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Clinical Trial Results:
Phase 3, Multicenter, Randomized, Double-blinded, Placebo-controlled, Parallel-group Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Intravenous MLN0002 (300 mg) Infusion in Induction and Maintenance Therapy in Japanese Subjects with Moderate or Severe Ulcerative Colitis

Summary
EudraCT number	2019-001198-10
Trial protocol	Outside EU/EEA
Global end of trial date	28 Jun 2018

Results information
Results version number	v1(current)
This version publication date	16 Jun 2019
First version publication date	16 Jun 2019
Other versions

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

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Trial information

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Sponsor protocol code

MLN0002/CCT-101

ISRCTN number

US NCT number

NCT02039505

WHO universal trial number (UTN)

U1111-1151-6762

Other trial identifiers

JapicCTI: JapicCTI-142403

Sponsor organisation name

Takeda

Sponsor organisation address

1-1, Doshomachi 4-chome, Chuo-ku, Osaka-shi, Osaka, Japan, 540-8645

Public contact

Medical Director, Takeda, +1877 8253327, trialdisclosures@takeda.com

Scientific contact

Medical Director, Takeda, +1877 8253327, trialdisclosures@takeda.com

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

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

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

Yes

Analysis stage

Final

Date of interim/final analysis

02 Oct 2018

Is this the analysis of the primary completion data?

Yes

Primary completion date

27 Feb 2018

Global end of trial reached?

Yes

Global end of trial date

28 Jun 2018

Was the trial ended prematurely?

Main objective of the trial

The purpose of the trial is to examine the efficacy, safety, and pharmacokinetics of intravenous Vedolizumab (300 mg) infusion in induction and maintenance therapy in Japanese patients with moderately or severely active ulcerative colitis (UC).

Protection of trial subjects

All study participants were required to read and sign an Informed Consent Form.

Background therapy

Evidence for comparator

Actual start date of recruitment

04 Feb 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Japan: 292

Worldwide total number of subjects

292

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

288

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Participants took part in the study at 86 investigative sites in Japan from 04 February 2014 to 28 June 2018.

Screening details

Participants with moderate to severe UC were enrolled. 292 participants enrolled in induction phase, 109 participants entered maintenance phase and 259 participants entered open-label cohort and received placebo or vedolizumab 300 mg and 188 completed. Open-label cohort occurred between Week 10 and Week 154 through study with maximum of 94 weeks.

Period 1 title

Induction Phase (Week 0 to Week 14)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Are arms mutually exclusive

Yes

Induction Phase: Cohort 1, Placebo

Arm description

Vedolizumab placebo-matching, intravenous (IV) infusion, once at Weeks 0, 2 and 6 in the induction phase.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate and solvent for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Vedolizumab-matching placebo on Weeks 2, 4 and 6.

Induction Phase: Cohort 1, Vedolizumab 300 mg

Arm description

Vedolizumab 300 mg, IV infusion, once at Weeks 0, 2, and 6 in the induction phase.

Arm type

Experimental

Investigational medicinal product name

Vedolizumab

Investigational medicinal product code

Other name

MLN0002

Pharmaceutical forms

Concentrate and solvent for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Vedolizumab 300 mg IV infusion on Weeks 2, 4 and 6

Induction Phase: Cohort 2, Vedolizumab 300 mg

Arm description

Vedolizumab 300 mg, IV infusion, once at Weeks 0, 2 and 6 in the induction phase.

Arm type

Experimental

Investigational medicinal product name

Vedolizumab

Investigational medicinal product code

Other name

MLN0002

Pharmaceutical forms

Concentrate and solvent for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Vedolizumab 300 mg IV infusion on Weeks 2, 4 and 6

Number of subjects in period 1	Induction Phase: Cohort 1, Placebo	Induction Phase: Cohort 1, Vedolizumab 300 mg	Induction Phase: Cohort 2, Vedolizumab 300 mg
Started	82	164	46
Completed	78	155	36
Not completed	4	9	10
Pretreatment Event/Adverse Event	2	8	7
Major Protocol Deviation	1	-	-
Lack of efficacy	1	1	3

Period 2 title

Intermediate Induction Phase

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Are arms mutually exclusive

Yes

Induction Phase: Cohort 1, Placebo

Arm description

Vedolizumab placebo-matching, intravenous (IV) infusion, once at Weeks 0, 2 and 6 in the induction phase.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Induction Phase: Cohort 1, Vedolizumab 300 mg

Arm description

Vedolizumab 300 mg, IV infusion, once at Weeks 0, 2, and 6 in the induction phase.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Induction Phase: Cohort 2, Vedolizumab 300 mg

Arm description

Vedolizumab 300 mg, IV infusion, once at Weeks 0, 2 and 6 in the induction phase.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 2	Induction Phase: Cohort 1, Placebo	Induction Phase: Cohort 1, Vedolizumab 300 mg	Induction Phase: Cohort 2, Vedolizumab 300 mg
Started	78	155	36
Completed	42	41	26
Not completed	36	114	10
Did not achieve clinical response	36	114	10

Period 3 title

Maintenance Phase (Week 14 to Week 60)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Are arms mutually exclusive

Yes

Maintenance Phase: Placebo

Arm description

Vedolizumab placebo-matching, IV infusion, once at Weeks 14, 22, 30, 38, 46 and 54 in maintenance phase. Participants received vedolizumab in induction phase and achieved clinical response at Week 10 and were randomized to receive placebo in maintenance phase.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate and solvent for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Matching placebo on Week 2, 4 and 6.

Maintenance Phase: Vedolizumab 300 mg

Arm description

Vedolizumab 300 mg, IV infusion, once at Weeks 14, 22, 30, 38, 46 and 54 in maintenance phase. Participants received vedolizumab in induction phase and achieved clinical response at Week 10 and were randomized to receive vedolizumab in maintenance phase.

Arm type

Experimental

Investigational medicinal product name

Vedolizumab

Investigational medicinal product code

Other name

MLN0002

Pharmaceutical forms

Concentrate and solvent for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Vedolizumab 300 mg IV infusion on Weeks 2, 4 and 6

Maintenance Phase: Placebo continuation

Arm description

Vedolizumab placebo-matching, IV infusion, once at Weeks 14, 22, 30, 38, 46 and 54 in maintenance phase. Participants received vedolizumab placebo-matching in induction phase and achieved clinical response at Week 10 received placebo in maintenance phase without randomization.

Arm type

Experimental

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate and solvent for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Matching placebo on Week 2, 4 and 6.

Number of subjects in period 3	Maintenance Phase: Placebo	Maintenance Phase: Vedolizumab 300 mg	Maintenance Phase: Placebo continuation
Started	42	41	26
Completed	18	30	12
Not completed	24	11	14
Pretreatment Event/Adverse Event	6	1	1
Voluntary Withdrawal	3	2	1
Pregnancy	2	-	-
Lack of efficacy	13	8	12

Baseline characteristics

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Reporting group title

Induction Phase: Cohort 1, Placebo

Reporting group description

Vedolizumab placebo-matching, intravenous (IV) infusion, once at Weeks 0, 2 and 6 in the induction phase.

Reporting group title

Induction Phase: Cohort 1, Vedolizumab 300 mg

Reporting group description

Vedolizumab 300 mg, IV infusion, once at Weeks 0, 2, and 6 in the induction phase.

Reporting group title

Induction Phase: Cohort 2, Vedolizumab 300 mg

Reporting group description

Vedolizumab 300 mg, IV infusion, once at Weeks 0, 2 and 6 in the induction phase.

Reporting group values	Induction Phase: Cohort 1, Placebo	Induction Phase: Cohort 1, Vedolizumab 300 mg	Induction Phase: Cohort 2, Vedolizumab 300 mg	Total
Number of subjects	82	164	46	292
Age categorical
Units: Subjects
Age Continuous
Units: years
arithmetic mean (standard deviation)	44.0 ( 15.97 )	42.3 ( 14.42 )	42.4 ( 15.60 )	-
Sex: Female, Male
Units: Subjects
Female	27	65	20	112
Male	55	99	26	180
Smoking Classification
Units: Subjects
Never smoked	44	85	23	152
Current smoker	3	9	5	17
Ex-smoker	35	70	18	123
Disease Localization
Units: Subjects
Total Colitis	51	101	32	184
Left-sided Colitis	31	63	14	108
Extraintestinal Manifestations
Units: Subjects
Had No Extraintestinal Manifestations	66	111	32	209
Had Extraintestinal Manifestations	16	53	14	83
Region of Enrollment
Units: Subjects
Japan	82	164	46	292
Weight
99999: Data was not analyzed for the subject analysis set.
Units: kg
arithmetic mean (standard deviation)	60.36 ( 12.411 )	58.58 ( 11.640 )	57.74 ( 10.559 )	-
Body Mass Index (BMI)
Body Mass Index = weight(kg)/[height(m)^2]. 99999: Data was not analyzed for the subject analysis set.
Units: kg/m^2
arithmetic mean (standard deviation)	21.76 ( 3.660 )	21.72 ( 3.411 )	21.12 ( 2.714 )	-
Duration of Ulcerative Colitis (UC)
Mean duration between the first diagnosis of ulcerative colitis and the start of the study was reported. 99999: Data was not analyzed for the subject analysis set.
Units: years
arithmetic mean (standard deviation)	8.57 ( 7.973 )	7.23 ( 6.230 )	9.19 ( 7.725 )	-
Complete Mayo Score
The Mayo Score is a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consists of 4 subscores: rectal bleeding, stool frequency, findings on endoscopy, and physician's global assessment. Each subscore is scored on a scale from 0 to 3 and the complete Mayo score ranges from 0 to 12 (higher scores indicate greater disease activity). 99999: Data was not analyzed for the subject analysis set.
Units: score on a scale
arithmetic mean (standard deviation)	8.1 ( 1.50 )	8.3 ( 1.54 )	8.3 ( 1.66 )	-

Subject analysis set title

Open-Label Cohort: Vedolizumab 300 mg

Subject analysis set type

Safety analysis

Subject analysis set description

Vedolizumab 300 mg, IV infusion, once at Weeks 0, 2 and 6 and then every 8 weeks thereafter up to Week 94 in open-label cohort.

Subject analysis sets values	Open-Label Cohort: Vedolizumab 300 mg
Number of subjects	259
Age categorical
Units: Subjects
Age Continuous
Units: years
arithmetic mean (standard deviation)	( )
Sex: Female, Male
Units: Subjects
Female
Male
Smoking Classification
Units: Subjects
Never smoked
Current smoker
Ex-smoker
Disease Localization
Units: Subjects
Total Colitis
Left-sided Colitis
Extraintestinal Manifestations
Units: Subjects
Had No Extraintestinal Manifestations
Had Extraintestinal Manifestations
Region of Enrollment
Units: Subjects
Japan
Weight
99999: Data was not analyzed for the subject analysis set.
Units: kg
arithmetic mean (standard deviation)	99999 ( 99999 )
Body Mass Index (BMI)
Body Mass Index = weight(kg)/[height(m)^2]. 99999: Data was not analyzed for the subject analysis set.
Units: kg/m^2
arithmetic mean (standard deviation)	99999 ( 99999 )
Duration of Ulcerative Colitis (UC)
Mean duration between the first diagnosis of ulcerative colitis and the start of the study was reported. 99999: Data was not analyzed for the subject analysis set.
Units: years
arithmetic mean (standard deviation)	99999 ( 99999 )
Complete Mayo Score
The Mayo Score is a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consists of 4 subscores: rectal bleeding, stool frequency, findings on endoscopy, and physician's global assessment. Each subscore is scored on a scale from 0 to 3 and the complete Mayo score ranges from 0 to 12 (higher scores indicate greater disease activity). 99999: Data was not analyzed for the subject analysis set.
Units: score on a scale
arithmetic mean (standard deviation)	99999 ( 99999 )

End points

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Reporting group title

Induction Phase: Cohort 1, Placebo

Reporting group description

Vedolizumab placebo-matching, intravenous (IV) infusion, once at Weeks 0, 2 and 6 in the induction phase.

Reporting group title

Induction Phase: Cohort 1, Vedolizumab 300 mg

Reporting group description

Vedolizumab 300 mg, IV infusion, once at Weeks 0, 2, and 6 in the induction phase.

Reporting group title

Induction Phase: Cohort 2, Vedolizumab 300 mg

Reporting group description

Vedolizumab 300 mg, IV infusion, once at Weeks 0, 2 and 6 in the induction phase.

Reporting group title

Induction Phase: Cohort 1, Placebo

Reporting group description

Vedolizumab placebo-matching, intravenous (IV) infusion, once at Weeks 0, 2 and 6 in the induction phase.

Reporting group title

Induction Phase: Cohort 1, Vedolizumab 300 mg

Reporting group description

Vedolizumab 300 mg, IV infusion, once at Weeks 0, 2, and 6 in the induction phase.

Reporting group title

Induction Phase: Cohort 2, Vedolizumab 300 mg

Reporting group description

Vedolizumab 300 mg, IV infusion, once at Weeks 0, 2 and 6 in the induction phase.

Reporting group title

Maintenance Phase: Placebo

Reporting group description

Reporting group title

Maintenance Phase: Vedolizumab 300 mg

Reporting group description

Reporting group title

Maintenance Phase: Placebo continuation

Reporting group description

Subject analysis set title

Open-Label Cohort: Vedolizumab 300 mg

Subject analysis set type

Safety analysis

Subject analysis set description

Vedolizumab 300 mg, IV infusion, once at Weeks 0, 2 and 6 and then every 8 weeks thereafter up to Week 94 in open-label cohort.

Primary: Percentage of Participants with a Clinical Response at Week 10 in Induction Phase

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End point title

Percentage of Participants with a Clinical Response at Week 10 in Induction Phase ^[1]

End point description

Clinical response is defined as a reduction in complete Mayo score of ≥3 points and ≥30% from Baseline with an accompanying decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding subscore of ≤1 point. Mayo Score is a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consists of 4 subscores (rectal bleeding, stool frequency, findings on endoscopy, and physician's global assessment), a global assessment by the physician, and an endoscopic subscore. Each subscore is scored on a scale from 0 to 3 and the complete Mayo score ranges from 0 to 12 (higher scores indicate greater disease activity). Full analysis set (FAS) included participants who were randomized and received at least one dose of the study drug in the induction phase. The FAS in the induction phase does not include participants allocated in the Cohort 2 in the induction phase.

End point type

Primary

End point timeframe

Week 10

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was performed only in the Induction Phase.

End point values	Induction Phase: Cohort 1, Placebo	Induction Phase: Cohort 1, Vedolizumab 300 mg
Number of subjects analysed	82	164
Units: percentage of participants
number (confidence interval 95%)	32.9 (22.942 to 44.186)	39.6 (32.093 to 47.557)

Statistical Analysis 1

Comparison groups

Induction Phase: Cohort 1, Vedolizumab 300 mg v Induction Phase: Cohort 1, Placebo

Number of subjects included in analysis

246

Analysis specification

Pre-specified

Analysis type

P-value

= 0.2722 ^[2]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Odds Ratio

Point estimate

1.37

Confidence interval

level

95%

sides

2-sided

lower limit

0.779

upper limit

2.399

Notes
[2] - Cochran-Mantel-Haenszel (CMH) test was used for analysis. Prior tumor necrosis factor alpha (TNFα) antagonist use (yes/no) was used as stratification factor.

Primary: Percentage of Participants with Clinical Remission at Week 60 in Maintenance Phase

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End point title

Percentage of Participants with Clinical Remission at Week 60 in Maintenance Phase

End point description

Clinical Remission is defined as a complete Mayo score of ≤2 points and no individual subscore >1 point. Mayo Score is a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consists of 4 subscores: rectal bleeding, stool frequency, findings on endoscopy, and physician's global assessment. Each subscore is scored on a scale from 0 to 3 and the complete Mayo score ranges from 0 to 12 (higher scores indicate greater disease activity). FAS included participants who were randomized and received at least one dose of the study drug in the maintenance phase. The FAS in the maintenance phase does not include participants who received placebo in the induction phase and were enrolled into the maintenance phase.

End point type

Primary

End point timeframe

Week 60

End point values	Maintenance Phase: Placebo	Maintenance Phase: Vedolizumab 300 mg
Number of subjects analysed	42	41
Units: percentage of participants
number (confidence interval 95%)	31.0 (17.622 to 47.086)	56.1 (39.750 to 71.531)

Statistical Analysis 1

Comparison groups

Maintenance Phase: Placebo v Maintenance Phase: Vedolizumab 300 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.021 ^[3]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Odds Ratio

Point estimate

2.88

Confidence interval

level

95%

sides

2-sided

lower limit

1.168

upper limit

7.108

Notes
[3] - CMH test was used for analysis. Prior TNFα antagonist use (yes/no) was used as stratification factor.

Primary: Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Events (TEAEs)

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End point title

Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Events (TEAEs) ^[4]

End point description

An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. Safety analysis set included participants who received at least one dose of the study drug in either the induction phase, the maintenance phase or the open-label cohort.

End point type

Primary

End point timeframe

From Baseline to 16 weeks after the last dose of study drug (Up to approximately 170 weeks)

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Statistical analyses were not planned for this endpoint.

End point values	Induction Phase: Cohort 1, Placebo	Maintenance Phase: Placebo	Induction Phase: Cohort 1, Vedolizumab 300 mg	Maintenance Phase: Vedolizumab 300 mg	Induction Phase: Cohort 2, Vedolizumab 300 mg	Maintenance Phase: Placebo continuation	Open-Label Cohort: Vedolizumab 300 mg
Number of subjects analysed	82	42	164	41	46	26	259
Units: participants	43	33	82	36	33	18	241

No statistical analyses for this end point

Primary: Number of Participants with TEAE Related to Body Weight

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End point title

Number of Participants with TEAE Related to Body Weight ^[5]

End point description

Safety analysis set included participants who received at least one dose of the study drug in either the induction phase, the maintenance phase or the open-label cohort.

End point type

Primary

End point timeframe

From Baseline to 16 weeks after the last dose of study drug (Up to approximately 170 weeks)

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Statistical analyses were not planned for this endpoint.

End point values	Induction Phase: Cohort 1, Placebo	Maintenance Phase: Placebo	Induction Phase: Cohort 1, Vedolizumab 300 mg	Maintenance Phase: Vedolizumab 300 mg	Induction Phase: Cohort 2, Vedolizumab 300 mg	Maintenance Phase: Placebo continuation	Open-Label Cohort: Vedolizumab 300 mg
Number of subjects analysed	82	42	164	41	46	26	259
Units: participants	0	0	0	0	0	0	0

No statistical analyses for this end point

Primary: Number of Participants with TEAE Related to Vital Signs

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End point title

Number of Participants with TEAE Related to Vital Signs ^[6]

End point description

Vital signs included body temperature (axilla), sitting blood pressure (after the participant has rested for at least 5 minutes), and pulse (bpm). Safety analysis set included participants who received at least one dose of the study drug in either the induction phase, the maintenance phase or the open-label cohort.

End point type

Primary

End point timeframe

From Baseline to 16 weeks after the last dose of study drug (Up to approximately 170 weeks)

Notes
[6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Statistical analyses were not planned for this endpoint.

End point values	Induction Phase: Cohort 1, Placebo	Maintenance Phase: Placebo	Induction Phase: Cohort 1, Vedolizumab 300 mg	Maintenance Phase: Vedolizumab 300 mg	Induction Phase: Cohort 2, Vedolizumab 300 mg	Maintenance Phase: Placebo continuation	Open-Label Cohort: Vedolizumab 300 mg
Number of subjects analysed	82	42	164	41	46	26	259
Units: participants	2	2	5	2	3	0	24

No statistical analyses for this end point

Primary: Number of Participants with TEAE Related to Electrocardiogram (ECG)

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End point title

Number of Participants with TEAE Related to Electrocardiogram (ECG) ^[7]

End point description

Safety analysis set included participants who received at least one dose of the study drug in either the induction phase, the maintenance phase or the open-label cohort.

End point type

Primary

End point timeframe

From Baseline to 16 weeks after the last dose of study drug (Up to approximately 170 weeks)

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Statistical analyses were not planned for this endpoint.

End point values	Induction Phase: Cohort 1, Placebo	Maintenance Phase: Placebo	Induction Phase: Cohort 1, Vedolizumab 300 mg	Maintenance Phase: Vedolizumab 300 mg	Induction Phase: Cohort 2, Vedolizumab 300 mg	Maintenance Phase: Placebo continuation	Open-Label Cohort: Vedolizumab 300 mg
Number of subjects analysed	82	42	164	41	46	26	259
Units: participants	1	0	1	0	0	1	1

No statistical analyses for this end point

Primary: Number of Participants with Markedly Abnormal Laboratory Parameters Values

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End point title

Number of Participants with Markedly Abnormal Laboratory Parameters Values ^[8]

End point description

The laboratory values outside the range (Hemoglobin <=7 g/dL, Lymphocytes <500 /µL, WBC <2000 /µL, Platelets <7.5 10^4/µL, Neutrophils <1000 /µL, alanine aminotransferase (ALT) >3.0 U/L x upper limit of normal (ULN), aspartate aminotransferase AST >3.0 U/L x ULN, Total Bilirubin >2.0 mg/dL x ULN, Amylase >2.0 (U/L) x ULN were considered markedly abnormal. Safety analysis set included participants who received at least one dose of the study drug in either the induction phase, the maintenance phase or the open-label cohort.

End point type

Primary

End point timeframe

From Baseline to 16 weeks after the last dose of study drug (Up to approximately 170 weeks)

Notes
[8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Statistical analyses were not planned for this endpoint.

End point values	Induction Phase: Cohort 1, Placebo	Maintenance Phase: Placebo	Induction Phase: Cohort 1, Vedolizumab 300 mg	Maintenance Phase: Vedolizumab 300 mg	Induction Phase: Cohort 2, Vedolizumab 300 mg	Maintenance Phase: Placebo continuation	Open-Label Cohort: Vedolizumab 300 mg
Number of subjects analysed	82	42	164	41	46	26	259
Units: participants
Hemoglobin (g/dL) <=7	1	0	4	0	1	0	6
Lymphocytes (/µL) <500	6	1	2	0	2	1	20
White Blood Cell (WBC) (/µL) <2000	0	0	0	0	1	0	0
Neutrophils (/µL) <1000	1	1	1	0	1	0	4
Alanine Aminotransferase (ALT) (U/L) >3.0 x ULN	1	1	0	0	0	0	4
Aspartate Aminotransferase (AST) (U/L) >3.0 x ULN	1	1	0	0	0	0	2
Total Bilirubin (mg/dL) >2.0 x ULN	0	0	2	0	0	0	1
Amylase (U/L) >2.0 x ULN	1	0	2	0	1	0	4

No statistical analyses for this end point

Secondary: Percentage of Participants with Clinical Remission at Week 10 in Induction Phase

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End point title

Percentage of Participants with Clinical Remission at Week 10 in Induction Phase ^[9]

End point description

Clinical Remission is defined as a complete Mayo score of ≤2 points and no individual subscore >1 point. Mayo Score is a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consists of 4 subscores: rectal bleeding, stool frequency, findings on endoscopy, and physician's global assessment. Each subscore is scored on a scale from 0 to 3 and the complete Mayo score ranges from 0 to 12 (higher scores indicate greater disease activity). FAS included participants who were randomized and received at least one dose of the study drug in the induction phase. The FAS in the induction phase does not include participants allocated in the Cohort 2 in the induction phase.

End point type

Secondary

End point timeframe

Week 10

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was performed only in the Induction Phase.

End point values	Induction Phase: Cohort 1, Placebo	Induction Phase: Cohort 1, Vedolizumab 300 mg
Number of subjects analysed	82	164
Units: percentage of participants
number (confidence interval 95%)	12.2 (6.006 to 21.286)	18.3 (12.695 to 25.072)

Statistical Analysis 1

Comparison groups

Induction Phase: Cohort 1, Placebo v Induction Phase: Cohort 1, Vedolizumab 300 mg

Number of subjects included in analysis

246

Analysis specification

Pre-specified

Analysis type

P-value

= 0.198 ^[10]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Odds Ratio

Point estimate

1.66

Confidence interval

level

95%

sides

2-sided

lower limit

0.762

upper limit

3.596

Notes
[10] - CMH test was used for analysis. Prior TNFα antagonist use (yes/no) was used as stratification factor.

Secondary: Percentage of Participants with Mucosal Healing at Week 10 in Induction Phase

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End point title

Percentage of Participants with Mucosal Healing at Week 10 in Induction Phase ^[11]

End point description

Mucosal healing is defined as a Mayo endoscopic subscore of ≤1 point. Mayo Score is a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consists of 4 subscores: rectal bleeding, stool frequency, findings on endoscopy, and physician's global assessment. Endoscopic findings were scored on a scale from 0 to 3 as follows: 0=Normal or inactive disease; 1=Mild disease (erythema, decreased vascular pattern, mild friability); 2=Moderate disease (marked erythema, lack of vascular pattern, friability, erosions); 3=Severe disease (spontaneous bleeding, ulceration). FAS included participants who were randomized and received at least one dose of the study drug in the induction phase. The FAS in the induction phase does not include participants allocated in the Cohort 2 in the induction phase.

End point type

Secondary

End point timeframe

Week 10

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was performed only in the Induction Phase.

End point values	Induction Phase: Cohort 1, Placebo	Induction Phase: Cohort 1, Vedolizumab 300 mg
Number of subjects analysed	82	164
Units: percentage of participants
number (confidence interval 95%)	30.5 (20.796 to 41.638)	36.6 (29.213 to 44.452)

Statistical Analysis 1

Comparison groups

Induction Phase: Cohort 1, Placebo v Induction Phase: Cohort 1, Vedolizumab 300 mg

Number of subjects included in analysis

246

Analysis specification

Pre-specified

Analysis type

P-value

= 0.3168 ^[12]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Odds Ratio

Point estimate

1.33

Confidence interval

level

95%

sides

2-sided

lower limit

0.755

upper limit

2.356

Notes
[12] - CMH test was used for analysis. Prior TNFα antagonist use (yes/no) was used as stratification factor.

Secondary: Percentage of Participants with Durable Clinical Response in Maintenance Phase

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End point title

Percentage of Participants with Durable Clinical Response in Maintenance Phase

End point description

Durable clinical response is defined as reduction in complete Mayo score of ≥3 points and ≥30% from Baseline (Week 0) with an accompanying decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding subscore of ≤1 point at both Weeks 10 and 60. Mayo Score is a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consists of 4 subscores: rectal bleeding, stool frequency, findings on endoscopy, and physician's global assessment. Each subscore is scored on a scale from 0 to 3 and the complete Mayo score ranges from 0 to 12 (higher scores indicate greater disease activity). FAS included participants who were randomized and received at least one dose of the study drug in the maintenance phase. The FAS in the maintenance phase does not include participants who received placebo in the induction phase and were enrolled into the maintenance phase.

End point type

Secondary

End point timeframe

Weeks 10 and 60

End point values	Maintenance Phase: Placebo	Maintenance Phase: Vedolizumab 300 mg
Number of subjects analysed	42	41
Units: percentage of participants
number (confidence interval 95%)	35.7 (21.551 to 51.974)	65.9 (49.405 to 79.917)

Statistical Analysis 1

Comparison groups

Maintenance Phase: Placebo v Maintenance Phase: Vedolizumab 300 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0067 ^[13]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Odds Ratio

Point estimate

3.48

Confidence interval

level

95%

sides

2-sided

lower limit

1.407

upper limit

8.626

Notes
[13] - CMH test was used for analysis. Prior TNFα antagonist use (yes/no) was used as stratification factor.

Secondary: Percentage of Participants with Mucosal Healing at Week 60 in Maintenance Phase

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End point title

Percentage of Participants with Mucosal Healing at Week 60 in Maintenance Phase

End point description

Mucosal healing is defined as a Mayo endoscopic subscore of ≤1 point. Mayo Score is a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consists of 4 subscores: rectal bleeding, stool frequency, findings on endoscopy, and physician's global assessment. Endoscopic findings were scored on a scale from 0 to 3 as follows: 0=Normal or inactive disease; 1=Mild disease (erythema, decreased vascular pattern, mild friability); 2=Moderate disease (marked erythema, lack of vascular pattern, friability, erosions); 3=Severe disease (spontaneous bleeding, ulceration). FAS included participants who were randomized and received at least one dose of the study drug in the maintenance phase. The FAS in the maintenance phase does not include participants who received placebo in the induction phase and were enrolled into the maintenance phase.

End point type

Secondary

End point timeframe

Week 60

End point values	Maintenance Phase: Placebo	Maintenance Phase: Vedolizumab 300 mg
Number of subjects analysed	42	41
Units: percentage of participants
number (confidence interval 95%)	33.3 (19.567 to 49.549)	63.4 (46.936 to 77.877)

Statistical Analysis 1

Comparison groups

Maintenance Phase: Placebo v Maintenance Phase: Vedolizumab 300 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0066

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Odds Ratio

Point estimate

3.49

Confidence interval

level

95%

sides

2-sided

lower limit

1.409

upper limit

8.642

Secondary: Percentage of Participants with Durable Remission in Maintenance Phase

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End point title

Percentage of Participants with Durable Remission in Maintenance Phase

End point description

Durable clinical remission is defined as complete Mayo score of ≤2 points and no individual subscore >1 point at both Weeks 10 and 60. Mayo Score is a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consists of 4 subscores: rectal bleeding, stool frequency, findings on endoscopy, and physician's global assessment. Each subscore is scored on a scale from 0 to 3 and the complete Mayo score ranges from 0 to 12 (higher scores indicate greater disease activity). FAS included participants who were randomized and received at least one dose of the study drug in the maintenance phase. The FAS in the maintenance phase does not include participants who received placebo in the induction phase and were enrolled into the maintenance phase.

End point type

Secondary

End point timeframe

Weeks 10 and 60

End point values	Maintenance Phase: Placebo	Maintenance Phase: Vedolizumab 300 mg
Number of subjects analysed	42	41
Units: percentage of participants
number (confidence interval 95%)	16.7 (6.974 to 31.364)	26.8 (14.221 to 42.944)

Statistical Analysis 1

Comparison groups

Maintenance Phase: Placebo v Maintenance Phase: Vedolizumab 300 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.209 ^[14]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Odds Ratio

Point estimate

2.02

Confidence interval

level

95%

sides

2-sided

lower limit

0.677

upper limit

6.033

Notes
[14] - CMH test was used for analysis. Prior TNFα antagonist use (yes/no) was used as stratification factor.

Secondary: Percentage of Participants with Corticosteroid-Free Remission at Week 60 in Maintenance Phase

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End point title

Percentage of Participants with Corticosteroid-Free Remission at Week 60 in Maintenance Phase

End point description

Clinical Remission is defined as a complete Mayo score of ≤2 points and no individual subscore >1 point. Corticosteroid-free clinical remission is defined as participants using oral corticosteroids at baseline (Week 0) who discontinued corticosteroids and were in clinical remission at Week 60. Mayo Score is a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consists of 4 subscores: rectal bleeding, stool frequency, findings on endoscopy, and physician's global assessment. Each subscore is scored on a scale from 0 to 3 and the complete Mayo score ranges from 0 to 12 (higher scores indicate greater disease activity). Participants from FAS included participants who were randomized and received at least one dose of the study drug in the maintenance phase and administered oral corticosteroids concomitantly at Week 0, were analyzed at the given timepoint.

End point type

Secondary

End point timeframe

Week 60

End point values	Maintenance Phase: Placebo	Maintenance Phase: Vedolizumab 300 mg
Number of subjects analysed	15	13
Units: percentage of participants
number (confidence interval 95%)	20.0 (4.331 to 48.089)	46.2 (19.223 to 74.865)

Statistical Analysis 1

Comparison groups

Maintenance Phase: Placebo v Maintenance Phase: Vedolizumab 300 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.1571 ^[15]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Odds Ratio

Point estimate

3.38

Confidence interval

level

95%

sides

2-sided

lower limit

0.636

upper limit

17.981

Notes
[15] - CMH test was used for analysis. Prior TNFα antagonist use (yes/no) was used as stratification factor.

Secondary: Serum Vedolizumab Concentration in Induction Phase

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End point title

Serum Vedolizumab Concentration in Induction Phase ^[16]

End point description

Participants from FAS, who received at least one dose of study drug in induction phase for whom sample was available for pharmacokinetic (PK) analysis. n=number of participants with evaluable data at the given time-point.

End point type

Secondary

End point timeframe

Pre-dose at Weeks 2, 6, 10 and 14

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was performed only in the Induction Phase.

End point values	Induction Phase: Cohort 1, Vedolizumab 300 mg	Induction Phase: Cohort 2, Vedolizumab 300 mg
Number of subjects analysed	164	46
Units: μg/mL
arithmetic mean (standard deviation)
Week 2 (n=104, 31)	31.93 ( 9.0617 )	33.96 ( 7.7002 )
Week 6 (n=96, 28)	29.58 ( 12.965 )	31.53 ( 12.937 )
Week 10 (n=110, 29)	31.42 ( 14.462 )	36.63 ( 16.058 )
Week 14 (n=45, 12)	16.09 ( 7.3624 )	19.04 ( 6.6528 )

No statistical analyses for this end point

Secondary: Serum Vedolizumab Concentration in Maintenance Phase

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End point title

Serum Vedolizumab Concentration in Maintenance Phase

End point description

Participants from FAS, who were randomized and received at least one dose of the study drug in the maintenance phase for whom sample was available for PK analysis. n=number of participants with evaluable data at the given time-point.

End point type

Secondary

End point timeframe

Pre-dose at Weeks 2, 6, 10, 14, 22, 30 and 60

End point values	Maintenance Phase: Placebo	Maintenance Phase: Vedolizumab 300 mg
Number of subjects analysed	42	41
Units: μg/mL
arithmetic mean (standard deviation)
Week 2 (n=31, 30)	32.87 ( 9.8729 )	34.92 ( 7.3732 )
Week 6 (n=29, 27)	32.80 ( 12.953 )	35.87 ( 11.983 )
Week 10 (n=32, 32)	39.21 ( 15.076 )	41.02 ( 11.955 )
Week 14 (n=27, 30)	16.05 ( 7.4224 )	17.31 ( 7.1914 )
Week 22 (n=25, 26)	2.913 ( 2.3243 )	14.45 ( 6.0327 )
Week 30 (n=25, 25)	0.2200 ( 0.48146 )	13.77 ( 6.3692 )
Week 60 (n=14, 25)	0.000 ( 0.0000 )	21.16 ( 8.9078 )

No statistical analyses for this end point

Secondary: Number of Participants with Anti-vedolizumab Antibodies (AVA) in Induction Phase

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End point title

Number of Participants with Anti-vedolizumab Antibodies (AVA) in Induction Phase ^[17]

End point description

Blood samples were collected and tested for serum concentration of anti-vedolizumab antibodies in a laboratory by means of electrochemoluminescent (ECL) assay. Participants who underwent proper AVA test out of "the FAS in the induction phase" and, "the participants who received at least one dose of study drug in the Cohort 2" were analyzed at the given timepoint. n=number of participants with evaluable data at the given time-point.

End point type

Secondary

End point timeframe

Weeks 0, 10 and 16 weeks after the last dose of study drug (Up to approximately 170 weeks)

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was performed only in the Induction Phase.

End point values	Induction Phase: Cohort 1, Vedolizumab 300 mg	Induction Phase: Cohort 2, Vedolizumab 300 mg
Number of subjects analysed	164	46
Units: participants
Week 0 (n=116, 36)	0	0
Week 10 (n=116, 36)	1	0
16 Weeks After Last Administration (n=7, 7)	1	1

No statistical analyses for this end point

Secondary: Number of Participants with Anti-vedolizumab Antibodies (AVA) in Maintenance Phase

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End point title

Number of Participants with Anti-vedolizumab Antibodies (AVA) in Maintenance Phase

End point description

Blood samples were collected and tested for serum concentration of anti-vedolizumab antibodies in a laboratory by means of ECL assay. Participants who underwent proper AVA test out of the FAS, the participants who received at least one dose of study drug in the maintenance phase were analyzed at the given timepoint. n=number of participants with evaluable data at the given time-point.

End point type

Secondary

End point timeframe

Weeks 0, 10, 30, 60 and 16 weeks after the last dose of study drug (Up to approximately 170 weeks)

End point values	Maintenance Phase: Placebo	Maintenance Phase: Vedolizumab 300 mg
Number of subjects analysed	42	41
Units: participants
Week 0 (n=32, 33)	0	0
Week 10 (n=32, 33)	0	0
Week 30 (n=31, 33)	4	0
Week 60 (n=17, 25)	1	0
16 Weeks After Last Administration (n=4, 2)	0	0

No statistical analyses for this end point

Secondary: Number of Participants with Neutralizing Anti-vedolizumab Antibodies (AVA) in Induction Phase

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End point title

Number of Participants with Neutralizing Anti-vedolizumab Antibodies (AVA) in Induction Phase ^[18]

End point description

Blood samples were collected, and serum neutralizing AVA was determined only for the AVA-positive samples in a laboratory by means of ECL assay. Participants who underwent proper AVA test out of "the FAS in the induction phase" and, "the participants who received at least one dose of study drug in the Cohort 2 were analyzed at the given timepoint. n=number of participants with evaluable data at the given time-point.

End point type

Secondary

End point timeframe

Weeks 0, 10 and 16 weeks after the last dose of study drug (Up to approximately 170 weeks)

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Statistical analyses were not planned for this endpoint.

End point values	Induction Phase: Cohort 1, Vedolizumab 300 mg	Induction Phase: Cohort 2, Vedolizumab 300 mg
Number of subjects analysed	164	46
Units: participants
Week 0 (n=116, 36)	0	0
Week 10 (n=116, 36)	1	0
16 Weeks After Last Administration (n=7, 7)	1	1

No statistical analyses for this end point

Secondary: Number of Participants with Neutralizing Anti-vedolizumab Antibodies (AVA) in Maintenance Phase

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End point title

Number of Participants with Neutralizing Anti-vedolizumab Antibodies (AVA) in Maintenance Phase

End point description

Blood samples were collected, and serum neutralizing AVA was determined only for the AVA-positive samples in a laboratory by means of ECL assay. Participants who underwent proper AVA test out of the FAS, the participants who received at least one dose of study drug in the maintenance phase were analyzed at the given timepoint. n=number of participants with evaluable data at the given time-point.

End point type

Secondary

End point timeframe

Weeks 0, 10, 30, 60 and 16 weeks after the last dose of study drug (Up to approximately 170 weeks)

End point values	Maintenance Phase: Placebo	Maintenance Phase: Vedolizumab 300 mg
Number of subjects analysed	42	41
Units: participants
Week 0 (n=32, 33)	0	0
Week 10 (n=32, 33)	0	0
Week 30 (n=31, 32)	3	0
Week 60 (n=17, 25)	0	0
16 Weeks After Last Administration (n=4, 2)	0	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From Baseline to 16 weeks after the last dose of study drug (Up to approximately 170 weeks)

Adverse event reporting additional description

At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

Induction Phase: Cohort 1, Placebo

Reporting group description

Vedolizumab placebo-matching, intravenous (IV) infusion, once at Weeks 0, 2 and 6 in the induction phase.

Reporting group title

Induction Phase: Cohort 1, Vedolizumab 300 mg

Reporting group description

Vedolizumab 300 mg, IV infusion, once at Weeks 0, 2, and 6 in the induction phase.

Reporting group title

Induction Phase: Cohort 2, Vedolizumab 300 mg

Reporting group description

Vedolizumab 300 mg, IV infusion, once at Weeks 0, 2 and 6 in the induction phase.

Reporting group title

Maintenance Phase: Placebo

Reporting group description

Reporting group title

Maintenance Phase: Vedolizumab 300 mg

Reporting group description

Reporting group title

Maintenance Phase: Placebo continuation

Reporting group description

Reporting group title

Open-Label Cohort: Vedolizumab 300 mg

Reporting group description

Vedolizumab 300 mg, IV infusion, once at Weeks 0, 2 and 6 and then every 8 weeks thereafter up to Week 94 in open-label cohort.

Serious adverse events	Induction Phase: Cohort 1, Placebo	Induction Phase: Cohort 1, Vedolizumab 300 mg	Induction Phase: Cohort 2, Vedolizumab 300 mg	Maintenance Phase: Placebo	Maintenance Phase: Vedolizumab 300 mg	Maintenance Phase: Placebo continuation	Open-Label Cohort: Vedolizumab 300 mg
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 82 (4.88%)	10 / 164 (6.10%)	6 / 46 (13.04%)	3 / 42 (7.14%)	4 / 41 (9.76%)	1 / 26 (3.85%)	48 / 259 (18.53%)
number of deaths (all causes)	0	0	0	0	0	0	0
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Uterine leiomyoma
subjects affected / exposed	0 / 82 (0.00%)	1 / 164 (0.61%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	0 / 259 (0.00%)
occurrences causally related to treatment / all	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
Colon adenoma
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	1 / 259 (0.39%)
occurrences causally related to treatment / all	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
Prostate cancer
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	1 / 259 (0.39%)
occurrences causally related to treatment / all	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
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 82 (0.00%)	1 / 164 (0.61%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	0 / 259 (0.00%)
occurrences causally related to treatment / all	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
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	1 / 41 (2.44%)	0 / 26 (0.00%)	0 / 259 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 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
Drug intolerance
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	1 / 259 (0.39%)
occurrences causally related to treatment / all	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
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	1 / 259 (0.39%)
occurrences causally related to treatment / all	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
Reproductive system and breast disorders
Cervical dysplasia
subjects affected / exposed	0 / 82 (0.00%)	1 / 164 (0.61%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	0 / 259 (0.00%)
occurrences causally related to treatment / all	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
Endometriosis
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	1 / 42 (2.38%)	0 / 41 (0.00%)	0 / 26 (0.00%)	0 / 259 (0.00%)
occurrences causally related to treatment / all	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
Investigations
White blood cell count decreased
subjects affected / exposed	0 / 82 (0.00%)	1 / 164 (0.61%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	0 / 259 (0.00%)
occurrences causally related to treatment / all	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
Chest X-ray abnormal
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	1 / 259 (0.39%)
occurrences causally related to treatment / all	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
Eosinophil count increased
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	1 / 259 (0.39%)
occurrences causally related to treatment / all	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
Injury, poisoning and procedural complications
Foreign body
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	1 / 259 (0.39%)
occurrences causally related to treatment / all	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
Lower limb fracture
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	1 / 259 (0.39%)
occurrences causally related to treatment / all	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
Radius fracture
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	1 / 259 (0.39%)
occurrences causally related to treatment / all	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
Spinal compression fracture
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	1 / 259 (0.39%)
occurrences causally related to treatment / all	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
Cardiac disorders
Angina pectoris
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	2 / 259 (0.77%)
occurrences causally related to treatment / all	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
Nervous system disorders
Facial paralysis
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	1 / 259 (0.39%)
occurrences causally related to treatment / all	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
Neuritis cranial
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	1 / 259 (0.39%)
occurrences causally related to treatment / all	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
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 82 (0.00%)	1 / 164 (0.61%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	0 / 259 (0.00%)
occurrences causally related to treatment / all	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
Eye disorders
Cataract
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	2 / 259 (0.77%)
occurrences causally related to treatment / all	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
Gastrointestinal disorders
Colitis ulcerative
subjects affected / exposed	2 / 82 (2.44%)	6 / 164 (3.66%)	4 / 46 (8.70%)	2 / 42 (4.76%)	2 / 41 (4.88%)	0 / 26 (0.00%)	25 / 259 (9.65%)
occurrences causally related to treatment / all	0 / 2	1 / 6	1 / 4	0 / 2	0 / 2	0 / 0	3 / 26
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	1 / 259 (0.39%)
occurrences causally related to treatment / all	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
Anal stenosis
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	1 / 259 (0.39%)
occurrences causally related to treatment / all	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
Duodenitis
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	1 / 259 (0.39%)
occurrences causally related to treatment / all	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
Gastritis erosive
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	1 / 259 (0.39%)
occurrences causally related to treatment / all	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
Internal hernia
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	1 / 259 (0.39%)
occurrences causally related to treatment / all	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
Small intestinal perforation
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	1 / 259 (0.39%)
occurrences causally related to treatment / all	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
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	1 / 259 (0.39%)
occurrences causally related to treatment / all	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
Skin and subcutaneous tissue disorders
Erythema nodosum
subjects affected / exposed	0 / 82 (0.00%)	1 / 164 (0.61%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	1 / 259 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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
Henoch-Schonlein purpura
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	1 / 46 (2.17%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	0 / 259 (0.00%)
occurrences causally related to treatment / all	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
Granulomatous dermatitis
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	1 / 42 (2.38%)	0 / 41 (0.00%)	0 / 26 (0.00%)	0 / 259 (0.00%)
occurrences causally related to treatment / all	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
Renal and urinary disorders
Acute prerenal failure
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	1 / 46 (2.17%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	0 / 259 (0.00%)
occurrences causally related to treatment / all	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
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	1 / 41 (2.44%)	0 / 26 (0.00%)	0 / 259 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 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
Myalgia
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	1 / 41 (2.44%)	0 / 26 (0.00%)	0 / 259 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 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
Lumbar spinal stenosis
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	1 / 259 (0.39%)
occurrences causally related to treatment / all	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
Osteoarthritis
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	1 / 259 (0.39%)
occurrences causally related to treatment / all	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
Vertebral foraminal stenosis
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	1 / 259 (0.39%)
occurrences causally related to treatment / all	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
Infections and infestations
Pneumonia
subjects affected / exposed	0 / 82 (0.00%)	1 / 164 (0.61%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	0 / 259 (0.00%)
occurrences causally related to treatment / all	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
Anal abscess
subjects affected / exposed	1 / 82 (1.22%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	0 / 259 (0.00%)
occurrences causally related to treatment / all	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
Clostridium difficile infection
subjects affected / exposed	1 / 82 (1.22%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	0 / 259 (0.00%)
occurrences causally related to treatment / all	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
Enterocolitis bacterial
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	1 / 42 (2.38%)	0 / 41 (0.00%)	1 / 26 (3.85%)	0 / 259 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	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
Appendicitis
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	1 / 41 (2.44%)	0 / 26 (0.00%)	2 / 259 (0.77%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	2 / 259 (0.77%)
occurrences causally related to treatment / all	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
Clostridium difficile colitis
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	1 / 259 (0.39%)
occurrences causally related to treatment / all	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
Enteritis infectious
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	1 / 259 (0.39%)
occurrences causally related to treatment / all	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
Enterocolitis viral
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	1 / 259 (0.39%)
occurrences causally related to treatment / all	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
Upper respiratory tract infection
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	1 / 259 (0.39%)
occurrences causally related to treatment / all	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
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	2 / 46 (4.35%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	1 / 259 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	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
Diabetes mellitus
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	1 / 46 (2.17%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	0 / 259 (0.00%)
occurrences causally related to treatment / all	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
Hyperglycaemia
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	1 / 46 (2.17%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	0 / 259 (0.00%)
occurrences causally related to treatment / all	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

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

Non-serious adverse events	Induction Phase: Cohort 1, Placebo	Induction Phase: Cohort 1, Vedolizumab 300 mg	Induction Phase: Cohort 2, Vedolizumab 300 mg	Maintenance Phase: Placebo	Maintenance Phase: Vedolizumab 300 mg	Maintenance Phase: Placebo continuation	Open-Label Cohort: Vedolizumab 300 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	10 / 82 (12.20%)	28 / 164 (17.07%)	15 / 46 (32.61%)	17 / 42 (40.48%)	27 / 41 (65.85%)	13 / 26 (50.00%)	191 / 259 (73.75%)
Investigations
White blood cell count decreased
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	2 / 42 (4.76%)	2 / 41 (4.88%)	2 / 26 (7.69%)	0 / 259 (0.00%)
occurrences all number	0	0	0	3	2	2	0
Nervous system disorders
Headache
subjects affected / exposed	2 / 82 (2.44%)	6 / 164 (3.66%)	3 / 46 (6.52%)	1 / 42 (2.38%)	2 / 41 (4.88%)	2 / 26 (7.69%)	23 / 259 (8.88%)
occurrences all number	2	9	5	1	5	2	27
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	17 / 259 (6.56%)
occurrences all number	0	0	0	0	0	0	26
Gastrointestinal disorders
Nausea
subjects affected / exposed	0 / 82 (0.00%)	2 / 164 (1.22%)	3 / 46 (6.52%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	0 / 259 (0.00%)
occurrences all number	0	2	3	0	0	0	0
Colitis ulcerative
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	4 / 42 (9.52%)	0 / 41 (0.00%)	1 / 26 (3.85%)	18 / 259 (6.95%)
occurrences all number	0	0	0	4	0	1	20
Vomiting
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	1 / 42 (2.38%)	3 / 41 (7.32%)	1 / 26 (3.85%)	0 / 259 (0.00%)
occurrences all number	0	0	0	3	3	1	0
Dental caries
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	4 / 41 (9.76%)	0 / 26 (0.00%)	0 / 259 (0.00%)
occurrences all number	0	0	0	0	4	0	0
Haemorrhoids
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	2 / 26 (7.69%)	0 / 259 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Stomatitis
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	14 / 259 (5.41%)
occurrences all number	0	0	0	0	0	0	15
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	3 / 41 (7.32%)	1 / 26 (3.85%)	0 / 259 (0.00%)
occurrences all number	0	0	0	0	3	1	0
Upper respiratory tract inflammation
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	3 / 41 (7.32%)	0 / 26 (0.00%)	14 / 259 (5.41%)
occurrences all number	0	0	0	0	3	0	22
Skin and subcutaneous tissue disorders
Eczema
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	3 / 42 (7.14%)	0 / 41 (0.00%)	0 / 26 (0.00%)	13 / 259 (5.02%)
occurrences all number	0	0	0	3	0	0	17
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	3 / 41 (7.32%)	1 / 26 (3.85%)	14 / 259 (5.41%)
occurrences all number	0	0	0	0	3	1	14
Back pain
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	22 / 259 (8.49%)
occurrences all number	0	0	0	0	0	0	25
Infections and infestations
Viral upper respiratory tract infection
subjects affected / exposed	8 / 82 (9.76%)	23 / 164 (14.02%)	12 / 46 (26.09%)	9 / 42 (21.43%)	18 / 41 (43.90%)	8 / 26 (30.77%)	130 / 259 (50.19%)
occurrences all number	10	25	17	22	27	11	281
Gastroenteritis
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	3 / 46 (6.52%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	13 / 259 (5.02%)
occurrences all number	0	0	3	0	0	0	16
Upper respiratory tract infection
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	1 / 42 (2.38%)	0 / 41 (0.00%)	2 / 26 (7.69%)	19 / 259 (7.34%)
occurrences all number	0	0	0	1	9	3	33
Influenza
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	24 / 259 (9.27%)
occurrences all number	0	0	0	0	0	0	24
Pharyngitis
subjects affected / exposed	0 / 82 (0.00%)	0 / 164 (0.00%)	0 / 46 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 26 (0.00%)	16 / 259 (6.18%)
occurrences all number	0	0	0	0	0	0	24

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants with a Clinical Response at Week 10 in Induction Phase

Primary: Percentage of Participants with a Clinical Response at Week 10 in Induction Phase

Primary: Percentage of Participants with Clinical Remission at Week 60 in Maintenance Phase

Primary: Percentage of Participants with Clinical Remission at Week 60 in Maintenance Phase

Primary: Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Events (TEAEs)

Primary: Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Events (TEAEs)

Primary: Number of Participants with TEAE Related to Body Weight

Primary: Number of Participants with TEAE Related to Body Weight

Primary: Number of Participants with TEAE Related to Vital Signs

Primary: Number of Participants with TEAE Related to Vital Signs

Primary: Number of Participants with TEAE Related to Electrocardiogram (ECG)

Primary: Number of Participants with TEAE Related to Electrocardiogram (ECG)

Primary: Number of Participants with Markedly Abnormal Laboratory Parameters Values

Primary: Number of Participants with Markedly Abnormal Laboratory Parameters Values

Secondary: Percentage of Participants with Clinical Remission at Week 10 in Induction Phase

Secondary: Percentage of Participants with Clinical Remission at Week 10 in Induction Phase

Secondary: Percentage of Participants with Mucosal Healing at Week 10 in Induction Phase

Secondary: Percentage of Participants with Mucosal Healing at Week 10 in Induction Phase

Secondary: Percentage of Participants with Durable Clinical Response in Maintenance Phase

Secondary: Percentage of Participants with Durable Clinical Response in Maintenance Phase

Secondary: Percentage of Participants with Mucosal Healing at Week 60 in Maintenance Phase

Secondary: Percentage of Participants with Mucosal Healing at Week 60 in Maintenance Phase

Secondary: Percentage of Participants with Durable Remission in Maintenance Phase

Secondary: Percentage of Participants with Durable Remission in Maintenance Phase

Secondary: Percentage of Participants with Corticosteroid-Free Remission at Week 60 in Maintenance Phase

Secondary: Percentage of Participants with Corticosteroid-Free Remission at Week 60 in Maintenance Phase

Secondary: Serum Vedolizumab Concentration in Induction Phase

Secondary: Serum Vedolizumab Concentration in Induction Phase

Secondary: Serum Vedolizumab Concentration in Maintenance Phase

Secondary: Serum Vedolizumab Concentration in Maintenance Phase

Secondary: Number of Participants with Anti-vedolizumab Antibodies (AVA) in Induction Phase

Secondary: Number of Participants with Anti-vedolizumab Antibodies (AVA) in Induction Phase

Secondary: Number of Participants with Anti-vedolizumab Antibodies (AVA) in Maintenance Phase

Secondary: Number of Participants with Anti-vedolizumab Antibodies (AVA) in Maintenance Phase

Secondary: Number of Participants with Neutralizing Anti-vedolizumab Antibodies (AVA) in Induction Phase

Secondary: Number of Participants with Neutralizing Anti-vedolizumab Antibodies (AVA) in Induction Phase

Secondary: Number of Participants with Neutralizing Anti-vedolizumab Antibodies (AVA) in Maintenance Phase

Secondary: Number of Participants with Neutralizing Anti-vedolizumab Antibodies (AVA) in Maintenance Phase

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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