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Clinical Trial Results:
A Phase 3B, Randomized, Double-Blind Clinical Trial to Evaluate the Efficacy and Safety of Abatacept SC in Combination with Methotrexate Compared to Methotrexate Monotherapy in Achieving Clinical Remission in Adults with Early Rheumatoid Arthritis who are Methotrexate Naive

Summary
EudraCT number	2015-001275-50
Trial protocol	CZ AT DE GB HU SE FR FI ES NL RO IT
Global end of trial date	19 Mar 2020

Results information
Results version number	v1(current)
This version publication date	04 Apr 2021
First version publication date	04 Apr 2021
Other versions

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

IM101-550

ISRCTN number

-

US NCT number

-

WHO universal trial number (UTN)

-

Sponsor organisation name

Bristol-Myers Squibb

Sponsor organisation address

Chaussée de la Hulpe 185, Brussels, Belgium, 1170

Public contact

EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, clinical.trials@bms.com

Scientific contact

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

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

No

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

No

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

No

Analysis stage

Final

Date of interim/final analysis

21 Aug 2020

Is this the analysis of the primary completion data?

Yes

Primary completion date

16 Jan 2017

Global end of trial reached?

Yes

Global end of trial date

19 Mar 2020

Was the trial ended prematurely?

No

Main objective of the trial

The primary objective for this study is to compare the clinical efficacy of weekly abatacept in combination with MTX to MTX alone in achieving Remission, defined as SDAI ≤ 3.3, at Week 24.

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

31 Aug 2015

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 141

Country: Number of subjects enrolled

Australia: 23

Country: Number of subjects enrolled

Austria: 3

Country: Number of subjects enrolled

Brazil: 110

Country: Number of subjects enrolled

Canada: 24

Country: Number of subjects enrolled

Colombia: 66

Country: Number of subjects enrolled

Finland: 4

Country: Number of subjects enrolled

France: 14

Country: Number of subjects enrolled

Hungary: 40

Country: Number of subjects enrolled

Israel: 15

Country: Number of subjects enrolled

Italy: 18

Country: Number of subjects enrolled

Korea, Republic of: 16

Country: Number of subjects enrolled

Monaco: 4

Country: Number of subjects enrolled

Mexico: 154

Country: Number of subjects enrolled

Peru: 59

Country: Number of subjects enrolled

Poland: 41

Country: Number of subjects enrolled

Qatar: 4

Country: Number of subjects enrolled

Romania: 1

Country: Number of subjects enrolled

Russian Federation: 40

Country: Number of subjects enrolled

Singapore: 4

Country: Number of subjects enrolled

Sweden: 7

Country: Number of subjects enrolled

United States: 239

Country: Number of subjects enrolled

Chile: 70

Country: Number of subjects enrolled

Czechia: 39

Country: Number of subjects enrolled

Germany: 69

Country: Number of subjects enrolled

Spain: 25

Country: Number of subjects enrolled

United Kingdom: 22

Country: Number of subjects enrolled

Japan: 124

Country: Number of subjects enrolled

Taiwan: 19

Country: Number of subjects enrolled

South Africa: 63

Worldwide total number of subjects

1458

EEA total number of subjects

261

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

1254

From 65 to 84 years

202

85 years and over

2

Subject disposition

Top of page

Recruitment details

-

Screening details

994 treated in the induction period (IP). 184 from IP randomized and treated in De-Escalation (DeE), 685 treated in the Open Label (OL) and 120 treated in the Open Label Extension (OLE) period. Subjects (pt) in IP could move to the OL period after IP completion or through early IP escape. PT from DeE could transfer to OL or to OLE.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Combination Therapy: Abatacept + Methotrexate (Cohort 1, IP)

Arm description

Abatacept 125 mg subcutaneous injection once per week + Methotrexate at least 15mg per week tablet or capsule orally once per week

Arm type

Experimental

Investigational medicinal product name

Abatacept

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

SC 125mg in 1ml pre-filled syringes

Investigational medicinal product name

Methotrexate

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

2.5 mg Tablet

Placebo + Methotrexate (Cohort 1, IP)

Arm description

Placebo of Abatacept 125 mg subcutaneous injection once per week + Methotrexate at least 15mg per week tablet or capsule orally once per week

Arm type

Placebo

Investigational medicinal product name

Abatacept

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

SC placebo in 1ml pre-filled syringes

Investigational medicinal product name

Methotrexate

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

2.5 mg Tablet

Combination Therapy: Abatacept + Methotrexate (Cohort 2, IP)

Arm description

Active abatacept SC (125 mg) weekly + methotrexate weekly

Arm type

Experimental

Investigational medicinal product name

Methotrexate

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

2.5 mg Tablet

Investigational medicinal product name

Abatacept

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

SC 125mg in 1ml pre-filled syringes

Number of subjects in period 1 ^[1]	Combination Therapy: Abatacept + Methotrexate (Cohort 1, IP)	Placebo + Methotrexate (Cohort 1, IP)	Combination Therapy: Abatacept + Methotrexate (Cohort 2, IP)
Started	451	301	242
Induction to Open Label (OL)	289 ^[2]	196 ^[3]	147 ^[4]
Early Escaped to Open Label	10 ^[5]	21 ^[6]	8 ^[7]
Induction to De-Escalation (DeE)	94 ^[8]	37 ^[9]	53 ^[10]
Completed	388	233	201
Not completed	63	68	41
Withdrawal of Consent	11	10	3
Adverse event, serious fatal	1	1	-
No Longer Meets Study Criteria	2	3	-
Poor/Non-Compliance	3	2	3
Not Disclosed	1	-	2
Adverse event, non-fatal	18	8	14
Pregnancy	2	-	-
Lost to follow-up	3	6	4
Subject Request to Discontinue	11	3	6
Lack of efficacy	11	35	9

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: 994 subjects enrolled and treated
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: This represents subjects who transitioned to DeEscalation or Open label periods
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: This represents subjects who transitioned to DeEscalation or Open label periods
[4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: This represents subjects who transitioned to DeEscalation or Open label periods
[5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: This represents subjects who transitioned to DeEscalation or Open label periods
[6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: This represents subjects who transitioned to DeEscalation or Open label periods
[7] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: This represents subjects who transitioned to DeEscalation or Open label periods
[8] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: This represents subjects who transitioned to DeEscalation or Open label periods
[9] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: This represents subjects who transitioned to DeEscalation or Open label periods
[10] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: This represents subjects who transitioned to DeEscalation or Open label periods

Baseline characteristics

Top of page

Reporting group title

Overall Study

Reporting group description

Inclusive of all treatments, all periods

Reporting group values	Overall Study	Total
Number of subjects	994	994
Age categorical
Units: Subjects
Adults (18-64 years)	865	865
From 65-84 years	129	129
Age Continuous
Units: years
arithmetic mean (standard deviation)	49.1 ± 13.17	-
Sex: Female, Male
Units: Participants
Female	781	781
Male	213	213
Race
Units: Subjects
WHITE	698	698
BLACK/AFRICAN AMERICAN	43	43
AMERICAN INDIAN/ALASKA NATIVE	4	4
ASIAN	140	140
RACE - OTHER/ NOT REPORTED	109	109
Ethnicity
Units: Subjects
Hispanic or Latino	22	22
Not Hispanic or Latino	112	112
Ethnicity not reported	860	860
MODIFIED SHARP/VAN DER HEIJDE TOTAL SCORE (mTSS)
The Modified Total Sharp Score (mTSS) is calculated as the bilateral sum of erosion and Joint Space Narrowing (JSN) scores across all joints of the hands and feet.The score range for mTSS is 0-448. Higher scores indicate more joint damage.
Units: Scores on a scale
arithmetic mean (standard deviation)	11.08 ± 17.839	-
Tender Joints - 28
number of painful joints from 28 joints
Units: Joint Count
arithmetic mean (standard deviation)	13.4 ± 6.76	-
Swollen Joints - 28
number of swollen joints from 28 joints
Units: Joint Count
arithmetic mean (standard deviation)	10.3 ± 5.77	-
Subject global assessment of disease activity
Subject’s global assessment of disease activity by using a Visual Analog Scale (VAS). The scale ranges from 0 mm to 100 mm, [0 mm=no pain to 100 mm=worst possible pain]
Units: mm
arithmetic mean (standard deviation)	64.5 ± 23.28	-
Physician global assessment of disease activity
physician's global assessment of disease activity using a Visual Analog Scale (VAS). The scale ranges from 0 to 100 mm, [0=no arthritis activity to 100 =extremely active arthritis]
Units: mm
arithmetic mean (standard deviation)	65.5 ± 18.99	-
C-Reactive Protein (CRP)
Units: mg/dL
arithmetic mean (standard deviation)	1.960 ± 2.5129	-
DAS28-CRP
The Disease Activity Score (DAS28-CRP) =0.56×sqrt(tender joints [count:1-28])+0.28×sqrt(swollen joints [count:1-28])+0.36×Ln(CRP level+1)+0.014×(patient’s disease assessment on 0-100 mm scale [100=most severe])+0.96. Range: 0.96 to no upper limit. Higher score=more severe disease.
Units: Scores on a scale
arithmetic mean (standard deviation)	5.58 ± 1.049	-
SDAI
Simple Disease Activity Index is the numerical sum of five outcome parameters: tender joint count and swollen joint count based on a 28-joint assessment, patient global assessment and physician global assessment assessed on a visual analogue scale scale (range 0 to 10 cm), and C-reactive protein measured in mg/dL. SDAI total score range: 0 to 86. SDAI <= 3.3 indicates disease remission and SDAI >26 = high disease activity.
Units: Scores on a scale
arithmetic mean (standard deviation)	38.69 ± 13.961	-

End points

Top of page

Reporting group title

Combination Therapy: Abatacept + Methotrexate (Cohort 1, IP)

Reporting group description

Abatacept 125 mg subcutaneous injection once per week + Methotrexate at least 15mg per week tablet or capsule orally once per week

Reporting group title

Placebo + Methotrexate (Cohort 1, IP)

Reporting group description

Placebo of Abatacept 125 mg subcutaneous injection once per week + Methotrexate at least 15mg per week tablet or capsule orally once per week

Reporting group title

Combination Therapy: Abatacept + Methotrexate (Cohort 2, IP)

Reporting group description

Active abatacept SC (125 mg) weekly + methotrexate weekly

Primary: Percentage of participants in Simple Disease Activity Index (SDAI) remission at Week 24

Top of page

End point title

Percentage of participants in Simple Disease Activity Index (SDAI) remission at Week 24

End point description

Simple Disease Activity Index (SDAI) is calculated using the following formula: TJC + SJC + PGA + MDGA + CRP (TJC = number of painful joints from 28 joints, SJC = number of swollen joints from 28 joints, PGA = patient global assessment on a visual analog scale 0-10 cm, MDGA = physician global assessment on a visual analog scale 0-10 cm, and CRP = c-reactive protein in mg/dL) SDAI Remission is defined as SDAI <= 3.3. Using a logistic regression model that includes treatment arm, randomization stratification factor, and baseline SDAI as continuous variable and point estimate of adjusted ORs, corresponding 95% CI and p-value was provided. SDAI total score range: 0 to 86. SDAI <= 3.3 indicates disease remission and SDAI >26 = high disease activity.

End point type

Primary

End point timeframe

Week 24

End point values	Combination Therapy: Abatacept + Methotrexate (Cohort 1, IP)	Placebo + Methotrexate (Cohort 1, IP)	Combination Therapy: Abatacept + Methotrexate (Cohort 2, IP)
Number of subjects analysed	225	150	0 ^[1]
Units: Percentage of participants
number (confidence interval 95%)	21.3 (16.0 to 26.7)	16.0 (10.1 to 21.9)	( to )

Notes
[1] - Arm is not part of the Analysis population

SDAI at 24 weeks

Comparison groups

Combination Therapy: Abatacept + Methotrexate (Cohort 1, IP) v Placebo + Methotrexate (Cohort 1, IP)

Number of subjects included in analysis

375

Analysis specification

Pre-specified

Analysis type

P-value

= 0.2359

Method

Regression, Logistic

Confidence interval

Secondary: Percentage of participants in Disease Activity Score (DAS)28 - c-reactive protein (CRP) remission at Week 24

Top of page

End point title

Percentage of participants in Disease Activity Score (DAS)28 - c-reactive protein (CRP) remission at Week 24

End point description

DAS28-CRP = Disease Activity Score 28 based on C-reactive protein DAS28-CRP Remission is defined as DAS28-CRP <= 2.6 Using a logistic regression model that includes treatment arm, stratification variable and baseline measure as continuous variable and point estimate of adjusted ORs, corresponding 95% CI and p-value was provided.

End point type

Secondary

End point timeframe

Week 24

End point values	Combination Therapy: Abatacept + Methotrexate (Cohort 1, IP)	Placebo + Methotrexate (Cohort 1, IP)	Combination Therapy: Abatacept + Methotrexate (Cohort 2, IP)
Number of subjects analysed	225	150	0 ^[2]
Units: Percentage of Participants
number (confidence interval 95%)	38.7 (32.3 to 45.0)	25.3 (18.4 to 32.3)	( to )

Notes
[2] - Arm is not part of the Analysis population

DAS 28

Comparison groups

Combination Therapy: Abatacept + Methotrexate (Cohort 1, IP) v Placebo + Methotrexate (Cohort 1, IP)

Number of subjects included in analysis

375

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0112

Method

Regression, Logistic

Confidence interval

Secondary: Percentage of participants in SDAI remission at Week 52

Top of page

End point title

Percentage of participants in SDAI remission at Week 52

End point description

Simple Disease Activity Index (SDAI) is calculated using the following formula: TJC + SJC + PGA + MDGA + CRP (TJC = number of painful joints from 28 joints, SJC = number of swollen joints from 28 joints, PGA = patient global assessment on a visual analog scale 0-10 cm, MDGA = physician global assessment on a visual analog scale 0-10 cm, and CRP = c-reactive protein in mg/dL) SDAI Remission is defined as SDAI <= 3.3. Using a logistic regression model that includes treatment arm, randomization stratification factor, and baseline SDAI as continuous variable and point estimate of adjusted ORs, corresponding 95% CI and p-value was provided. SDAI total score range: 0 to 86. SDAI <= 3.3 indicates disease remission and SDAI >26 = high disease activity.

End point type

Secondary

End point timeframe

Week 52

End point values	Combination Therapy: Abatacept + Methotrexate (Cohort 1, IP)	Placebo + Methotrexate (Cohort 1, IP)	Combination Therapy: Abatacept + Methotrexate (Cohort 2, IP)
Number of subjects analysed	225	150	0 ^[3]
Units: Percentage of participants
number (confidence interval 95%)	29.8 (23.8 to 35.8)	15.3 (9.6 to 21.1)	( to )

Notes
[3] - Arm is not part of the Analysis population

SDAI at 52 weeks

Comparison groups

Combination Therapy: Abatacept + Methotrexate (Cohort 1, IP) v Placebo + Methotrexate (Cohort 1, IP)

Number of subjects included in analysis

375

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0021

Method

Regression, Logistic

Confidence interval

Secondary: Mean change from baseline in radiographic progression of joint damage as measured by modified Sharp/van der Heijide Total Sharp scores (TSS) at Week 52

Top of page

End point title

Mean change from baseline in radiographic progression of joint damage as measured by modified Sharp/van der Heijide Total Sharp scores (TSS) at Week 52

End point description

The Modified Total Sharp Score (mTSS) is calculated as the bilateral sum of erosion and Joint Space Narrowing (JSN) scores across all joints of the hands and feet.The score range for mTSS is 0-448. Higher scores indicate more joint damage. The mean change from baseline in TSS using modified Sharp/van der Heijide scores was assessed using a rank-based nonparametric ANCOVA model.

End point type

Secondary

End point timeframe

Week 52

End point values	Combination Therapy: Abatacept + Methotrexate (Cohort 1, IP)	Placebo + Methotrexate (Cohort 1, IP)	Combination Therapy: Abatacept + Methotrexate (Cohort 2, IP)
Number of subjects analysed	401	249	0 ^[4]
Units: Total Sharp Score
arithmetic mean (standard deviation)	0.53 ± 2.279	2.52 ± 6.205	±

Notes
[4] - Arm is not part of the Analysis population

TTS

Comparison groups

Combination Therapy: Abatacept + Methotrexate (Cohort 1, IP) v Placebo + Methotrexate (Cohort 1, IP)

Number of subjects included in analysis

650

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

rank-based ANCOVA

Confidence interval

Secondary: Percentage of participants in Boolean remission at Week 52

Top of page

End point title

Percentage of participants in Boolean remission at Week 52

End point description

Boolean Remission is defined as Tender joint count less than 1, Swollen joint count less than 1, CRP less than 1 mg/dL, patient global assessment less than 1 (on 0 to 10 VAS scale). Logistic regression was used for this endpoint.

End point type

Secondary

End point timeframe

Week 52

End point values	Combination Therapy: Abatacept + Methotrexate (Cohort 1, IP)	Placebo + Methotrexate (Cohort 1, IP)	Combination Therapy: Abatacept + Methotrexate (Cohort 2, IP)
Number of subjects analysed	451	301	0 ^[5]
Units: Percentage of participants
number (confidence interval 95%)	21.5 (17.7 to 25.3)	11.6 (8.0 to 15.2)	( to )

Notes
[5] - Arm is not part of the Analysis population

Boolean Remission

Comparison groups

Combination Therapy: Abatacept + Methotrexate (Cohort 1, IP) v Placebo + Methotrexate (Cohort 1, IP)

Number of subjects included in analysis

752

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0006

Method

Regression, Logistic

Confidence interval

Adverse events

Top of page

Timeframe for reporting adverse events

Adverse events were collected from start of treatment up to 56 days after last treatment.

Adverse event reporting additional description

Randomization of DeE lead to 4 arms: Aba Weekly + MTX(50 subjects), Aba EoW + MTX (50 subjects), Aba Mono (47 subjects) , MTX alone (37 subjects) which had a total of 184 subjects.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.0

Reporting group title

Cohort 1:Aba + MTX

Reporting group description

Subjects received abatacept 125 milligram (mg) subcutaneously (sc) with a combination of methotrexate of at least 15 mg tablet administered orally once per week (qw) up to week 24.

Reporting group title

Cohort 1:MTX Alone

Reporting group description

Subjects received abatacept matching placebo 125 mg sc with a combination of methotrexate of at least 15 mg tablet administered orally qw up to week 24.

Reporting group title

Cohort 2:Aba + MTX

Reporting group description

Subjects received abatacept 125 mg sc with a combination of methotrexate of at least 15 mg tablet administered orally qw up to week 56.

Reporting group title

Aba Weekly + MTX

Reporting group description

Subjects who completed the 56 week Induction Period were randomized to this De-escalation Period received abatacept 125 mg sc with a combination of methotrexate of at least 15 mg tablet administered orally qw up to week 104.

Reporting group title

Aba EOW + MTX

Reporting group description

Subjects who completed the 56 week Induction Period were randomized to this De-escalation Period received abatacept 125 mg sc every other week (EOW) alternating with a matching placebo of abatacept with a combination of methotrexate of at least 15 mg tablet administered orally weekly up to week 80.

Reporting group title

Aba Mono

Reporting group description

Subjects who completed the 56 week Induction Period were randomized to this De-escalation Period received abatacept 125 mg sc with a combination of methotrexate matching placebo of at least 15 mg tablet administered orally weekly up to week 104.

Reporting group title

MTX Alone

Reporting group description

Subjects who completed the 56 week Induction Period were randomized to this De-escalation Period received abatacept matching placebo 125 mg sc with a combination of methotrexate of at least 15 mg tablet administered orally weekly up to week 104.

Reporting group title

OL Aba + MTX

Reporting group description

Subjects who completed the 104 week of treatment entered Open-Label Period received abatacept 125 mg sc with a combination of methotrexate matching placebo of at least 15 mg tablet administered orally qw up to week 104.

Reporting group title

OLE Aba

Reporting group description

Subjects who completed the Induction Period and De-escalation Period with escape or remission entered 24 week optional Open Label Extension Period andreceived abatacept 125 mg sc qw up to week 128.

Serious adverse events	Cohort 1:Aba + MTX	Cohort 1:MTX Alone	Cohort 2:Aba + MTX	Aba Weekly + MTX	Aba EOW + MTX	Aba Mono	MTX Alone	OL Aba + MTX	OLE Aba
Total subjects affected by serious adverse events
subjects affected / exposed	32 / 451 (7.10%)	9 / 301 (2.99%)	23 / 242 (9.50%)	3 / 50 (6.00%)	3 / 50 (6.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	40 / 685 (5.84%)	0 / 120 (0.00%)
number of deaths (all causes)	1	1	0	0	1	0	0	1	0
number of deaths resulting from adverse events	0	0	0	0	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Carcinoid tumour of the gastrointestinal tract
subjects affected / exposed	1 / 451 (0.22%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatic carcinoma
subjects affected / exposed	1 / 451 (0.22%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Benign ovarian tumour
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	1 / 242 (0.41%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cervix carcinoma
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	1 / 242 (0.41%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intraductal proliferative breast lesion
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	1 / 242 (0.41%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Invasive ductal breast carcinoma
subjects affected / exposed	0 / 451 (0.00%)	1 / 301 (0.33%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to lung
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal cancer
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	1 / 451 (0.22%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of skin
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Superficial spreading melanoma stage unspecified
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Uterine leiomyoma
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypotension
subjects affected / exposed	1 / 451 (0.22%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Knee operation
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	1 / 50 (2.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	1 / 50 (2.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	1 / 451 (0.22%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Adenomyosis
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Benign prostatic hyperplasia
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	1 / 50 (2.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hydrometra
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	1 / 242 (0.41%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metrorrhagia
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian cyst
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vaginal polyp
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchiectasis
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	1 / 242 (0.41%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	1 / 242 (0.41%)	0 / 50 (0.00%)	1 / 50 (2.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary congestion
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	1 / 242 (0.41%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Bipolar disorder
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Oxygen saturation decreased
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	1 / 242 (0.41%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Overdose
subjects affected / exposed	2 / 451 (0.44%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	1 / 451 (0.22%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	1 / 242 (0.41%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fracture displacement
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	1 / 451 (0.22%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meniscus injury
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	1 / 242 (0.41%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumoconiosis
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	1 / 242 (0.41%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin laceration
subjects affected / exposed	1 / 451 (0.22%)	1 / 301 (0.33%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Angina unstable
subjects affected / exposed	1 / 451 (0.22%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 451 (0.22%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	1 / 451 (0.22%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Cardiac failure congestive
subjects affected / exposed	0 / 451 (0.00%)	1 / 301 (0.33%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	1 / 451 (0.22%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery occlusion
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	1 / 242 (0.41%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Subarachnoid haemorrhage
subjects affected / exposed	1 / 451 (0.22%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	1 / 451 (0.22%)	0 / 301 (0.00%)	1 / 242 (0.41%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	1 / 451 (0.22%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysarthria
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	1 / 242 (0.41%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	1 / 242 (0.41%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	1 / 242 (0.41%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lacunar infarction
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lacunar stroke
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	1 / 242 (0.41%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoxic-Ischaemic encephalopathy
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	1 / 242 (0.41%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	2 / 685 (0.29%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	1 / 451 (0.22%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Macular degeneration
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Macular hole
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Gastritis erosive
subjects affected / exposed	1 / 451 (0.22%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 451 (0.22%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	1 / 451 (0.22%)	0 / 301 (0.00%)	1 / 242 (0.41%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal ischaemia
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malocclusion
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Melaena
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	1 / 242 (0.41%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	1 / 50 (2.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis acute
subjects affected / exposed	1 / 451 (0.22%)	0 / 301 (0.00%)	2 / 242 (0.83%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis chronic
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	1 / 50 (2.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Bladder prolapse
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Goitre
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	1 / 242 (0.41%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 451 (0.22%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	2 / 451 (0.44%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	1 / 451 (0.22%)	1 / 301 (0.33%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rheumatoid arthritis
subjects affected / exposed	0 / 451 (0.00%)	1 / 301 (0.33%)	1 / 242 (0.41%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal pain
subjects affected / exposed	1 / 451 (0.22%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spondylolisthesis
subjects affected / exposed	1 / 451 (0.22%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Synovial cyst
subjects affected / exposed	1 / 451 (0.22%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Exostosis
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	1 / 451 (0.22%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 451 (0.00%)	1 / 301 (0.33%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 451 (0.22%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	2 / 451 (0.44%)	2 / 301 (0.66%)	1 / 242 (0.41%)	0 / 50 (0.00%)	1 / 50 (2.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	2 / 685 (0.29%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	1 / 2	1 / 2	1 / 1	0 / 0	1 / 1	0 / 0	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	0 / 451 (0.00%)	1 / 301 (0.33%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	2 / 451 (0.44%)	1 / 301 (0.33%)	1 / 242 (0.41%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	1 / 2	1 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abscess intestinal
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemophilus infection
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	1 / 242 (0.41%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infectious mononucleosis
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	1 / 50 (2.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peritonsillar abscess
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	1 / 242 (0.41%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumocystis jirovecii pneumonia
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tuberculosis
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	1 / 242 (0.41%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hyperglycaemia
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	1 / 242 (0.41%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	0 / 451 (0.00%)	0 / 301 (0.00%)	1 / 242 (0.41%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	0 / 685 (0.00%)	0 / 120 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Cohort 1:Aba + MTX	Cohort 1:MTX Alone	Cohort 2:Aba + MTX	Aba Weekly + MTX	Aba EOW + MTX	Aba Mono	MTX Alone	OL Aba + MTX	OLE Aba
Total subjects affected by non serious adverse events
subjects affected / exposed	237 / 451 (52.55%)	152 / 301 (50.50%)	123 / 242 (50.83%)	12 / 50 (24.00%)	22 / 50 (44.00%)	10 / 47 (21.28%)	16 / 37 (43.24%)	230 / 685 (33.58%)	15 / 120 (12.50%)
Investigations
Alanine aminotransferase increased
subjects affected / exposed	24 / 451 (5.32%)	15 / 301 (4.98%)	10 / 242 (4.13%)	2 / 50 (4.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	20 / 685 (2.92%)	0 / 120 (0.00%)
occurrences all number	33	20	11	2	0	0	0	23	0
Aspartate aminotransferase increased
subjects affected / exposed	14 / 451 (3.10%)	10 / 301 (3.32%)	9 / 242 (3.72%)	3 / 50 (6.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	11 / 685 (1.61%)	0 / 120 (0.00%)
occurrences all number	16	14	11	3	0	0	0	11	0
Influenza a virus test positive
subjects affected / exposed	1 / 451 (0.22%)	0 / 301 (0.00%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	1 / 47 (2.13%)	2 / 37 (5.41%)	1 / 685 (0.15%)	0 / 120 (0.00%)
occurrences all number	1	0	0	0	0	1	2	1	0
Vascular disorders
Hypertension
subjects affected / exposed	11 / 451 (2.44%)	8 / 301 (2.66%)	5 / 242 (2.07%)	0 / 50 (0.00%)	3 / 50 (6.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	4 / 685 (0.58%)	0 / 120 (0.00%)
occurrences all number	11	8	5	0	3	0	0	4	0
Nervous system disorders
Headache
subjects affected / exposed	31 / 451 (6.87%)	21 / 301 (6.98%)	8 / 242 (3.31%)	0 / 50 (0.00%)	1 / 50 (2.00%)	1 / 47 (2.13%)	1 / 37 (2.70%)	20 / 685 (2.92%)	0 / 120 (0.00%)
occurrences all number	38	24	12	0	1	1	1	23	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	12 / 451 (2.66%)	18 / 301 (5.98%)	4 / 242 (1.65%)	1 / 50 (2.00%)	1 / 50 (2.00%)	0 / 47 (0.00%)	1 / 37 (2.70%)	10 / 685 (1.46%)	1 / 120 (0.83%)
occurrences all number	12	22	5	1	1	0	1	11	1
General disorders and administration site conditions
Drug intolerance
subjects affected / exposed	7 / 451 (1.55%)	4 / 301 (1.33%)	0 / 242 (0.00%)	0 / 50 (0.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	2 / 37 (5.41%)	4 / 685 (0.58%)	0 / 120 (0.00%)
occurrences all number	7	5	0	0	0	0	2	4	0
Gastrointestinal disorders
Nausea
subjects affected / exposed	42 / 451 (9.31%)	24 / 301 (7.97%)	22 / 242 (9.09%)	1 / 50 (2.00%)	2 / 50 (4.00%)	0 / 47 (0.00%)	1 / 37 (2.70%)	23 / 685 (3.36%)	0 / 120 (0.00%)
occurrences all number	56	27	25	1	4	0	1	24	0
Stomatitis
subjects affected / exposed	27 / 451 (5.99%)	8 / 301 (2.66%)	1 / 242 (0.41%)	0 / 50 (0.00%)	1 / 50 (2.00%)	2 / 47 (4.26%)	2 / 37 (5.41%)	21 / 685 (3.07%)	2 / 120 (1.67%)
occurrences all number	45	14	3	0	1	9	4	31	4
Abdominal pain upper
subjects affected / exposed	12 / 451 (2.66%)	5 / 301 (1.66%)	14 / 242 (5.79%)	1 / 50 (2.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	0 / 37 (0.00%)	8 / 685 (1.17%)	1 / 120 (0.83%)
occurrences all number	12	6	15	1	0	0	0	9	1
Diarrhoea
subjects affected / exposed	17 / 451 (3.77%)	12 / 301 (3.99%)	13 / 242 (5.37%)	1 / 50 (2.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	1 / 37 (2.70%)	13 / 685 (1.90%)	1 / 120 (0.83%)
occurrences all number	17	13	17	1	0	0	4	15	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	15 / 451 (3.33%)	16 / 301 (5.32%)	13 / 242 (5.37%)	1 / 50 (2.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	1 / 37 (2.70%)	11 / 685 (1.61%)	1 / 120 (0.83%)
occurrences all number	16	17	13	1	0	0	1	11	1
Infections and infestations
Nasopharyngitis
subjects affected / exposed	63 / 451 (13.97%)	43 / 301 (14.29%)	36 / 242 (14.88%)	2 / 50 (4.00%)	6 / 50 (12.00%)	4 / 47 (8.51%)	5 / 37 (13.51%)	59 / 685 (8.61%)	6 / 120 (5.00%)
occurrences all number	81	60	47	3	7	4	6	75	9
Pharyngitis
subjects affected / exposed	22 / 451 (4.88%)	17 / 301 (5.65%)	14 / 242 (5.79%)	0 / 50 (0.00%)	1 / 50 (2.00%)	1 / 47 (2.13%)	2 / 37 (5.41%)	18 / 685 (2.63%)	0 / 120 (0.00%)
occurrences all number	24	19	14	0	1	1	3	18	0
Upper respiratory tract infection
subjects affected / exposed	24 / 451 (5.32%)	16 / 301 (5.32%)	18 / 242 (7.44%)	1 / 50 (2.00%)	2 / 50 (4.00%)	1 / 47 (2.13%)	3 / 37 (8.11%)	28 / 685 (4.09%)	3 / 120 (2.50%)
occurrences all number	28	20	18	1	3	1	3	31	4
Bronchitis
subjects affected / exposed	19 / 451 (4.21%)	12 / 301 (3.99%)	16 / 242 (6.61%)	3 / 50 (6.00%)	6 / 50 (12.00%)	1 / 47 (2.13%)	0 / 37 (0.00%)	24 / 685 (3.50%)	1 / 120 (0.83%)
occurrences all number	20	12	20	3	6	1	0	25	1
Gastroenteritis
subjects affected / exposed	13 / 451 (2.88%)	9 / 301 (2.99%)	10 / 242 (4.13%)	0 / 50 (0.00%)	3 / 50 (6.00%)	1 / 47 (2.13%)	2 / 37 (5.41%)	13 / 685 (1.90%)	1 / 120 (0.83%)
occurrences all number	13	10	11	0	4	1	2	13	1
Herpes zoster
subjects affected / exposed	3 / 451 (0.67%)	2 / 301 (0.66%)	1 / 242 (0.41%)	1 / 50 (2.00%)	0 / 50 (0.00%)	0 / 47 (0.00%)	2 / 37 (5.41%)	7 / 685 (1.02%)	0 / 120 (0.00%)
occurrences all number	3	4	1	1	0	0	2	7	0
Urinary tract infection
subjects affected / exposed	17 / 451 (3.77%)	9 / 301 (2.99%)	13 / 242 (5.37%)	2 / 50 (4.00%)	1 / 50 (2.00%)	1 / 47 (2.13%)	0 / 37 (0.00%)	26 / 685 (3.80%)	0 / 120 (0.00%)
occurrences all number	20	13	18	2	1	1	0	34	0

More information

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Were there any global substantial amendments to the protocol? Yes

29 Sep 2015

Incorporates changes in response to health authorities in countries participating in the Voluntary Harmonization Procedure (VHP)

22 Feb 2016

Provide clarifications of interpretation of the protocol and increase consistency in the protocol

27 Nov 2017

Added a new period (Optional Open Label Abatacept Extension for Subjects who Complete the DE Period); added a section 3.1.6.5 to describe the new period; added a sentence in Section 8.4.3, Safety analyses, to describe the analyses of those subjects. Updated the Medical Monitor Contact, added name of the Study Director, added abatacept/placebo and MTX reconciliation at Week 56 of IP, deleted BNP sample collection, added CRP collection at DE Week 64, added HAQ at Week 64, clarified corticosteroid rescue treatment to be for RA, corrected SAE reporting section.

08 Jan 2018

Corrected errors in Section 5.1, Table 5.1-6. Indicated the second phone call visit is at Week 112, deleted CRP testing at the office visits, added dosing of weekly SC abatacept, added diary cards will be collected at Week 116 and Week 128/ET, and indicated the office visit will be +/- 3 days of the target visit day.

26 Apr 2018

Updated the schematic in both the synopsis and body of the protocol to add the new optional open label SC abatacept period for DE completers. Added a paragraph in the synopsis to describe the optional open label SC abatacept period for DE completers. Modified the definition of serious breach. Two corrections made to Table 5.1-4 for procedures required at the ET or Final Visit.

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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