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Clinical Trial Results:
A Phase IIB Randomized, Placebo-Controlled Study to Evaluate the Clinical Efficacy and Safety of Induction and Maintenance Therapy with BMS-936557 in Subjects with Active Ulcerative Colitis

Summary
EudraCT number	2010-022506-41
Trial protocol	DE AT HU BE PL IT
Global end of trial date	05 Jan 2015

Results information
Results version number	v1(current)
This version publication date	31 Aug 2016
First version publication date	31 Aug 2016
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

IM129-005

ISRCTN number

-

US NCT number

NCT01294410

WHO universal trial number (UTN)

-

Sponsor organisation name

Bristol-Myers Squibb

Sponsor organisation address

Bristol-Myers Squibb International Corporation, Chaussée de la Hulpe 185, Brussels, Belgium, 1170

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)

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

05 Jan 2015

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

05 Jan 2015

Was the trial ended prematurely?

Yes

Main objective of the trial

The primary objective of this study was to compare the efficacy of BMS-936557 vs placebo for induction of clinical remission (defined as Mayo score <=2 points with no individual subscore >1 point) at Week 11.

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

27 Mar 2011

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 33

Country: Number of subjects enrolled

Brazil: 22

Country: Number of subjects enrolled

Canada: 21

Country: Number of subjects enrolled

Mexico: 37

Country: Number of subjects enrolled

South Africa: 10

Country: Number of subjects enrolled

United States: 114

Country: Number of subjects enrolled

Netherlands: 10

Country: Number of subjects enrolled

Poland: 50

Country: Number of subjects enrolled

Austria: 12

Country: Number of subjects enrolled

Belgium: 4

Country: Number of subjects enrolled

France: 42

Country: Number of subjects enrolled

Germany: 11

Country: Number of subjects enrolled

Hungary: 31

Country: Number of subjects enrolled

Italy: 14

Worldwide total number of subjects

411

EEA total number of subjects

174

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)

384

From 65 to 84 years

27

85 years and over

0

Subject disposition

Top of page

Recruitment details

A total of 411 subjects were enrolled at 75 sites in 14 countries.

Screening details

A total of 411 subjects were enrolled, 305 subjects were randomised and treated in the induction period. Reasons for 106 subjects not randomised were: Adverse event-1; Subject withdrew consent-15; Lost to follow up-5; Poor/Non-compliance-2; Study criteria not met-74; Administrative reason by sponsor-1; other-8.

Period 1 title

Induction Phase

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Are arms mutually exclusive

Yes

Placebo

Arm description

Subjects received BMS-936557 matching placebo, intravenous infusion, once a week for first two weeks and every other week thereafter, up to 11 weeks.

Arm type

Experimental

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received placebo matching with BMS 936557 via intravenous infusion over 90 minutes once a week for first two weeks and every other week thereafter, up to 11 weeks.

BMS-936557 15 mg/kg

Arm description

Subjects received BMS-936557 15 mg/kg, intravenous infusion, once a week for first two weeks and every other week thereafter, up to 11 weeks.

Arm type

Experimental

Investigational medicinal product name

BMS-936557

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received BMS-936557 15 mg/kg via intravenous infusion over 90 minutes, once a week for first two weeks and every other week thereafter, up to 11 weeks.

BMS-936557 25 mg/kg

Arm description

Subjects received BMS-936557 25 mg/kg, intravenous infusion, once a week for first two weeks and every other week thereafter, up to 11 weeks.

Arm type

Experimental

Investigational medicinal product name

BMS-936557

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received BMS-936557 25 mg/kg via intravenous infusion over 90 minutes, once a week for first two weeks and every other week thereafter, up to 11 weeks.

Number of subjects in period 1 ^[1]	Placebo	BMS-936557 15 mg/kg	BMS-936557 25 mg/kg
Started	100	102	103
Completed	85	90	90
Not completed	15	12	13
Consent withdrawn by subject	3	1	3
Adverse event, non-fatal	1	5	5
Subject request to discontinue study treatment	3	2	1
Other reasons	1	-	-
Lost to follow-up	-	1	1
Subject no longer meets study criteria	-	-	1
Lack of efficacy	7	3	2

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: The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial as out of total 411 subjects who were enrolled, 305 subjects were randomised and treated in the induction period. Reasons for 106 subjects not randomised were: Adverse event-1; Subject withdrew consent-15; Lost to follow up-5; Poor/Non-compliance-2; Study criteria not met-74; Administrative reason by sponsor-1; other-8.

Period 2 title

Maintenance Period

Is this the baseline period?

No

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Are arms mutually exclusive

Yes

Placebo to Placebo

Arm description

Subjects who received placebo in the induction period received placebo intravenous infusion over 90 minutes, every other week for up to 108 weeks.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received placebo via intravenous infusion over 90 minutes, every other week for up to 108 weeks.

BMS-936557 to Placebo

Arm description

Subjects who received any dose of BMS-936557 in the induction period received placebo via intravenous infusion over 90 minutes, every other week for up to 108 weeks.

Arm type

Experimental

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received placebo via intravenous infusion over 90 minutes, every other week for up to 108 weeks.

BMS-936557 5 mg/kg

Arm description

Subjects received BMS-936557 5 mg/kg, intravenous infusion over 90 minutes, every other week for up to 108 weeks.

Arm type

Experimental

Investigational medicinal product name

BMS-936557

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received BMS-936557 5 mg/kg via intravenous infusion over 90 minutes, every other week for up to 108 weeks.

BMS-936557 10 mg/kg

Arm description

Subjects received BMS-936557 10 mg/kg, intravenous infusion over 90 minutes, every other week for up to 108 weeks.

Arm type

Experimental

Investigational medicinal product name

BMS-936557

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received BMS-936557 10 mg/kg via intravenous infusion over 90 minutes, every other week for up to 108 weeks.

BMS-936557 20 mg/kg

Arm description

Subjects received BMS-936557 20 mg/kg, intravenous infusion over 90 minutes, every other week for up to 108 weeks.

Arm type

Experimental

Investigational medicinal product name

BMS-936557

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received BMS-936557 20 mg/kg via intravenous infusion over 90 minutes, every other week for up to 108 weeks.

Number of subjects in period 2 ^[2]	Placebo to Placebo	BMS-936557 to Placebo	BMS-936557 5 mg/kg	BMS-936557 10 mg/kg	BMS-936557 20 mg/kg
Started	30	22	24	22	21
Completed	7	4	5	5	5
Not completed	23	18	19	17	16
Consent withdrawn by subject	1	1	-	-	1
Adverse event, non-fatal	-	-	-	2	2
Subject request to discontinue study treatment	2	1	2	2	1
Pregnancy	-	1	-	-	-
Other reasons	-	1	-	-	-
Lost to follow-up	-	-	1	-	-
Lack of efficacy	20	14	16	13	12

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 265 subjects who completed the induction period, only 119 subjects entered the maintenance period. 142 subjects discontinued and moved directly into the open label period.

Period 3 title

Open-Label Period

Is this the baseline period?

No

Allocation method

Not applicable

Blinding used

Not blinded

BMS-936557 10 mg/kg

Arm description

Subjects received BMS-936557 10 mg/kg, intravenous infusion over 90 minutes, every other week for up to 41 months.

Arm type

Experimental

Investigational medicinal product name

BMS-936557

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects were adminstered BMS-936557 ~10 mg/kg via intravenous infusion over 90 minutes, every other week for up to 41 months.

Number of subjects in period 3 ^[3]	BMS-936557 10 mg/kg
Started	23
Completed	0
Not completed	237
Consent withdrawn by subject	20
Adverse event, non-fatal	15
Subject request to discontinue study treatment	16
Death	1
Poor/Non-compliance	1
Other reasons	7
Lost to follow-up	2
Subject no longer meets study criteria	1
Lack of efficacy	95
Administrative reason by sponsor	79
Joined	214
Continued from IP and MP	214

Notes
[3] - 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: Among the 119 subjects treated in the maintenance phase, 26 subjects completed and entered the open label period. 142 subjects moved directly into open label period from the induction period. A total of 238 subjects entered the open label period of whom 237 subjects were treated and 1 subject from the induction period was not treated. 214 subjects continued from IP and MP.

Baseline characteristics

Top of page

Reporting group title

Placebo

Reporting group description

Subjects received BMS-936557 matching placebo, intravenous infusion, once a week for first two weeks and every other week thereafter, up to 11 weeks.

Reporting group title

BMS-936557 15 mg/kg

Reporting group description

Subjects received BMS-936557 15 mg/kg, intravenous infusion, once a week for first two weeks and every other week thereafter, up to 11 weeks.

Reporting group title

BMS-936557 25 mg/kg

Reporting group description

Subjects received BMS-936557 25 mg/kg, intravenous infusion, once a week for first two weeks and every other week thereafter, up to 11 weeks.

Reporting group values	Placebo	BMS-936557 15 mg/kg	BMS-936557 25 mg/kg	Total
Number of subjects	100	102	103	305
Age categorical
Units: Subjects
18 - <40 years	42	54	55	151
40 - <65 years	51	42	42	135
>=65 - <75 years	7	5	5	17
>=75 years	0	1	1	2
Gender categorical
Units: Subjects
Female	47	36	47	130
Male	53	66	56	175

Subject analysis set title

IP - Placebo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects received BMS-936557 matching placebo, intravenously, once weekly for the first two weeks and every other week thereafter up to 11 weeks (Post-amendment 4).

Subject analysis set title

IP- BMS-936557 15 mg/kg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects received BMS 936557 15 mg/kg intravenous infusion, once a week for the first two weeks and every other week thereafter, up to 11 weeks (Post-amendment 4).

Subject analysis set title

IP BMS-936557 25 mg/kg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects received BMS 936557 25 mg/kg intravenous infusion, once a week for the first two weeks and every other week thereafter, up to 11 weeks (Post-amendment 4).

Subject analysis sets values	IP - Placebo	IP- BMS-936557 15 mg/kg	IP BMS-936557 25 mg/kg
Number of subjects	83	84	85
Age categorical
Units: Subjects
18 - <40 years	38	45	48
40 - <65 years	39	33	34
>=65 - <75 years	6	5	2
>=75 years	0	1	1
Age continuous
Units:
	( )	( )	( )
Gender categorical
Units: Subjects
Female	40	30	41
Male	43	54	44

End points

Top of page

Reporting group title

Placebo

Reporting group description

Subjects received BMS-936557 matching placebo, intravenous infusion, once a week for first two weeks and every other week thereafter, up to 11 weeks.

Reporting group title

BMS-936557 15 mg/kg

Reporting group description

Subjects received BMS-936557 15 mg/kg, intravenous infusion, once a week for first two weeks and every other week thereafter, up to 11 weeks.

Reporting group title

BMS-936557 25 mg/kg

Reporting group description

Subjects received BMS-936557 25 mg/kg, intravenous infusion, once a week for first two weeks and every other week thereafter, up to 11 weeks.

Reporting group title

Placebo to Placebo

Reporting group description

Subjects who received placebo in the induction period received placebo intravenous infusion over 90 minutes, every other week for up to 108 weeks.

Reporting group title

BMS-936557 to Placebo

Reporting group description

Subjects who received any dose of BMS-936557 in the induction period received placebo via intravenous infusion over 90 minutes, every other week for up to 108 weeks.

Reporting group title

BMS-936557 5 mg/kg

Reporting group description

Subjects received BMS-936557 5 mg/kg, intravenous infusion over 90 minutes, every other week for up to 108 weeks.

Reporting group title

BMS-936557 10 mg/kg

Reporting group description

Subjects received BMS-936557 10 mg/kg, intravenous infusion over 90 minutes, every other week for up to 108 weeks.

Reporting group title

BMS-936557 20 mg/kg

Reporting group description

Subjects received BMS-936557 20 mg/kg, intravenous infusion over 90 minutes, every other week for up to 108 weeks.

Reporting group title

BMS-936557 10 mg/kg

Reporting group description

Subjects received BMS-936557 10 mg/kg, intravenous infusion over 90 minutes, every other week for up to 41 months.

Subject analysis set title

IP - Placebo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects received BMS-936557 matching placebo, intravenously, once weekly for the first two weeks and every other week thereafter up to 11 weeks (Post-amendment 4).

Subject analysis set title

IP- BMS-936557 15 mg/kg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects received BMS 936557 15 mg/kg intravenous infusion, once a week for the first two weeks and every other week thereafter, up to 11 weeks (Post-amendment 4).

Subject analysis set title

IP BMS-936557 25 mg/kg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects received BMS 936557 25 mg/kg intravenous infusion, once a week for the first two weeks and every other week thereafter, up to 11 weeks (Post-amendment 4).

Primary: Percentage of Subjects Who Achieved Clinical Remission at Week 11 (Induction period)

Top of page

End point title

Percentage of Subjects Who Achieved Clinical Remission at Week 11 (Induction period)

End point description

Clinical remission was defined as a total Mayo score of at least 2 and no individual sub-score greater than 1. The Mayo scoring system is a composite index consisting of 4 disease variables (each scored on a scale of 0 to 3, with higher scores indicating greater frequency or severity): stool frequency, rectal bleeding, findings on endoscopy, and the physician’s global assessment. Mayo scores range from 0 to 12 points and utilize all 4 disease variables, with higher scores indicating more severe disease. The analysis was performed in all treated subjects who received any study drug.

End point type

Primary

End point timeframe

Start of induction period (Day 1) up to Week 11

End point values	IP - Placebo	IP- BMS-936557 15 mg/kg	IP BMS-936557 25 mg/kg
Number of subjects analysed	83	84	85
Units: Percentage of subjects
number (confidence interval 95%)	9.6 (3.3 to 16)	13.1 (5.9 to 20.3)	17.6 (9.5 to 25.8)

BMS-936557 15mg/kg vs Placebo

Comparison groups

IP- BMS-936557 15 mg/kg v IP - Placebo

Number of subjects included in analysis

167

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.515

Method

Cochran-Mantel-Haenszel Chi-square test

Parameter type

Absolute treatment difference

Point estimate

3.1

Confidence interval

level

97.5%

sides

2-sided

lower limit

-8.3

upper limit

14.5

BMS-936557 25mg/kg vs Placebo

Comparison groups

IP - Placebo v IP BMS-936557 25 mg/kg

Number of subjects included in analysis

168

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.158

Method

Cochran-Mantel-Haenszel Chi-square test

Parameter type

Absolute treatment difference

Point estimate

7.6

Confidence interval

level

97.5%

sides

2-sided

lower limit

-3.9

upper limit

19.2

Secondary: Mean Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total and Subscale Scores (Bowel, Systemic, Social, and emotional Symptoms) at Week 11

Top of page

End point title

Mean Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total and Subscale Scores (Bowel, Systemic, Social, and emotional Symptoms) at Week 11

End point description

IBDQ was used to measure disease specific quality of life (QoL). The IBDQ consists of a self-administered 32-item questionnaire that evaluates QoL across 4 dimensional scores: Bowel, Systemic, Social and Emotional. The response to each question can range from 1 to 7, with 1 indicating severe problem and 7 indicating normal health. The total IBDQ is computed as the sum of the responses to the individual IBDQ questions. The total score can range between 32 to 224 with higher scores indicating a better QoL. The analysis was performed in all treated subjects who received the study drug. Here "n" refers to the number of treated subjects with non-missing baseline and post-baseline values.

End point type

Secondary

End point timeframe

Baseline, Week 11

End point values	IP - Placebo	IP- BMS-936557 15 mg/kg	IP BMS-936557 25 mg/kg
Number of subjects analysed	83	84	85
Units: Score on a scale
arithmetic mean (standard deviation)
Bowel symptoms (n=78, 75, 74)	4.18 ( 13.551 )	8.41 ( 10.205 )	11.16 ( 13.673 )
Systemic symptoms (n=78, 75, 74)	2.08 ( 6.326 )	3.95 ( 5.46 )	4.3 ( 6.957 )
Emotional symptoms (n=78, 75, 74)	4.98 ( 14.601 )	7.75 ( 11.722 )	9.65 ( 16.686 )
Social symptoms (n=78, 75, 74)	1.93 ( 7.903 )	3.92 ( 6.594 )	3.82 ( 8.744 )
Total Score (n=78, 75, 74)	13.17 ( 38.955 )	24.03 ( 30.082 )	28.93 ( 43.136 )

No statistical analyses for this end point

Secondary: Percentage of Subjects With Inflammatory Bowel Disease Questionnaire (IBDQ) Response at Week 11 (IP-78)

Top of page

End point title

Percentage of Subjects With Inflammatory Bowel Disease Questionnaire (IBDQ) Response at Week 11 (IP-78)

End point description

IBDQ response was defined as change from baseline in IBDQ score of >=16 points. The analysis was performed in all treated subjects who received the study drug.

End point type

Secondary

End point timeframe

Week 11

End point values	IP - Placebo	IP- BMS-936557 15 mg/kg	IP BMS-936557 25 mg/kg
Number of subjects analysed	83	84	85
Units: Percentage of subjects
number (confidence interval 95%)	38.6 (28.1 to 49)	45.2 (34.6 to 55.9)	51.8 (41.1 to 62.4)

No statistical analyses for this end point

Secondary: Percentage of Subjects Who Achieved Clinical Response at Week 11

Top of page

End point title

Percentage of Subjects Who Achieved Clinical Response at Week 11

End point description

Clinical response was defined as reduction from baseline in Mayo score of at least 3 points and at least 30%, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or an absolute subscore for rectal bleeding of 0 or 1. The Mayo scoring system is a composite index consisting of 4 disease variables (each scored on a scale of 0 to 3, with higher scores indicating greater frequency or severity): stool frequency, rectal bleeding, findings on endoscopy, and the physician’s global assessment. Mayo scores range from 0 to 12 points and utilize all 4 disease variables, with higher scores indicating more severe disease. The analysis was performed in all treated subjects who received any study drug.

End point type

Secondary

End point timeframe

Start of induction period (Day 1) up to Week 11

End point values	IP - Placebo	IP- BMS-936557 15 mg/kg	IP BMS-936557 25 mg/kg
Number of subjects analysed	83	84	85
Units: Percentage of subjects
number (confidence interval 95%)	31.3 (21.3 to 41.3)	44 (33.4 to 54.7)	47.1 (36.4 to 57.7)

No statistical analyses for this end point

Secondary: Percentage of Subjects Who Achieved Mucosal Healing at Week 11

Top of page

End point title

Percentage of Subjects Who Achieved Mucosal Healing at Week 11

End point description

Mucosal healing was defined as endoscopic subscore <=1 point. Endoscopy was performed using Sigmoidoscopy. Findings of flexible proctosigmoidoscopy were rated as: 0 = Normal or inactive disease, 1 = Mild disease (erythema, decreased vascular pattern, mild friability), 2 = Moderate disease (marked erythema, absent vascular pattern, friability, erosions), and 3 = Severe disease (spontaneous bleeding, ulceration). The analysis was performed in all the subjects who were randomised and received any study drug.

End point type

Secondary

End point timeframe

Start of induction period (Day 1) up to Week 11

End point values	IP - Placebo	IP- BMS-936557 15 mg/kg	IP BMS-936557 25 mg/kg
Number of subjects analysed	83	84	85
Units: Percentage of subjects
number (confidence interval 95%)	27.7 (18.1 to 37.3)	29.8 (20 to 39.5)	31.8 (21.9 to 41.7)

No statistical analyses for this end point

Secondary: Number of Subjects With Adverse Events (AEs), Drug related AEs, Discontinuation due to AEs, Serious Adverse Events (SAEs), Drug related SAEs, Discontinuation Due to SAEs, and Who Died

Top of page

End point title

Number of Subjects With Adverse Events (AEs), Drug related AEs, Discontinuation due to AEs, Serious Adverse Events (SAEs), Drug related SAEs, Discontinuation Due to SAEs, and Who Died

End point description

An AE is any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. An SAE is a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. The analysis was performed in all the subjects who received any study medication.

End point type

Secondary

End point timeframe

Baseline (Day 1) up to 56 days after the last dose in the induction period/start of the subsequent phase treatment, which ever occurred first.

End point values	IP - Placebo	IP- BMS-936557 15 mg/kg	IP BMS-936557 25 mg/kg
Number of subjects analysed	83	84	85
Units: Subjects
AEs	57	56	60
Drug related AEs	16	27	33
Discontinuation due to AEs	4	5	4
SAEs	8	4	4
Drug related SAEs	0	1	2
Discontinuation Due to SAEs	4	2	2
Death	0	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With Marked Hematology Laboratory Abnormalities During Induction period

Top of page

End point title

Number of Subjects With Marked Hematology Laboratory Abnormalities During Induction period

End point description

Erythrocytes, Low: if value <0.75*baseline value (PRE) and < lower limit of normal (LLN); Hematocrit, Low: if value <0.75*PRE and <LLN; Hemoglobin, Low: <PRE –30 and <LLN; Platelet Count, Low: if LLN <= PRE <= upper limit of normal (ULN) and value <0.67*LLN, or if PRE <LLN and value <0.5*PRE and value <100; Platelet Count, High: if LLN <=PRE <=ULN and value >1.5*ULN; Total White Blood Cells (WBC) count, Low: if LLN <=PRE <=limit of normal (ULN) and value <0.75*LLN, or if PRE <LLN and Value <0.8*PRE, or if PRE >ULN and value <LLN; Total WBC Count, High: if LLN <=PRE <=ULN and value >1.25*ULN, or if PRE <LLN and value >ULN, or if PRE >ULN and value >1.2*PRE. Lymphocytes, Low (absolute): if value <0.75 and <LLN; Lymphocytes, High (absolute): if value >7.5 and >ULN; Neutrophils, Low (absolute): if value <1.0 and <LLN. The analysis was performed in all the subjects who received any study drug. Here, 'n' signifies evaluable subjects for specified categories in respective treatment arms.

End point type

Secondary

End point timeframe

Baseline (Day 1) up to 56 days after the last dose in the induction period/start of the subsequent phase treatment, which ever occurred first.

End point values	IP - Placebo	IP- BMS-936557 15 mg/kg	IP BMS-936557 25 mg/kg
Number of subjects analysed	83	84	85
Units: Subjects
Erythrocytes, Low (n=83, 82, 84)	1	1	0
Hematocrit, Low (n=83, 82, 84)	2	0	1
Hemoglobin, Low (n=83, 82, 84)	3	0	1
Platelet Count, Low (n=83, 82, 84)	0	0	0
Platelet Count, High (n=83, 82, 84)	2	0	1
Total WBC count, Low (n=83, 82, 84)	1	0	1
Total WBC count, High (n=83, 82, 84)	3	6	2
Lymphocytes, Low (absolute) (n=83, 82, 84)	17	15	19
Lymphocytes, High (absolute) (n=83, 82, 84)	1	0	0
Neutrophils, Low (absolute) (n=83, 82, 84)	0	0	1

No statistical analyses for this end point

Secondary: Number of Subjects With Marked Liver and Kidney Function Laboratory Abnormalities During Induction Period

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End point title

Number of Subjects With Marked Liver and Kidney Function Laboratory Abnormalities During Induction Period

End point description

Alanine Aminotransferase (ALT), High: if lower limit of normal (LLN) <= baseline value (PRE) <=upper limit of normal (ULN) and value >3*ULN, or if PRE >ULN and value >4*PRE; Alkaline Phosphatase (ALP), High: if LLN <=PRE <=ULN and value >2*ULN, or if PRE >ULN and value >3*PRE; Aspartate Aminotransferase (AST), High: if LLN <=PRE <=ULN and value >3*ULN, or if PRE >ULN and value >4*PRE; Bilirubin, Total, High: if LLN <=PRE <=ULN and value >2*ULN, or if PRE >ULN and value >4*PRE; G-Glutamyl Transferase (GGT), High: if LLN <=PRE <=ULN and value >2*ULN, or if PRE >ULN and value >3*PRE; Creatinine, High: if value >1.5*PRE and >ULN. The analysis was performed in all the subjects who received any study drug. Here, 'n' signifies evaluable subjects for specified categories in respective treatment arms.

End point type

Secondary

End point timeframe

Baseline (Day 1) up to 56 days after the last dose in the induction period/start of the subsequent phase treatment, which ever occurred first.

End point values	IP - Placebo	IP- BMS-936557 15 mg/kg	IP BMS-936557 25 mg/kg
Number of subjects analysed	83	84	85
Units: Subjects
ALT, High (n=83, 82, 84)	0	0	1
ALP, High (n=83, 82, 84)	0	0	0
AST, High (n=83, 82, 84)	0	1	1
Total Bilirubin,High (n=83, 82, 84)	0	0	0
GGT, High (n=83, 82, 84)	2	1	1
Creatinine, High (n=83, 82, 84)	0	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With Marked Chemistry Laboratory Abnormalities During Induction period

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End point title

Number of Subjects With Marked Chemistry Laboratory Abnormalities During Induction period

End point description

Glucose (fasting serum), Low: if lower limit of normal (LLN) <=baseline value (PRE) <=upper limit of normal (ULN) and value <0.8*LLN, or if PRE <LLN and value <0.8*PRE, or if PRE >ULN and value <LLN; Glucose (fasting serum), High: if LLN <=PRE <=ULN and value >1.5*ULN, or if PRE <LLN and value >ULN, or if PRE >ULN and value >2.0*PRE; Albumin, Low: if LLN <=PRE <=ULN and value <0.9*LLN, or if PRE <LLN and value <0.75*PRE. The analysis was performed in all the subjects who received any study drug. Here, 'n' signifies evaluable subjects for specified categories in respective treatment arms.

End point type

Secondary

End point timeframe

Baseline (Day 1) up to 56 days after the last dose in the induction period/start of the subsequent phase treatment, which ever occurred first.

End point values	IP - Placebo	IP- BMS-936557 15 mg/kg	IP BMS-936557 25 mg/kg
Number of subjects analysed	83	84	85
Units: Subjects
Glucose (fasting serum) Low (n=63, 66, 62)	1	2	0
Glucose (fasting serum) High (n=63, 66, 62)	2	0	0
Albumin, Low (n=83, 82, 84)	2	0	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

On-Treatment period (up to 56 days after the last dose of the study drug)

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.1

Reporting group title

IP: Placebo

Reporting group description

Subjects received BMS-936557 matching placebo, intravenous infusion, once a week for first two weeks and every other week thereafter, up to 11 weeks.

Reporting group title

IP: BMS-936557 15 mg/kg

Reporting group description

Subjects received BMS-936557 15 mg/kg, intravenous infusion, once a week for first two weeks and every other week thereafter, up to 11 weeks.

Reporting group title

IP: BMS-936557 25 mg/kg

Reporting group description

Subjects received BMS-936557 25 mg/kg, intravenous infusion, once a week for first two weeks and every other week thereafter, up to 11 weeks.

Reporting group title

MP: Placebo to Placebo

Reporting group description

Subjects who received placebo in the induction period received placebo intravenous infusion over 90 minutes, every other week for up to 108 weeks.

Reporting group title

MP: BMS-936557 to Placebo

Reporting group description

Subjects who received any dose of BMS-936557 in the induction period received placebo via intravenous infusion over 90 minutes, every other week for up to 108 weeks.

Reporting group title

MP: BMS-936557 5 mg/kg

Reporting group description

Subjects received BMS-936557 5 mg/kg, intravenous infusion over 90 minutes, every other week for up to 108 weeks.

Reporting group title

MP: BMS-936557 10 mg/kg

Reporting group description

Subjects received BMS-936557 10 mg/kg, intravenous infusion over 90 minutes, every other week for up to 108 weeks.

Reporting group title

MP: BMS-936557 20 mg/kg

Reporting group description

Subjects received BMS-936557 20 mg/kg, intravenous infusion over 90 minutes, every other week for up to 108 weeks.

Reporting group title

OL: BMS-936557 10 mg/kg

Reporting group description

Subjects received BMS-936557 10 mg/kg, intravenous infusion over 90 minutes, every other week for up to 41 months.

Serious adverse events	IP: Placebo	IP: BMS-936557 15 mg/kg	IP: BMS-936557 25 mg/kg	MP: Placebo to Placebo	MP: BMS-936557 to Placebo	MP: BMS-936557 5 mg/kg	MP: BMS-936557 10 mg/kg	MP: BMS-936557 20 mg/kg	OL: BMS-936557 10 mg/kg
Total subjects affected by serious adverse events
subjects affected / exposed	9 / 100 (9.00%)	6 / 102 (5.88%)	5 / 103 (4.85%)	2 / 30 (6.67%)	1 / 22 (4.55%)	2 / 24 (8.33%)	3 / 22 (13.64%)	2 / 21 (9.52%)	45 / 237 (18.99%)
number of deaths (all causes)	0	0	0	0	0	0	0	0	0
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	1 / 100 (1.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	1 / 30 (3.33%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 237 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Prostate cancer
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
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	0 / 100 (0.00%)	1 / 102 (0.98%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	1 / 22 (4.55%)	0 / 21 (0.00%)	0 / 237 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 100 (0.00%)	1 / 102 (0.98%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral artery thrombosis
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Venous thrombosis
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
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
Chills
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oedema
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	1 / 21 (4.76%)	0 / 237 (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
Pyrexia
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	1 / 103 (0.97%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 237 (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
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	1 / 103 (0.97%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
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
Prostatitis
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	1 / 30 (3.33%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 237 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 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
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism
subjects affected / exposed	0 / 100 (0.00%)	1 / 102 (0.98%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 237 (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
Psychiatric disorders
Disorientation
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Major depression
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	1 / 22 (4.55%)	0 / 21 (0.00%)	0 / 237 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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
Suicidal ideation
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	1 / 22 (4.55%)	0 / 21 (0.00%)	0 / 237 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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
Investigations
Cytomegalovirus test positive
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemoglobin decreased
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
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
Infusion related reaction
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	1 / 103 (0.97%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 237 (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
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
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 / 100 (1.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
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 failure
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
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	1 / 100 (1.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	2 / 237 (0.84%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
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
Diplopia
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
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
Abdominal pain
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	2 / 237 (0.84%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	1 / 21 (4.76%)	0 / 237 (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
Colitis ulcerative
subjects affected / exposed	5 / 100 (5.00%)	5 / 102 (4.90%)	2 / 103 (1.94%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	1 / 22 (4.55%)	0 / 21 (0.00%)	21 / 237 (8.86%)
occurrences causally related to treatment / all	0 / 5	1 / 5	0 / 4	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	1 / 22
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colon dysplasia
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diverticular perforation
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	1 / 24 (4.17%)	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 237 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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
Faecaloma
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	1 / 21 (4.76%)	0 / 237 (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
Haematochezia
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
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	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
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 chronic
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Proctitis
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
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 and subcutaneous tissue disorders
Urticaria
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
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
Calculus ureteric
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	1 / 100 (1.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
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 failure acute
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
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 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	1 / 22 (4.55%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 237 (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
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	1 / 24 (4.17%)	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 237 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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
Intervertebral disc protrusion
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
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 pain
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	1 / 21 (4.76%)	0 / 237 (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
Abscess limb
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anal abscess
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anal infection
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Catheter site infection
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
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 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic tonsillitis
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cytomegalovirus colitis
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
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 salmonella
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mycotic aneurysm
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
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	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
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
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	1 / 21 (4.76%)	0 / 237 (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
Rectal abscess
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Streptococcal endocarditis
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	1 / 30 (3.33%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 237 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 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
Subcutaneous abscess
subjects affected / exposed	1 / 100 (1.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 237 (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
Tonsillitis streptococcal
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
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	1 / 100 (1.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 237 (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
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	2 / 237 (0.84%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Type 1 diabetes mellitus
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	1 / 30 (3.33%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 237 (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

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

Non-serious adverse events	IP: Placebo	IP: BMS-936557 15 mg/kg	IP: BMS-936557 25 mg/kg	MP: Placebo to Placebo	MP: BMS-936557 to Placebo	MP: BMS-936557 5 mg/kg	MP: BMS-936557 10 mg/kg	MP: BMS-936557 20 mg/kg	OL: BMS-936557 10 mg/kg
Total subjects affected by non serious adverse events
subjects affected / exposed	44 / 100 (44.00%)	42 / 102 (41.18%)	53 / 103 (51.46%)	14 / 30 (46.67%)	13 / 22 (59.09%)	16 / 24 (66.67%)	17 / 22 (77.27%)	13 / 21 (61.90%)	149 / 237 (62.87%)
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	2 / 30 (6.67%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	2 / 237 (0.84%)
occurrences all number	0	0	0	2	0	0	0	0	2
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	1 / 100 (1.00%)	2 / 102 (1.96%)	3 / 103 (2.91%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	13 / 237 (5.49%)
occurrences all number	1	2	7	0	0	0	0	0	16
Nervous system disorders
Dizziness
subjects affected / exposed	1 / 100 (1.00%)	3 / 102 (2.94%)	3 / 103 (2.91%)	1 / 30 (3.33%)	0 / 22 (0.00%)	2 / 24 (8.33%)	0 / 22 (0.00%)	0 / 21 (0.00%)	7 / 237 (2.95%)
occurrences all number	2	3	3	1	0	2	0	0	9
Headache
subjects affected / exposed	6 / 100 (6.00%)	12 / 102 (11.76%)	18 / 103 (17.48%)	0 / 30 (0.00%)	3 / 22 (13.64%)	5 / 24 (20.83%)	6 / 22 (27.27%)	3 / 21 (14.29%)	23 / 237 (9.70%)
occurrences all number	10	19	25	0	3	28	16	4	51
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 100 (1.00%)	4 / 102 (3.92%)	5 / 103 (4.85%)	0 / 30 (0.00%)	2 / 22 (9.09%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	13 / 237 (5.49%)
occurrences all number	1	4	5	0	2	0	0	0	13
General disorders and administration site conditions
Asthenia
subjects affected / exposed	6 / 100 (6.00%)	2 / 102 (1.96%)	5 / 103 (4.85%)	3 / 30 (10.00%)	1 / 22 (4.55%)	0 / 24 (0.00%)	1 / 22 (4.55%)	0 / 21 (0.00%)	8 / 237 (3.38%)
occurrences all number	6	2	9	6	2	0	1	0	18
Fatigue
subjects affected / exposed	1 / 100 (1.00%)	4 / 102 (3.92%)	3 / 103 (2.91%)	1 / 30 (3.33%)	0 / 22 (0.00%)	1 / 24 (4.17%)	2 / 22 (9.09%)	0 / 21 (0.00%)	11 / 237 (4.64%)
occurrences all number	1	5	3	1	0	1	2	0	12
Influenza like illness
subjects affected / exposed	2 / 100 (2.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	3 / 30 (10.00%)	2 / 22 (9.09%)	2 / 24 (8.33%)	1 / 22 (4.55%)	0 / 21 (0.00%)	8 / 237 (3.38%)
occurrences all number	4	0	0	7	2	3	1	0	10
Pyrexia
subjects affected / exposed	4 / 100 (4.00%)	4 / 102 (3.92%)	4 / 103 (3.88%)	1 / 30 (3.33%)	4 / 22 (18.18%)	3 / 24 (12.50%)	2 / 22 (9.09%)	2 / 21 (9.52%)	20 / 237 (8.44%)
occurrences all number	4	4	5	1	8	3	3	2	21
Immune system disorders
Hypersensitivity
subjects affected / exposed	2 / 100 (2.00%)	6 / 102 (5.88%)	7 / 103 (6.80%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	1 / 22 (4.55%)	3 / 21 (14.29%)	7 / 237 (2.95%)
occurrences all number	2	7	7	0	0	0	1	5	11
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	1 / 100 (1.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	2 / 22 (9.09%)	0 / 21 (0.00%)	3 / 237 (1.27%)
occurrences all number	1	0	0	0	0	0	2	0	3
Abdominal pain
subjects affected / exposed	6 / 100 (6.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	4 / 30 (13.33%)	0 / 22 (0.00%)	2 / 24 (8.33%)	0 / 22 (0.00%)	1 / 21 (4.76%)	15 / 237 (6.33%)
occurrences all number	6	0	0	9	0	2	0	1	20
Abdominal pain upper
subjects affected / exposed	0 / 100 (0.00%)	1 / 102 (0.98%)	0 / 103 (0.00%)	1 / 30 (3.33%)	0 / 22 (0.00%)	1 / 24 (4.17%)	0 / 22 (0.00%)	2 / 21 (9.52%)	6 / 237 (2.53%)
occurrences all number	0	3	0	1	0	1	0	3	6
Constipation
subjects affected / exposed	1 / 100 (1.00%)	1 / 102 (0.98%)	0 / 103 (0.00%)	1 / 30 (3.33%)	2 / 22 (9.09%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	2 / 237 (0.84%)
occurrences all number	1	1	0	2	6	0	0	0	2
Diarrhoea
subjects affected / exposed	1 / 100 (1.00%)	1 / 102 (0.98%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	2 / 24 (8.33%)	1 / 22 (4.55%)	0 / 21 (0.00%)	7 / 237 (2.95%)
occurrences all number	1	1	0	0	0	2	1	0	9
Dyspepsia
subjects affected / exposed	3 / 100 (3.00%)	1 / 102 (0.98%)	3 / 103 (2.91%)	2 / 30 (6.67%)	0 / 22 (0.00%)	0 / 24 (0.00%)	2 / 22 (9.09%)	0 / 21 (0.00%)	16 / 237 (6.75%)
occurrences all number	3	1	3	2	0	0	2	0	19
Nausea
subjects affected / exposed	6 / 100 (6.00%)	6 / 102 (5.88%)	7 / 103 (6.80%)	1 / 30 (3.33%)	0 / 22 (0.00%)	2 / 24 (8.33%)	1 / 22 (4.55%)	0 / 21 (0.00%)	15 / 237 (6.33%)
occurrences all number	7	7	8	1	0	7	1	0	24
Vomiting
subjects affected / exposed	0 / 100 (0.00%)	3 / 102 (2.94%)	5 / 103 (4.85%)	1 / 30 (3.33%)	1 / 22 (4.55%)	0 / 24 (0.00%)	2 / 22 (9.09%)	0 / 21 (0.00%)	8 / 237 (3.38%)
occurrences all number	0	3	5	1	1	0	2	0	13
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	4 / 100 (4.00%)	2 / 102 (1.96%)	5 / 103 (4.85%)	0 / 30 (0.00%)	1 / 22 (4.55%)	6 / 24 (25.00%)	3 / 22 (13.64%)	2 / 21 (9.52%)	12 / 237 (5.06%)
occurrences all number	4	2	10	0	1	7	4	2	13
Nasal congestion
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	1 / 103 (0.97%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	0 / 22 (0.00%)	2 / 21 (9.52%)	4 / 237 (1.69%)
occurrences all number	0	0	1	0	0	0	0	2	5
Skin and subcutaneous tissue disorders
Dermal cyst
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	2 / 22 (9.09%)	0 / 21 (0.00%)	0 / 237 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0
Rash erythematous
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	2 / 22 (9.09%)	0 / 21 (0.00%)	1 / 237 (0.42%)
occurrences all number	0	0	0	0	0	0	2	0	2
Psychiatric disorders
Anxiety
subjects affected / exposed	1 / 100 (1.00%)	1 / 102 (0.98%)	2 / 103 (1.94%)	1 / 30 (3.33%)	1 / 22 (4.55%)	1 / 24 (4.17%)	2 / 22 (9.09%)	0 / 21 (0.00%)	6 / 237 (2.53%)
occurrences all number	1	1	2	1	1	1	2	0	7
Depression
subjects affected / exposed	0 / 100 (0.00%)	1 / 102 (0.98%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	2 / 24 (8.33%)	1 / 22 (4.55%)	0 / 21 (0.00%)	3 / 237 (1.27%)
occurrences all number	0	1	0	0	0	2	1	0	4
Insomnia
subjects affected / exposed	2 / 100 (2.00%)	2 / 102 (1.96%)	2 / 103 (1.94%)	0 / 30 (0.00%)	1 / 22 (4.55%)	2 / 24 (8.33%)	0 / 22 (0.00%)	0 / 21 (0.00%)	3 / 237 (1.27%)
occurrences all number	3	2	2	0	2	2	0	0	5
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	6 / 100 (6.00%)	3 / 102 (2.94%)	4 / 103 (3.88%)	5 / 30 (16.67%)	3 / 22 (13.64%)	5 / 24 (20.83%)	3 / 22 (13.64%)	0 / 21 (0.00%)	21 / 237 (8.86%)
occurrences all number	6	3	5	6	3	6	4	0	35
Back pain
subjects affected / exposed	2 / 100 (2.00%)	2 / 102 (1.96%)	4 / 103 (3.88%)	2 / 30 (6.67%)	0 / 22 (0.00%)	2 / 24 (8.33%)	1 / 22 (4.55%)	1 / 21 (4.76%)	14 / 237 (5.91%)
occurrences all number	2	2	5	3	0	2	1	1	19
Musculoskeletal pain
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	2 / 103 (1.94%)	0 / 30 (0.00%)	0 / 22 (0.00%)	0 / 24 (0.00%)	1 / 22 (4.55%)	2 / 21 (9.52%)	1 / 237 (0.42%)
occurrences all number	0	0	2	0	0	0	3	2	1
Myalgia
subjects affected / exposed	2 / 100 (2.00%)	2 / 102 (1.96%)	2 / 103 (1.94%)	0 / 30 (0.00%)	0 / 22 (0.00%)	2 / 24 (8.33%)	1 / 22 (4.55%)	0 / 21 (0.00%)	6 / 237 (2.53%)
occurrences all number	2	3	2	0	0	2	1	0	6
Pain in extremity
subjects affected / exposed	1 / 100 (1.00%)	0 / 102 (0.00%)	1 / 103 (0.97%)	0 / 30 (0.00%)	0 / 22 (0.00%)	2 / 24 (8.33%)	1 / 22 (4.55%)	0 / 21 (0.00%)	4 / 237 (1.69%)
occurrences all number	1	0	1	0	0	2	1	0	4
Infections and infestations
Gastroenteritis
subjects affected / exposed	1 / 100 (1.00%)	1 / 102 (0.98%)	0 / 103 (0.00%)	0 / 30 (0.00%)	2 / 22 (9.09%)	3 / 24 (12.50%)	2 / 22 (9.09%)	1 / 21 (4.76%)	12 / 237 (5.06%)
occurrences all number	1	1	0	0	2	4	2	1	16
Genital candidiasis
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	2 / 24 (8.33%)	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 237 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0
Influenza
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	2 / 103 (1.94%)	0 / 30 (0.00%)	1 / 22 (4.55%)	6 / 24 (25.00%)	1 / 22 (4.55%)	1 / 21 (4.76%)	9 / 237 (3.80%)
occurrences all number	0	0	2	0	1	8	2	2	12
Nasopharyngitis
subjects affected / exposed	5 / 100 (5.00%)	4 / 102 (3.92%)	10 / 103 (9.71%)	4 / 30 (13.33%)	1 / 22 (4.55%)	2 / 24 (8.33%)	3 / 22 (13.64%)	0 / 21 (0.00%)	39 / 237 (16.46%)
occurrences all number	8	4	11	7	1	4	5	0	65
Oral herpes
subjects affected / exposed	2 / 100 (2.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	1 / 30 (3.33%)	0 / 22 (0.00%)	0 / 24 (0.00%)	2 / 22 (9.09%)	0 / 21 (0.00%)	5 / 237 (2.11%)
occurrences all number	2	0	0	2	0	0	5	0	7
Pharyngitis
subjects affected / exposed	0 / 100 (0.00%)	2 / 102 (1.96%)	0 / 103 (0.00%)	2 / 30 (6.67%)	2 / 22 (9.09%)	0 / 24 (0.00%)	1 / 22 (4.55%)	2 / 21 (9.52%)	5 / 237 (2.11%)
occurrences all number	0	2	0	3	2	0	1	2	7
Rhinitis
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	1 / 103 (0.97%)	2 / 30 (6.67%)	0 / 22 (0.00%)	1 / 24 (4.17%)	0 / 22 (0.00%)	1 / 21 (4.76%)	3 / 237 (1.27%)
occurrences all number	0	0	5	2	0	1	0	1	5
Sinusitis
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	1 / 103 (0.97%)	1 / 30 (3.33%)	2 / 22 (9.09%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	9 / 237 (3.80%)
occurrences all number	0	0	1	3	2	0	0	0	12
Upper respiratory tract infection
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	2 / 103 (1.94%)	1 / 30 (3.33%)	1 / 22 (4.55%)	2 / 24 (8.33%)	3 / 22 (13.64%)	2 / 21 (9.52%)	24 / 237 (10.13%)
occurrences all number	0	0	2	1	1	2	5	2	31
Urinary tract infection
subjects affected / exposed	3 / 100 (3.00%)	1 / 102 (0.98%)	2 / 103 (1.94%)	1 / 30 (3.33%)	1 / 22 (4.55%)	0 / 24 (0.00%)	0 / 22 (0.00%)	0 / 21 (0.00%)	14 / 237 (5.91%)
occurrences all number	3	1	2	1	2	0	0	0	17
Viral upper respiratory tract infection
subjects affected / exposed	0 / 100 (0.00%)	0 / 102 (0.00%)	0 / 103 (0.00%)	0 / 30 (0.00%)	0 / 22 (0.00%)	2 / 24 (8.33%)	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 237 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

20 Jun 2011

• Added Drug-induced liver injury language. • Deleted 84 and 112 days post dosing visits. • Deleted requirement for male contraception. • Exclusion Criteria were modified to be more specific, Added ''Lichtiger score of >=10 and Subjects with evidence of active CMV (cytomegalovirus) infection or CMV colitis should also be excluded from the study''. • Added vital signs to each clinic and infusion visit in the T&E. • Added storage time for biopsy and exploratory biomarkers samples. • Revised to indicate a Physician’s Assistant can perform the Complete Physical Exam and the PGA for the Full Mayo Score. • Deleted creatinine from the urinalysis testing. • Added information that the diary entries should be collected prior to the preparation day for the endoscopy. • Added two secondary endpoints to match secondary objectives.

20 Oct 2011

• Changed the duration of the Induction Period (IP) to be 11 weeks and the primary endpoint to IP-78 throughout the protocol. • Changed Post Dosing Follow-up Visit from 14 days post last dose to 28 days. • Specified criteria for dose decrease and limited the option to decrease the dose to 10 mg/kg only during Open-Label. • Clarified requirements and procedures for drug administration.

19 Mar 2013

• Added severe and/or serious acute infusion reactions as a reason for discontinuation. • Clarified the infusion rate for induction period, maintenance Phase, and open label period.

16 Dec 2013

• Allowed all subjects to enter open label period regardless of clinical remission or relapse.

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.

The sponsor decided not to pursue further clinical development of BMS-936557 due to an insufficient demonstration of efficacy across studies in Inflammatory Bowel Disease .

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