 70 Responses at Days 169, 729, 1261, 1821

Secondary: Open-Label LT Period: Mean Change From Baseline in Disease Activity Score in 28 Joints (DAS28) Using C-reactive Protein (CRP) at Days 169, 729, 1261, 1821

Secondary: Open-Label LT Period: Mean Change From Baseline in Disease Activity Score in 28 Joints (DAS28) Using C-reactive Protein (CRP) at Days 169, 729, 1261, 1821

Secondary: Open-Label LT Period: Number of Subjects Achieving DAS 28 Remission at Days 169, 729, 1261, 1821

Secondary: Open-Label LT Period: Number of Subjects Achieving DAS 28 Remission at Days 169, 729, 1261, 1821

Secondary: Open-Label LT Period: Number of Subjects Achieving DAS 28 Low Disease Activity (LDA) at Days 169, 729, 1261, 1821

Secondary: Open-Label LT Period: Number of Subjects Achieving DAS 28 Low Disease Activity (LDA) at Days 169, 729, 1261, 1821

Secondary: Open-Label LT Period: Number of Subjects With HAQ-DI Response at Days 169, 729, 1261, 1821

Secondary: Open-Label LT Period: Number of Subjects With HAQ-DI Response at Days 169, 729, 1261, 1821

Secondary: Open-Label LT Period: Number of Subjects With Death As Outcome, Serious Adverse Events (SAEs), Treatment-related SAEs, SAEs Leading to Discontinuation, Adverse Events (AEs), Treatment-related AEs, or AEs Leading to Discontinuation

Secondary: Open-Label LT Period: Number of Subjects With Death As Outcome, Serious Adverse Events (SAEs), Treatment-related SAEs, SAEs Leading to Discontinuation, Adverse Events (AEs), Treatment-related AEs, or AEs Leading to Discontinuation

Secondary: Open-Label LT Period: Number of Subjects With Adverse Events (AEs) of Special Interest

Secondary: Open-Label LT Period: Number of Subjects With Adverse Events (AEs) of Special Interest

Secondary: Open-Label LT Period: Number of Subjects With Clinically Significant Abnormalities in Vital Sign Measurements

Secondary: Open-Label LT Period: Number of Subjects With Clinically Significant Abnormalities in Vital Sign Measurements

Secondary: Open-Label LT Period: Number of Subjects With Clinically Significant Laboratory Abnormalities

Secondary: Open-Label LT Period: Number of Subjects With Clinically Significant Laboratory Abnormalities

Adverse events

Adverse events

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