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Clinical Trial Results:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Induction Study of the Efficacy and Safety of Upadacitinib (ABT-494) in Subjects With Moderately to Severely Active Crohn's Disease Who Have Inadequately Responded to or Are Intolerant to Biologic Therapy

Summary
EudraCT number	2017-001226-18
Trial protocol	SK SE DK AT PT BE IE GB LV HU DE PL CZ LT EE ES BG SI HR IT RO
Global end of trial date	11 Aug 2021

Results information
Results version number	v1(current)
This version publication date	03 Aug 2022
First version publication date	03 Aug 2022
Other versions

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

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Trial information

Top of page

Sponsor protocol code

M14-431

ISRCTN number

-

US NCT number

NCT03345836

WHO universal trial number (UTN)

-

Sponsor organisation name

AbbVie Deutschland GmbH & Co. KG

Sponsor organisation address

AbbVie House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire, United Kingdom, SL6 4UB

Public contact

Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.com

Scientific contact

Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.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

11 Aug 2021

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

11 Aug 2021

Was the trial ended prematurely?

No

Main objective of the trial

The main objective of this study is to evaluate the efficacy and safety of upadacitinib compared to placebo as induction therapy in participants with moderately and severely active Crohn’s disease (CD).

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

29 Nov 2017

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Puerto Rico: 3

Country: Number of subjects enrolled

United States: 180

Country: Number of subjects enrolled

Czechia: 4

Country: Number of subjects enrolled

Egypt: 8

Country: Number of subjects enrolled

Malaysia: 1

Country: Number of subjects enrolled

Portugal: 4

Country: Number of subjects enrolled

Russian Federation: 9

Country: Number of subjects enrolled

Greece: 4

Country: Number of subjects enrolled

Austria: 7

Country: Number of subjects enrolled

Korea, Democratic People's Republic of: 8

Country: Number of subjects enrolled

Netherlands: 22

Country: Number of subjects enrolled

China: 55

Country: Number of subjects enrolled

Brazil: 4

Country: Number of subjects enrolled

Poland: 6

Country: Number of subjects enrolled

Slovenia: 3

Country: Number of subjects enrolled

Slovakia: 5

Country: Number of subjects enrolled

Chile: 7

Country: Number of subjects enrolled

France: 24

Country: Number of subjects enrolled

Serbia: 5

Country: Number of subjects enrolled

Bosnia and Herzegovina: 2

Country: Number of subjects enrolled

Croatia: 3

Country: Number of subjects enrolled

Argentina: 3

Country: Number of subjects enrolled

Romania: 3

Country: Number of subjects enrolled

Hungary: 3

Country: Number of subjects enrolled

Japan: 44

Country: Number of subjects enrolled

United Kingdom: 18

Country: Number of subjects enrolled

Switzerland: 5

Country: Number of subjects enrolled

Spain: 23

Country: Number of subjects enrolled

Canada: 53

Country: Number of subjects enrolled

Turkey: 2

Country: Number of subjects enrolled

Belgium: 24

Country: Number of subjects enrolled

Taiwan: 4

Country: Number of subjects enrolled

Denmark: 10

Country: Number of subjects enrolled

Mexico: 3

Country: Number of subjects enrolled

Italy: 19

Country: Number of subjects enrolled

South Africa: 9

Country: Number of subjects enrolled

Israel: 10

Country: Number of subjects enrolled

Australia: 15

Country: Number of subjects enrolled

Germany: 9

Country: Number of subjects enrolled

Estonia: 3

Worldwide total number of subjects

624

EEA total number of subjects

176

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)

603

From 65 to 84 years

21

85 years and over

0

Subject disposition

Top of page

Recruitment details

This study had 3 Parts: Part 1: A randomized, double-blind, placebo-controlled Induction Period, Part 2: A single-arm active Induction Period to receive upadacitinib. Part 3: An Extended Treatment Period for clinical non-responders from Parts 1 or 2.

Screening details

Once the enrollment for Part 1 was complete, participants were further enrolled in an open-label, single-arm active Induction Period to receive upadacitinib.in Part 2. Part 3 has 3 cohorts: Cohorts 1 and 2 included participants who received placebo and upadacitinib in Part 1, respectively; Cohort 3 included participants from Part 2.

Period 1 title

DB and OL Induction (12 Weeks)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Data analyst, Carer

Blinding implementation details

Blinding was applicable only to Part 1 where participants received upadacitinib 45 mg once daily (QD) or matching placebo for 12 weeks in a double-blind (DB) way. Part 2 was implemented in a non-blinded manner, with participants receiving open label (OL) upadacitinib 45 mg QD for 12 weeks.

Are arms mutually exclusive

Yes

Part 1 (DB): Placebo

Arm description

Participants received upadacitinib matching placebo tablets, orally, once daily (QD) for 12 weeks during the Double-blind (DB) Induction Period.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Upadacitinib matching placebo tablets, orally

Part 1 (DB): Upadacitinib 45 mg

Arm description

Participants received upadacitinib 45 mg tablets, orally, QD for 12 weeks during the DB Induction Period.

Arm type

Experimental

Investigational medicinal product name

Upadacitinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Upadacitinib 45 mg tablets, orally

Part 2 (OL): Upadacitinib 45 mg

Arm description

Participants received upadacitinib 45 mg tablets, orally, QD for 12 weeks during the Open-label (OL) Induction Period.

Arm type

Experimental

Investigational medicinal product name

Upadacitinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Upadacitinib 45 mg tablets, orally

Number of subjects in period 1	Part 1 (DB): Placebo	Part 1 (DB): Upadacitinib 45 mg	Part 2 (OL): Upadacitinib 45 mg
Started	171	324	129
Completed	149	291	123
Not completed	22	33	6
Adverse event	5	17	2
Withdrew consent	8	8	3
Reason not specified	1	3	1
Lost to follow-up	-	1	-
Lack of efficacy	8	4	-

Period 2 title

12-Week Extended Treatment (ET)

Is this the baseline period?

No

Allocation method

Non-randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Data analyst, Carer

Blinding implementation details

Participants from Part 1 arm groups remained blinded to treatment in Part 3 to avoid unmasking the treatment received during Part 1. Participants from Part 2 arm group received OL treatment in Part 3.

Are arms mutually exclusive

Yes

Part 3 (ET DB): Upadacitinib 45 mg From Part 1 DB Placebo

Arm description

Participants received upadacitinib 45 mg tablets, orally, QD for 12 weeks (until Week 24) during the Extended Treatment (ET) Period. Participants who received placebo in Part 1 and did not achieve clinical response at Week 12 were included in this group.

Arm type

Experimental

Investigational medicinal product name

Upadacitinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Upadacitinib 45 mg tablets, orally

Part3(ET DB):Upadacitinib 30mg From Part1 DB Upadacitinib 45mg

Arm description

Participants received upadacitinib 30 mg tablets, orally, QD for 12 weeks (until Week 24) during the ET Period. Participants who received DB upadacitinib 45 mg in Part 1 and did not achieve clinical response at Week 12 were included in this group.

Arm type

Experimental

Investigational medicinal product name

Upadacitinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Upadacitinib 30 mg tablets, orally

Part3(ET OL):Upadacitinib 30mg From Part2 OL Upadacitinib 45mg

Arm description

Participants received upadacitinib 30 mg tablets, orally, QD for 12 weeks (until Week 24) during the ET Period. Participants who received OL upadacitinib 45 mg during Part 2 and did not achieve clinical response at Week 12 were included in this group.

Arm type

Experimental

Investigational medicinal product name

Upadacitinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Upadacitinib 30 mg tablets, orally

Number of subjects in period 2 ^[1]	Part 3 (ET DB): Upadacitinib 45 mg From Part 1 DB Placebo	Part3(ET DB):Upadacitinib 30mg From Part1 DB Upadacitinib 45mg	Part3(ET OL):Upadacitinib 30mg From Part2 OL Upadacitinib 45mg
Started	78	69	14
Completed	67	51	8
Not completed	11	18	6
Adverse event	8	5	-
COVID-19 logistical restrictions	-	1	-
Reason not specified	1	1	1
Withdrew consent	-	5	1
Lost to follow-up	-	-	1
Lack of efficacy	2	6	3

Notes
[1] - 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: Subjects included as ‘Completed’ in Period 1=completed study. Non-responders from Parts 1 or 2 were enroled into the Extended Treatment Period (Part 3).

Baseline characteristics

Top of page

Reporting group title

Part 1 (DB): Placebo

Reporting group description

Participants received upadacitinib matching placebo tablets, orally, once daily (QD) for 12 weeks during the Double-blind (DB) Induction Period.

Reporting group title

Part 1 (DB): Upadacitinib 45 mg

Reporting group description

Participants received upadacitinib 45 mg tablets, orally, QD for 12 weeks during the DB Induction Period.

Reporting group title

Part 2 (OL): Upadacitinib 45 mg

Reporting group description

Participants received upadacitinib 45 mg tablets, orally, QD for 12 weeks during the Open-label (OL) Induction Period.

Reporting group values	Part 1 (DB): Placebo	Part 1 (DB): Upadacitinib 45 mg	Part 2 (OL): Upadacitinib 45 mg	Total
Number of subjects	171	324	129	624
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (full range (min-max))	37.5 (18 to 74)	38.4 (18 to 73)	39.1 (18 to 68)	-
Gender categorical
Units: Subjects
Female	75	155	60	290
Male	96	169	69	334
Ethnicity
Units: Subjects
Hispanic or Latino	8	24	8	40
Not Hispanic or Latino	163	300	121	584
Unknown or Not Reported	0	0	0	0
Race
Units: Subjects
American Indian or Alaska Native	1	1	0	2
Asian	38	69	11	118
Native Hawaiian or Other Pacific Islander	0	0	0	0
Black or African American	6	19	5	30
White	126	230	113	469
More than one race	0	5	0	5
Unknown or Not Reported	0	0	0	0

End points

Top of page

Reporting group title

Part 1 (DB): Placebo

Reporting group description

Participants received upadacitinib matching placebo tablets, orally, once daily (QD) for 12 weeks during the Double-blind (DB) Induction Period.

Reporting group title

Part 1 (DB): Upadacitinib 45 mg

Reporting group description

Participants received upadacitinib 45 mg tablets, orally, QD for 12 weeks during the DB Induction Period.

Reporting group title

Part 2 (OL): Upadacitinib 45 mg

Reporting group description

Participants received upadacitinib 45 mg tablets, orally, QD for 12 weeks during the Open-label (OL) Induction Period.

Reporting group title

Part 3 (ET DB): Upadacitinib 45 mg From Part 1 DB Placebo

Reporting group description

Participants received upadacitinib 45 mg tablets, orally, QD for 12 weeks (until Week 24) during the Extended Treatment (ET) Period. Participants who received placebo in Part 1 and did not achieve clinical response at Week 12 were included in this group.

Reporting group title

Part3(ET DB):Upadacitinib 30mg From Part1 DB Upadacitinib 45mg

Reporting group description

Participants received upadacitinib 30 mg tablets, orally, QD for 12 weeks (until Week 24) during the ET Period. Participants who received DB upadacitinib 45 mg in Part 1 and did not achieve clinical response at Week 12 were included in this group.

Reporting group title

Part3(ET OL):Upadacitinib 30mg From Part2 OL Upadacitinib 45mg

Reporting group description

Participants received upadacitinib 30 mg tablets, orally, QD for 12 weeks (until Week 24) during the ET Period. Participants who received OL upadacitinib 45 mg during Part 2 and did not achieve clinical response at Week 12 were included in this group.

Primary: Percentage of Participants With Clinical Remission Per Patient-Reported Outcomes (PROs) at Week 12

Top of page

End point title

Percentage of Participants With Clinical Remission Per Patient-Reported Outcomes (PROs) at Week 12 ^[1]

End point description

Clinical remission per PROs was defined as average daily very soft or liquid stool frequency (SF) ≤2.8 and average daily abdominal pain (AP) score ≤1.0 and both not greater than Baseline. The number of soft or liquid stools and abdominal pain rated on a scale of 0=none to 3=severe were recorded in an electronic diary. Results were based on non-responder imputation incorporating multiple imputation to handle missing data due to coronavirus disease (COVID-19) [NRI-C]. ITT1 Population included all randomised participants who received at least one dose of DB study drug during Part 1.

End point type

Primary

End point timeframe

Baseline to Week 12

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: Only Part 1 Double-blind arms are applicable to this endpoint.

End point values	Part 1 (DB): Placebo	Part 1 (DB): Upadacitinib 45 mg
Number of subjects analysed	171	324
Units: percentage of participants
number (confidence interval 95%)	14.0 (8.8 to 19.2)	39.8 (34.5 to 45.1)

Statistical Analysis 1

Comparison groups

Part 1 (DB): Placebo v Part 1 (DB): Upadacitinib 45 mg

Number of subjects included in analysis

495

Analysis specification

Pre-specified

Analysis type

superiority ^[2]

P-value

< 0.0001 ^[3]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Treatment Difference

Point estimate

25.9

Confidence interval

level

95%

sides

2-sided

lower limit

18.7

upper limit

33.1

Notes
[2] - Point estimate and 95% CI were calculated using CMH.
[3] - P-value was calculated using CMH test adjusted for randomization stratification factors.

Primary: Percentage of Participants With Endoscopic Response at Week 12

Top of page

End point title

Percentage of Participants With Endoscopic Response at Week 12 ^[4]

End point description

Endoscopic response was defined as greater than 50% decrease in Simple Endoscopic Score for Crohn's Disease (SES-CD) from Baseline of the induction study (or for participants with an SES-CD of 4 at Baseline of the induction study, at least a 2-point reduction from Baseline), as scored by Central Reviewer. SES-CD is calculated based the sum of individual segment values for four endoscopic variables (presence and size of ulcers, ulcerated surface, affected surface and presence of narrowing). Each variable in each segment is scored 0 to 3 resulting in SES-CD values ranging from 0 to 56 with higher scores indicating more severe disease. Intent-to-Treat (ITT)1 Population included all randomised participants who received at least one dose of DB study drug during Part 1. Results were based on NRI-C.

End point type

Primary

End point timeframe

Baseline to Week 12

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Part 1 Double-blind arms are applicable to this endpoint.

End point values	Part 1 (DB): Placebo	Part 1 (DB): Upadacitinib 45 mg
Number of subjects analysed	171	324
Units: percentage of participants
number (confidence interval 95%)	3.5 (0.8 to 6.3)	34.6 (29.4 to 39.8)

Statistical Analysis 1

Comparison groups

Part 1 (DB): Placebo v Part 1 (DB): Upadacitinib 45 mg

Number of subjects included in analysis

495

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

P-value

< 0.0001 ^[6]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Treatment Difference

Point estimate

31.2

Confidence interval

level

95%

sides

2-sided

lower limit

25.5

upper limit

37

Notes
[5] - Point estimate and 95% confidence interval (CI) were calculated using Cochran-Mantel-Haenszel test (CMH).
[6] - P-value was calculated using CMH test adjusted for randomization stratification factors.

Primary: Number of Participants With Adverse Events

Top of page

End point title

Number of Participants With Adverse Events ^[7]

End point description

An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not the event is considered causally related to the use of the product. Safety Population for Part 1 (SA1)=all participants who received at least one dose of the study drug in Part 1, SA2=all participants who received at least one dose of the study drug in Part 2, and SA3=all participants who received at least one dose of the study drug (upadacitinib 30 mg or upadacitinib 45 mg) in Part 3.

End point type

Primary

End point timeframe

From first dose of study drug until 30 days following last dose of study drug (up to approximately 28 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: No statistical analyses are reported for this endpoint.

End point values	Part 1 (DB): Placebo	Part 3 (ET DB): Upadacitinib 45 mg From Part 1 DB Placebo	Part 1 (DB): Upadacitinib 45 mg	Part3(ET DB):Upadacitinib 30mg From Part1 DB Upadacitinib 45mg	Part 2 (OL): Upadacitinib 45 mg	Part3(ET OL):Upadacitinib 30mg From Part2 OL Upadacitinib 45mg
Number of subjects analysed	171	78	324	69	129	14
Units: participants	112	53	221	45	86	9

No statistical analyses for this end point

Secondary: Percentage of Participants With Clinical Remission Per Crohn's Disease Activity Index (CDAI) at Week 12

Top of page

End point title

Percentage of Participants With Clinical Remission Per Crohn's Disease Activity Index (CDAI) at Week 12 ^[8]

End point description

The CDAI was used to evaluate the activity of Crohn's disease. Clinical remission per CDAI is defined as CDAI <150. The CDAI is calculated on the basis of a one-week evaluation of 8 items: frequency of liquid or very soft stool, abdominal pain, complications of Crohn's disease (e.g., uveitis, arthritis, fistula, and abscess), abdominal mass, hematocrit, body weight, use of antidiarrheals, and general condition. Total score ranges from 0 to 600. Higher CDAI scores indicate more severe disease. CDAI scores below 150 represent remission and scores over 450 represent very severe Crohn's disease. ITT1 Population included all randomised participants who received at least one dose of DB study drug during Part 1. Results were based on NRI-C.

End point type

Secondary

End point timeframe

Week 12

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Part 1 Double-blind arms are applicable to this endpoint.

End point values	Part 1 (DB): Placebo	Part 1 (DB): Upadacitinib 45 mg
Number of subjects analysed	171	324
Units: percentage of participants
number (confidence interval 95%)	21.1 (14.9 to 27.2)	38.9 (33.6 to 44.2)

Statistical Analysis 1

Comparison groups

Part 1 (DB): Placebo v Part 1 (DB): Upadacitinib 45 mg

Number of subjects included in analysis

495

Analysis specification

Pre-specified

Analysis type

superiority ^[9]

P-value

< 0.0001 ^[10]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Risk Difference

Point estimate

17.9

Confidence interval

level

95%

sides

2-sided

lower limit

10

upper limit

25.8

Notes
[9] - Point estimate and 95% CI were calculated using CMH risk difference estimate.
[10] - P-value was calculated using CMH test adjusted for randomization stratification factors.

Secondary: Percentage of Participants With Clinical Remission Per Patient Reported Outcomes (PROs) at Week 4

Top of page

End point title

Percentage of Participants With Clinical Remission Per Patient Reported Outcomes (PROs) at Week 4 ^[11]

End point description

Clinical remission per PROs was defined as average daily very soft or liquid stool frequency (SF) ≤2.8 and average daily abdominal pain (AP) score ≤1.0 and both not greater than Baseline. The number of soft or liquid stools and abdominal pain rated on a scale of 0=none to 3=severe were recorded in an electronic diary. Results were based on NRI-C. ITT1 Population included all randomised participants who received at least one dose of DB study drug during Part 1.

End point type

Secondary

End point timeframe

Week 4

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: Only Part 1 Double-blind arms are applicable to this endpoint.

End point values	Part 1 (DB): Placebo	Part 1 (DB): Upadacitinib 45 mg
Number of subjects analysed	171	324
Units: percentage of participants
number (confidence interval 95%)	9.4 (5.0 to 13.7)	32.4 (27.3 to 37.5)

Statistical Analysis 1

Comparison groups

Part 1 (DB): Placebo v Part 1 (DB): Upadacitinib 45 mg

Number of subjects included in analysis

495

Analysis specification

Pre-specified

Analysis type

superiority ^[12]

P-value

< 0.0001 ^[13]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Treatment Difference

Point estimate

23.3

Confidence interval

level

95%

sides

2-sided

lower limit

16.6

upper limit

29.9

Notes
[12] - Point estimate and 95% CI were calculated using CMH.
[13] - P-value was calculated using CMH test adjusted for randomization stratification factors.

Secondary: Percentage of Participants With Endoscopic Remission at Week 12

Top of page

End point title

Percentage of Participants With Endoscopic Remission at Week 12 ^[14]

End point description

Endoscopic remission was defined per SES-CD. SES-CD ≤4 and at least 2-point reduction from Baseline and no subscore >1 in any individual variable, as scored by Central Reviewer. SES-CD is calculated based the sum of individual segment values for four endoscopic variables (presence and size of ulcers, ulcerated surface, affected surface and presence of narrowing). Each variable in each segment is scored 0 to 3 resulting in SES-CD values ranging from 0 to 56 with higher scores indicating more severe disease. Results were based on NRI-C. ITT1 Population included all randomised participants who received at least one dose of DB study drug during Part 1.

End point type

Secondary

End point timeframe

Baseline to Week 12

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Part 1 Double-blind arms are applicable to this endpoint.

End point values	Part 1 (DB): Placebo	Part 1 (DB): Upadacitinib 45 mg
Number of subjects analysed	171	324
Units: percentage of participants
number (confidence interval 95%)	2.3 (0.1 to 4.6)	19.1 (14.9 to 23.4)

Statistical Analysis 1

Comparison groups

Part 1 (DB): Placebo v Part 1 (DB): Upadacitinib 45 mg

Number of subjects included in analysis

495

Analysis specification

Pre-specified

Analysis type

superiority ^[15]

P-value

< 0.0001 ^[16]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Treatment Difference

Point estimate

16.8

Confidence interval

level

95%

sides

2-sided

lower limit

12

upper limit

21.6

Notes
[15] - Point estimate and 95% CI were calculated using CMH.
[16] - P-value was calculated using CMH test adjusted for randomization stratification factors.

Secondary: Percentage of Participants who Discontinued Corticosteroid Use for Crohn's Disease (CD) and Achieved Clinical Remission per PROs at Week 12, in Participants Taking Corticosteroids at Baseline

Top of page

End point title

Percentage of Participants who Discontinued Corticosteroid Use for Crohn's Disease (CD) and Achieved Clinical Remission per PROs at Week 12, in Participants Taking Corticosteroids at Baseline ^[17]

End point description

Clinical remission per PROs was defined as average daily very soft or liquid stool frequency (SF) ≤2.8 and average daily abdominal pain (AP) score ≤1.0 and both not greater than Baseline. The number of soft or liquid stools and abdominal pain rated on a scale of 0=none to 3=severe were recorded in an electronic diary. Results were based on NRI-C. ITT1 Population=participants receiving at least one dose of DB study drug during Part 1. Number of subjects analysed=number of participants who were taking corticosteroids at Baseline.

End point type

Secondary

End point timeframe

Week 12

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: Only Part 1 Double-blind arms are applicable to this endpoint.

End point values	Part 1 (DB): Placebo	Part 1 (DB): Upadacitinib 45 mg
Number of subjects analysed	60	108
Units: percentage of participants
number (confidence interval 95%)	6.7 (0.4 to 13.0)	37.0 (27.9 to 46.1)

Statistical Analysis 1

Comparison groups

Part 1 (DB): Placebo v Part 1 (DB): Upadacitinib 45 mg

Number of subjects included in analysis

168

Analysis specification

Pre-specified

Analysis type

superiority ^[18]

P-value

< 0.0001 ^[19]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Treatment Difference

Point estimate

30.2

Confidence interval

level

95%

sides

2-sided

lower limit

19.4

upper limit

41

Notes
[18] - Point estimate and 95% CI were calculated using CMH.
[19] - P-value was calculated using CMH test adjusted for randomisation stratification factors.

Secondary: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Total Score at Week 12

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End point title

Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Total Score at Week 12 ^[20]

End point description

The FACIT-F questionnaire was developed to assess fatigue associated with anemia. It consists of 13 fatigue-related questions. The responses to the 13 items on the FACIT-F questionnaire are each measured on a 5-point Likert scale. The responses to the answers are the following: 0= not at all; 1= a little bit; 2= somewhat; 3= quite a bit; 4=very much. Thus, the total score ranges from 0 to 52. High scores represent less fatigue. A positive change from Baseline indicates improvement. ITT1 Population included all randomised participants who received at least one dose of DB study drug during Part 1. Overall number of subjects analyzed are the number of subjects with data available for analyses.

End point type

Secondary

End point timeframe

Baseline and Week 12

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Part 1 Double-blind arms are applicable to this endpoint.

End point values	Part 1 (DB): Placebo	Part 1 (DB): Upadacitinib 45 mg
Number of subjects analysed	129	278
Units: score on a scale
least squares mean (standard error)	3.9 ± 0.97	11.4 ± 0.69

Statistical Analysis 1

Comparison groups

Part 1 (DB): Placebo v Part 1 (DB): Upadacitinib 45 mg

Number of subjects included in analysis

407

Analysis specification

Pre-specified

Analysis type

superiority ^[21]

P-value

< 0.0001 ^[22]

Method

MMRM

Parameter type

Adjusted Treatment Difference

Point estimate

7.5

Confidence interval

level

95%

sides

2-sided

lower limit

5.2

upper limit

9.8

Notes
[21] - Point estimate and 95% CI were calculated using MMRM.
[22] - P-value was calculated using MMRM with Baseline, treatment, visit, treatment by visit interaction and stratification factors in the model.

Secondary: Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Week 12

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End point title

Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Week 12 ^[23]

End point description

The IBDQ is a disease-specific instrument composed of 32 Likert-scaled items. The IBDQ scale contains 4 component subscales: bowel symptoms (10 items), systemic symptoms (5 items), emotional function (12 items), and social function(5 items). Each item is scored on a 7-point scale where: 1=worst to 7=best. The total score ranges from 32 to 224, with higher scores indicating better health-related quality of life. A positive change from Baseline indicates improvement. ITT1 Population included all randomised participants who received at least one dose of DB study drug during Part 1. Overall number of subjects analyzed are the number of subjects with data available for analyses.

End point type

Secondary

End point timeframe

Baseline and Week 12

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Part 1 Double-blind arms are applicable to this endpoint.

End point values	Part 1 (DB): Placebo	Part 1 (DB): Upadacitinib 45 mg
Number of subjects analysed	130	280
Units: score on a scale
least squares mean (standard error)	21.6 ± 3.02	46.0 ± 2.14

Statistical Analysis 1

Comparison groups

Part 1 (DB): Placebo v Part 1 (DB): Upadacitinib 45 mg

Number of subjects included in analysis

410

Analysis specification

Pre-specified

Analysis type

superiority ^[24]

P-value

< 0.0001 ^[25]

Method

Mixed Model Repeated Measures (MMRM)

Parameter type

Adjusted Treatment Difference

Point estimate

24.3

Confidence interval

level

95%

sides

2-sided

lower limit

17.2

upper limit

31.5

Notes
[24] - Point estimate and 95% CI were calculated using MMRM.
[25] - P-value was calculated using MMRM with Baseline, treatment, visit, treatment by visit interaction and stratification factors in the model.

Secondary: Percentage of Participants Achieving Clinical Response 100 (CR-100) at Week 2

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End point title

Percentage of Participants Achieving Clinical Response 100 (CR-100) at Week 2 ^[26]

End point description

CR-100 is defined as a decrease of at least 100 points in CDAI from Baseline at week 2. The CDAI is used to evaluate the activity of Crohn’s disease. The CDAI is calculated on the basis of a one-week evaluation of 8 items: frequency of liquid or very soft stool, abdominal pain, complications of Crohn’s disease (e.g., uveitis, arthritis, fistula, and abscess), abdominal mass, hematocrit, body weight, use of antidiarrheals, and general condition. Total score ranges from 0 to about 600. Higher CDAI scores indicate more severe disease. CDAI scores below 150 represent remission and scores over 450 represent very severe Crohn’s disease. Results were based on NRI-C. ITT1 Population included all randomized participants who received at least one dose of DB study drug during Part 1.

End point type

Secondary

End point timeframe

Baseline to Week 2

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Part 1 Double-blind arms are applicable to this endpoint.

End point values	Part 1 (DB): Placebo	Part 1 (DB): Upadacitinib 45 mg
Number of subjects analysed	171	324
Units: percentage of participants
number (confidence interval 95%)	12.4 (7.4 to 17.4)	33.2 (28.0 to 38.3)

Statistical Analysis 1

Comparison groups

Part 1 (DB): Placebo v Part 1 (DB): Upadacitinib 45 mg

Number of subjects included in analysis

495

Analysis specification

Pre-specified

Analysis type

superiority ^[27]

P-value

< 0.0001 ^[28]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Treatment Difference

Point estimate

20.7

Confidence interval

level

95%

sides

2-sided

lower limit

13.7

upper limit

27.8

Notes
[27] - Point estimate and 95% CI were calculated using CMH.
[28] - P-value was calculated using CMH test adjusted for randomization stratification factors.

Secondary: Percentage of Participants Achieving Clinical Response 100 (CR-100) at Week 12

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End point title

Percentage of Participants Achieving Clinical Response 100 (CR-100) at Week 12 ^[29]

End point description

CR-100 is defined as a decrease of at least 100 points in CDAI from Baseline at Week 12. The CDAI is used to evaluate the activity of Crohn’s disease. The CDAI is calculated on the basis of a one-week evaluation of 8 items: frequency of liquid or very soft stool, abdominal pain, complications of Crohn’s disease (e.g., uveitis, arthritis, fistula, and abscess), abdominal mass, hematocrit, body weight, use of antidiarrheals, and general condition. Total score ranges from 0 to about 600. Higher CDAI scores indicate more severe disease. CDAI scores below 150 represent remission and scores over 450 represent very severe Crohn’s disease. Results were based on NRI-C. ITT1 Population included all randomised participants who received at least one dose of DB study drug during Part 1.

End point type

Secondary

End point timeframe

Baseline to Week 12

Notes
[29] - 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: Only Part 1 Double-blind arms are applicable to this endpoint.

End point values	Part 1 (DB): Placebo	Part 1 (DB): Upadacitinib 45 mg
Number of subjects analysed	171	324
Units: percentage of participants
number (confidence interval 95%)	27.5 (20.8 to 34.2)	50.5 (45.1 to 56.0)

Statistical Analysis 1

Comparison groups

Part 1 (DB): Placebo v Part 1 (DB): Upadacitinib 45 mg

Number of subjects included in analysis

495

Analysis specification

Pre-specified

Analysis type

superiority ^[30]

P-value

< 0.0001 ^[31]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Treatment Difference

Point estimate

22.8

Confidence interval

level

95%

sides

2-sided

lower limit

14.4

upper limit

31.2

Notes
[30] - Point estimate and 95% CI were calculated using CMH.
[31] - P-value was calculated using CMH test adjusted for randomization stratification factors.

Secondary: Percentage of Participants With Hospitalizations Due to Crohn's Disease (CD) During Part 1 (12-week Double-blind Induction Period)

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End point title

Percentage of Participants With Hospitalizations Due to Crohn's Disease (CD) During Part 1 (12-week Double-blind Induction Period) ^[32]

End point description

ITT1 Population included all randomised participants who received at least one dose of DB study drug during Part 1.

End point type

Secondary

End point timeframe

Up to Week 12 in Part 1: Double-blind Induction Period

Notes
[32] - 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: Only Part 1 Double-blind arms are applicable to this endpoint.

End point values	Part 1 (DB): Placebo	Part 1 (DB): Upadacitinib 45 mg
Number of subjects analysed	171	324
Units: percentage of participants
number (confidence interval 95%)	8.8 (4.5 to 13.0)	6.2 (3.6 to 8.8)

Statistical Analysis 1

Comparison groups

Part 1 (DB): Placebo v Part 1 (DB): Upadacitinib 45 mg

Number of subjects included in analysis

495

Analysis specification

Pre-specified

Analysis type

superiority ^[33]

P-value

= 0.2834 ^[34]

Method

Chi-squared

Parameter type

Treatment Difference

Point estimate

-2.6

Confidence interval

level

95%

sides

2-sided

lower limit

-7.6

upper limit

2.4

Notes
[33] - Point estimate and 95% CI were calculated using Chi-squared test.
[34] - P-value was calculated using Chi-squared test.

Secondary: Percentage of Participants With Resolution of Extra-Intestinal Manifestations (EIMs) at Week 12, in Participants With EIMs at Baseline

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End point title

Percentage of Participants With Resolution of Extra-Intestinal Manifestations (EIMs) at Week 12, in Participants With EIMs at Baseline ^[35]

End point description

EIMs are defined as manifestations of Crohn's disease in areas of the body other than the digestive tract, including eyes, skin, joints, mouth, and liver. ITT1 Population included all randomised participants who received at least one dose of DB study drug during Part 1. Number of subjects analysed is the number of participants with any EIMs at Baseline.

End point type

Secondary

End point timeframe

Week 12

Notes
[35] - 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: Only Part 1 Double-blind arms are applicable to this endpoint.

End point values	Part 1 (DB): Placebo	Part 1 (DB): Upadacitinib 45 mg
Number of subjects analysed	60	131
Units: percentage of participants
number (confidence interval 95%)	21.7 (11.2 to 32.1)	32.8 (24.8 to 40.9)

Statistical Analysis 1

Comparison groups

Part 1 (DB): Placebo v Part 1 (DB): Upadacitinib 45 mg

Number of subjects included in analysis

191

Analysis specification

Pre-specified

Analysis type

superiority ^[36]

P-value

= 0.0833 ^[37]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Treatment Difference

Point estimate

11.5

Confidence interval

level

95%

sides

2-sided

lower limit

-1.5

upper limit

24.4

Notes
[36] - Point estimate and 95% CI were calculated using CMH.
[37] - P-value was calculated using CMH test adjusted for randomisation stratification factors.

Adverse events

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Timeframe for reporting adverse events

From first dose of study drug until 30 days following last dose of study drug (up to approximately 28 weeks)

Adverse event reporting additional description

Safety Population for Part 1 (SA1)=all participants who received at least one dose of the study drug in Part 1,SA2=all participants who received at least one dose of the study drug in Part 2, and SA3=all participants who received at least one dose of the study drug (upadacitinib 30 mg or upadacitinib 45 mg) in Part 3.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.0

Reporting group title

Part 1 (Double Blind): Upadacitinib 45 mg

Reporting group description

Participants received upadacitinib 45 mg tablets, orally, QD for 12 weeks during the Double-blind Induction Period.

Reporting group title

Part3(ET OL):Upadacitinib 30mg From Part2 OL Upadacitinib 45mg

Reporting group description

Participants received upadacitinib 30 mg tablets, orally, QD for 12 weeks (until Week 24) during the Extended Treatment Period. Participants who received OL upadacitinib 45 mg during Part 2 and did not achieve clinical response at Week 12 were included in this group.

Reporting group title

Part 3 (ET DB): Upadacitinib 45 mg From Part 1 DB Placebo

Reporting group description

Participants received upadacitinib 45 mg tablets, orally, QD for 12 weeks (until Week 24) during the Extended Treatment Period. Participants who received placebo in Part 1 and did not achieve clinical response at Week 12 were included in this group.

Reporting group title

Part3(ET DB):Upadacitinib 30mg From Part1 DB Upadacitinib 45mg

Reporting group description

Participants received upadacitinib 30 mg tablets, orally, QD for 12 weeks (until Week 24) during the Extended Treatment Period. Participants who received DB upadacitinib 45 mg in Part 1 and did not achieve clinical response at Week 12 were included in this group.

Reporting group title

Part 1 (Double Blind): Placebo

Reporting group description

Participants received upadacitinib matching placebo tablets, orally, QD for 12 weeks during the Double-blind Induction Period.

Reporting group title

Part 2 (Open Label): Upadacitinib 45 mg

Reporting group description

Participants received upadacitinib 45 mg tablets, orally, QD for 12 weeks during the Open-label Induction Period.

Serious adverse events	Part 1 (Double Blind): Upadacitinib 45 mg	Part3(ET OL):Upadacitinib 30mg From Part2 OL Upadacitinib 45mg	Part 3 (ET DB): Upadacitinib 45 mg From Part 1 DB Placebo	Part3(ET DB):Upadacitinib 30mg From Part1 DB Upadacitinib 45mg	Part 1 (Double Blind): Placebo	Part 2 (Open Label): Upadacitinib 45 mg
Total subjects affected by serious adverse events
subjects affected / exposed	30 / 324 (9.26%)	5 / 14 (35.71%)	11 / 78 (14.10%)	7 / 69 (10.14%)	17 / 171 (9.94%)	9 / 129 (6.98%)
number of deaths (all causes)	1	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0
General disorders and administration site conditions
PYREXIA
subjects affected / exposed	0 / 324 (0.00%)	0 / 14 (0.00%)	1 / 78 (1.28%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 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
Reproductive system and breast disorders
FEMALE GENITAL TRACT FISTULA
subjects affected / exposed	1 / 324 (0.31%)	0 / 14 (0.00%)	0 / 78 (0.00%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	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
UTERINE POLYP
subjects affected / exposed	1 / 324 (0.31%)	0 / 14 (0.00%)	0 / 78 (0.00%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	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
Respiratory, thoracic and mediastinal disorders
LUNG DISORDER
subjects affected / exposed	1 / 324 (0.31%)	0 / 14 (0.00%)	0 / 78 (0.00%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	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
Psychiatric disorders
DEPRESSION
subjects affected / exposed	0 / 324 (0.00%)	0 / 14 (0.00%)	1 / 78 (1.28%)	0 / 69 (0.00%)	1 / 171 (0.58%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	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
DRUG ABUSE
subjects affected / exposed	1 / 324 (0.31%)	0 / 14 (0.00%)	0 / 78 (0.00%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	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
DRUG USE DISORDER
subjects affected / exposed	1 / 324 (0.31%)	0 / 14 (0.00%)	0 / 78 (0.00%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	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
PSYCHOTIC DISORDER
subjects affected / exposed	1 / 324 (0.31%)	0 / 14 (0.00%)	0 / 78 (0.00%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	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
Injury, poisoning and procedural complications
FALL
subjects affected / exposed	0 / 324 (0.00%)	0 / 14 (0.00%)	1 / 78 (1.28%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	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
POSTOPERATIVE ILEUS
subjects affected / exposed	0 / 324 (0.00%)	0 / 14 (0.00%)	1 / 78 (1.28%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	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
SPINAL COMPRESSION FRACTURE
subjects affected / exposed	0 / 324 (0.00%)	0 / 14 (0.00%)	1 / 78 (1.28%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	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
Blood and lymphatic system disorders
ANAEMIA
subjects affected / exposed	0 / 324 (0.00%)	0 / 14 (0.00%)	0 / 78 (0.00%)	0 / 69 (0.00%)	1 / 171 (0.58%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	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
FEBRILE NEUTROPENIA
subjects affected / exposed	0 / 324 (0.00%)	0 / 14 (0.00%)	0 / 78 (0.00%)	1 / 69 (1.45%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	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
LEUKOPENIA
subjects affected / exposed	0 / 324 (0.00%)	0 / 14 (0.00%)	0 / 78 (0.00%)	1 / 69 (1.45%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	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
Ear and labyrinth disorders
VERTIGO
subjects affected / exposed	1 / 324 (0.31%)	0 / 14 (0.00%)	0 / 78 (0.00%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	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
Gastrointestinal disorders
ABDOMINAL PAIN
subjects affected / exposed	1 / 324 (0.31%)	0 / 14 (0.00%)	1 / 78 (1.28%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
ABDOMINAL PAIN UPPER
subjects affected / exposed	0 / 324 (0.00%)	0 / 14 (0.00%)	0 / 78 (0.00%)	0 / 69 (0.00%)	1 / 171 (0.58%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	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
COLITIS
subjects affected / exposed	0 / 324 (0.00%)	0 / 14 (0.00%)	0 / 78 (0.00%)	0 / 69 (0.00%)	1 / 171 (0.58%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CONSTIPATION
subjects affected / exposed	0 / 324 (0.00%)	0 / 14 (0.00%)	0 / 78 (0.00%)	0 / 69 (0.00%)	1 / 171 (0.58%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CROHN'S DISEASE
subjects affected / exposed	7 / 324 (2.16%)	3 / 14 (21.43%)	3 / 78 (3.85%)	4 / 69 (5.80%)	10 / 171 (5.85%)	4 / 129 (3.10%)
occurrences causally related to treatment / all	1 / 7	0 / 3	1 / 3	0 / 5	0 / 13	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ENTEROCUTANEOUS FISTULA
subjects affected / exposed	0 / 324 (0.00%)	0 / 14 (0.00%)	1 / 78 (1.28%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 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
GASTROINTESTINAL HAEMORRHAGE
subjects affected / exposed	3 / 324 (0.93%)	0 / 14 (0.00%)	0 / 78 (0.00%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	1 / 3	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
HAEMATOCHEZIA
subjects affected / exposed	0 / 324 (0.00%)	0 / 14 (0.00%)	0 / 78 (0.00%)	0 / 69 (0.00%)	1 / 171 (0.58%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	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
HAEMORRHOIDS
subjects affected / exposed	0 / 324 (0.00%)	0 / 14 (0.00%)	1 / 78 (1.28%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	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
ILEAL PERFORATION
subjects affected / exposed	0 / 324 (0.00%)	0 / 14 (0.00%)	1 / 78 (1.28%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 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
ILEUS
subjects affected / exposed	1 / 324 (0.31%)	0 / 14 (0.00%)	0 / 78 (0.00%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	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
INTESTINAL OBSTRUCTION
subjects affected / exposed	1 / 324 (0.31%)	0 / 14 (0.00%)	1 / 78 (1.28%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
INTESTINAL PERFORATION
subjects affected / exposed	1 / 324 (0.31%)	0 / 14 (0.00%)	0 / 78 (0.00%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	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
INTESTINAL STENOSIS
subjects affected / exposed	1 / 324 (0.31%)	0 / 14 (0.00%)	0 / 78 (0.00%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	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
PANCREATITIS ACUTE
subjects affected / exposed	0 / 324 (0.00%)	0 / 14 (0.00%)	0 / 78 (0.00%)	0 / 69 (0.00%)	1 / 171 (0.58%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	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
SMALL INTESTINAL OBSTRUCTION
subjects affected / exposed	1 / 324 (0.31%)	0 / 14 (0.00%)	0 / 78 (0.00%)	1 / 69 (1.45%)	0 / 171 (0.00%)	1 / 129 (0.78%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	1 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
CHOLELITHIASIS
subjects affected / exposed	1 / 324 (0.31%)	0 / 14 (0.00%)	0 / 78 (0.00%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	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
Skin and subcutaneous tissue disorders
ANGIOEDEMA
subjects affected / exposed	0 / 324 (0.00%)	0 / 14 (0.00%)	1 / 78 (1.28%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 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
Renal and urinary disorders
NEPHROLITHIASIS
subjects affected / exposed	1 / 324 (0.31%)	0 / 14 (0.00%)	0 / 78 (0.00%)	1 / 69 (1.45%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
URETEROLITHIASIS
subjects affected / exposed	1 / 324 (0.31%)	0 / 14 (0.00%)	0 / 78 (0.00%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	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
Musculoskeletal and connective tissue disorders
ANKYLOSING SPONDYLITIS
subjects affected / exposed	0 / 324 (0.00%)	0 / 14 (0.00%)	0 / 78 (0.00%)	0 / 69 (0.00%)	1 / 171 (0.58%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	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
Infections and infestations
ABDOMINAL ABSCESS
subjects affected / exposed	0 / 324 (0.00%)	1 / 14 (7.14%)	0 / 78 (0.00%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	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
ABDOMINAL WALL ABSCESS
subjects affected / exposed	0 / 324 (0.00%)	0 / 14 (0.00%)	0 / 78 (0.00%)	0 / 69 (0.00%)	0 / 171 (0.00%)	1 / 129 (0.78%)
occurrences causally related to treatment / all	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
ANAL ABSCESS
subjects affected / exposed	3 / 324 (0.93%)	0 / 14 (0.00%)	0 / 78 (0.00%)	0 / 69 (0.00%)	2 / 171 (1.17%)	1 / 129 (0.78%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0	0 / 0	0 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
COLONIC ABSCESS
subjects affected / exposed	0 / 324 (0.00%)	0 / 14 (0.00%)	0 / 78 (0.00%)	0 / 69 (0.00%)	0 / 171 (0.00%)	1 / 129 (0.78%)
occurrences causally related to treatment / all	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
COVID-19
subjects affected / exposed	1 / 324 (0.31%)	0 / 14 (0.00%)	0 / 78 (0.00%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	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
COVID-19 PNEUMONIA
subjects affected / exposed	0 / 324 (0.00%)	0 / 14 (0.00%)	0 / 78 (0.00%)	0 / 69 (0.00%)	0 / 171 (0.00%)	2 / 129 (1.55%)
occurrences causally related to treatment / all	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
CYTOMEGALOVIRUS INFECTION
subjects affected / exposed	1 / 324 (0.31%)	0 / 14 (0.00%)	0 / 78 (0.00%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	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
GASTROENTERITIS
subjects affected / exposed	0 / 324 (0.00%)	1 / 14 (7.14%)	0 / 78 (0.00%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	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
GASTROENTERITIS VIRAL
subjects affected / exposed	0 / 324 (0.00%)	0 / 14 (0.00%)	0 / 78 (0.00%)	0 / 69 (0.00%)	1 / 171 (0.58%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMOCYSTIS JIROVECII PNEUMONIA
subjects affected / exposed	1 / 324 (0.31%)	0 / 14 (0.00%)	0 / 78 (0.00%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	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
PYELONEPHRITIS ACUTE
subjects affected / exposed	1 / 324 (0.31%)	0 / 14 (0.00%)	0 / 78 (0.00%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	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
RETROPERITONEAL ABSCESS
subjects affected / exposed	0 / 324 (0.00%)	0 / 14 (0.00%)	1 / 78 (1.28%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 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
SEPTIC SHOCK
subjects affected / exposed	1 / 324 (0.31%)	0 / 14 (0.00%)	0 / 78 (0.00%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	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
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	0 / 324 (0.00%)	0 / 14 (0.00%)	1 / 78 (1.28%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 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
URINARY TRACT INFECTION
subjects affected / exposed	1 / 324 (0.31%)	0 / 14 (0.00%)	0 / 78 (0.00%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	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
Metabolism and nutrition disorders
GOUT
subjects affected / exposed	1 / 324 (0.31%)	0 / 14 (0.00%)	0 / 78 (0.00%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	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
HYPOKALAEMIA
subjects affected / exposed	0 / 324 (0.00%)	1 / 14 (7.14%)	0 / 78 (0.00%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	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
TYPE 1 DIABETES MELLITUS
subjects affected / exposed	0 / 324 (0.00%)	0 / 14 (0.00%)	0 / 78 (0.00%)	0 / 69 (0.00%)	1 / 171 (0.58%)	0 / 129 (0.00%)
occurrences causally related to treatment / all	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

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

Non-serious adverse events	Part 1 (Double Blind): Upadacitinib 45 mg	Part3(ET OL):Upadacitinib 30mg From Part2 OL Upadacitinib 45mg	Part 3 (ET DB): Upadacitinib 45 mg From Part 1 DB Placebo	Part3(ET DB):Upadacitinib 30mg From Part1 DB Upadacitinib 45mg	Part 1 (Double Blind): Placebo	Part 2 (Open Label): Upadacitinib 45 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	126 / 324 (38.89%)	7 / 14 (50.00%)	29 / 78 (37.18%)	12 / 69 (17.39%)	69 / 171 (40.35%)	44 / 129 (34.11%)
Investigations
BLOOD PHOSPHORUS DECREASED
subjects affected / exposed	1 / 324 (0.31%)	1 / 14 (7.14%)	0 / 78 (0.00%)	0 / 69 (0.00%)	0 / 171 (0.00%)	1 / 129 (0.78%)
occurrences all number	1	2	0	0	0	1
Nervous system disorders
HEADACHE
subjects affected / exposed	20 / 324 (6.17%)	0 / 14 (0.00%)	2 / 78 (2.56%)	0 / 69 (0.00%)	9 / 171 (5.26%)	8 / 129 (6.20%)
occurrences all number	24	0	2	0	10	8
Blood and lymphatic system disorders
ANAEMIA
subjects affected / exposed	16 / 324 (4.94%)	0 / 14 (0.00%)	3 / 78 (3.85%)	1 / 69 (1.45%)	9 / 171 (5.26%)	6 / 129 (4.65%)
occurrences all number	17	0	3	1	12	6
General disorders and administration site conditions
PYREXIA
subjects affected / exposed	13 / 324 (4.01%)	0 / 14 (0.00%)	4 / 78 (5.13%)	1 / 69 (1.45%)	8 / 171 (4.68%)	4 / 129 (3.10%)
occurrences all number	13	0	4	1	8	5
Gastrointestinal disorders
ABDOMINAL PAIN
subjects affected / exposed	9 / 324 (2.78%)	0 / 14 (0.00%)	3 / 78 (3.85%)	0 / 69 (0.00%)	12 / 171 (7.02%)	1 / 129 (0.78%)
occurrences all number	10	0	3	0	14	1
CONSTIPATION
subjects affected / exposed	7 / 324 (2.16%)	0 / 14 (0.00%)	1 / 78 (1.28%)	0 / 69 (0.00%)	1 / 171 (0.58%)	7 / 129 (5.43%)
occurrences all number	7	0	1	0	1	7
CROHN'S DISEASE
subjects affected / exposed	12 / 324 (3.70%)	1 / 14 (7.14%)	5 / 78 (6.41%)	4 / 69 (5.80%)	13 / 171 (7.60%)	5 / 129 (3.88%)
occurrences all number	12	1	5	4	13	5
NAUSEA
subjects affected / exposed	15 / 324 (4.63%)	2 / 14 (14.29%)	3 / 78 (3.85%)	1 / 69 (1.45%)	8 / 171 (4.68%)	3 / 129 (2.33%)
occurrences all number	15	2	3	1	9	3
VOMITING
subjects affected / exposed	8 / 324 (2.47%)	2 / 14 (14.29%)	0 / 78 (0.00%)	0 / 69 (0.00%)	4 / 171 (2.34%)	0 / 129 (0.00%)
occurrences all number	8	2	0	0	5	0
Skin and subcutaneous tissue disorders
ACNE
subjects affected / exposed	15 / 324 (4.63%)	0 / 14 (0.00%)	5 / 78 (6.41%)	0 / 69 (0.00%)	4 / 171 (2.34%)	18 / 129 (13.95%)
occurrences all number	16	0	5	0	4	18
ALOPECIA
subjects affected / exposed	3 / 324 (0.93%)	1 / 14 (7.14%)	0 / 78 (0.00%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences all number	3	1	0	0	0	0
Renal and urinary disorders
HAEMATURIA
subjects affected / exposed	0 / 324 (0.00%)	1 / 14 (7.14%)	0 / 78 (0.00%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences all number	0	1	0	0	0	0
Psychiatric disorders
INSOMNIA
subjects affected / exposed	5 / 324 (1.54%)	1 / 14 (7.14%)	1 / 78 (1.28%)	0 / 69 (0.00%)	2 / 171 (1.17%)	1 / 129 (0.78%)
occurrences all number	5	1	1	0	2	1
Musculoskeletal and connective tissue disorders
ARTHRALGIA
subjects affected / exposed	7 / 324 (2.16%)	0 / 14 (0.00%)	2 / 78 (2.56%)	1 / 69 (1.45%)	11 / 171 (6.43%)	2 / 129 (1.55%)
occurrences all number	7	0	2	1	11	2
BACK PAIN
subjects affected / exposed	4 / 324 (1.23%)	0 / 14 (0.00%)	2 / 78 (2.56%)	1 / 69 (1.45%)	11 / 171 (6.43%)	0 / 129 (0.00%)
occurrences all number	4	0	2	1	12	0
FISTULA DISCHARGE
subjects affected / exposed	0 / 324 (0.00%)	1 / 14 (7.14%)	0 / 78 (0.00%)	0 / 69 (0.00%)	0 / 171 (0.00%)	0 / 129 (0.00%)
occurrences all number	0	1	0	0	0	0
Infections and infestations
INFLUENZA
subjects affected / exposed	9 / 324 (2.78%)	1 / 14 (7.14%)	2 / 78 (2.56%)	3 / 69 (4.35%)	2 / 171 (1.17%)	1 / 129 (0.78%)
occurrences all number	10	1	2	3	2	1
FOLLICULITIS
subjects affected / exposed	5 / 324 (1.54%)	0 / 14 (0.00%)	5 / 78 (6.41%)	0 / 69 (0.00%)	1 / 171 (0.58%)	2 / 129 (1.55%)
occurrences all number	5	0	5	0	1	2
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	17 / 324 (5.25%)	0 / 14 (0.00%)	2 / 78 (2.56%)	2 / 69 (2.90%)	5 / 171 (2.92%)	1 / 129 (0.78%)
occurrences all number	18	0	3	2	5	1
NASOPHARYNGITIS
subjects affected / exposed	23 / 324 (7.10%)	0 / 14 (0.00%)	3 / 78 (3.85%)	2 / 69 (2.90%)	5 / 171 (2.92%)	2 / 129 (1.55%)
occurrences all number	24	0	4	2	5	2

More information

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Were there any global substantial amendments to the protocol? Yes

02 Oct 2017

The following changes were implemented with Amendment 1: -Updated eligibility criteria. -Updated the duration of the maintenance part of Substudy 1 from 48 to 52 weeks. -Revised ranked secondary and additional secondary efficacy endpoints.

24 Jan 2018

The following changes were implemented with Amendment 2: -Added vedolizumab as a prohibited biologic therapy during the study. -Clarified that the primary variables would be analysed for subjects enroled in Part 1. -Clarified that the secondary variables would be analysed for subjects enroled in Part 1. -Added SES-CD ≤ 2 at Week 12 to be consistent with pre-specified endpoint analysis for descriptive statistics. -Clarification on the pre-specified endpoint analysis for descriptive statistics for subjects enroled in Part 2. -Added pre-specified endpoints for descriptive statistics for subjects enroled in Part 3. -Clarification on the analysis methods considered for continuous secondary endpoints.

24 Aug 2018

The following changes were implemented with Amendment 3: -Updated the introduction to add 52-week data from AbbVie Study M13-740 (NCT02365649) and to clarify that the once-daily modified release formulation is being used in this study. -Updated overall study design and plan to note that the minimum Screening Period duration was corrected to reflect the minimum number of days for abdominal pain and stool frequency, accounting for the exclusion of non-usable days due to endoscopy-related procedures. -Updated eligibility criteria. -Clarified and provided additional guidance on the use of corticosteroids during the study. -Corrected the cutoff age for females in defining postmenopausal and updated contraception language. -Added the Montreal classification for Crohn's disease at Screening for the assessment of disease severity.

08 Apr 2019

The following changes were implemented with Amendment 4: -Updated overall study design and plan. -Updated exclusion criteria to ensure more appropriate selection of subjects into the study to avoid interference with efficacy assessments, to minimize or better manage the potential risks to the participants, and/or to provide further clarifications. -Removed mention of Japan and China from text describing conditions under which a chest x-ray will not be required, as a prior computerized tomography (CT) scan can apply to subjects from any country. -Updated toxicity management to align with the entire upadacitinib clinical programs, based on cumulative data with the compound. -Updated secondary efficacy variables to ensure accurate descriptions of statistical methods.

29 Apr 2020

The following changes were implemented with Amendment 5: -Updated introduction to include results of recent long-term integrated data from the Phase 3 Rheumatoid Arthritis program and the recent risk updates to the Janus kinase (JAK) inhibitor class. -Updated overall study design. -Updated eligibility criteria. -Updated efficacy variables: Changed co-primary efficacy endpoint to clinical remission based on CDAI for the United States Food and Drug Administration (US/FDA). -The European Union/European Medicines Agency (EU/EMA) co-primary efficacy endpoint for clinical remission remained based on PROs. -Ranked secondary variables then included change from Baseline in IBDQ at Week 12, proportion of subjects achieving CR-100 at Week 2 and Week 12, and assessment of extraintestinal manifestations. -Four variables (proportion of subjects with enhanced clinical response, ≥50% reduction in draining fistulas, response in IBDQ bowel domain at Week 12 and change from baseline in CSS) were not to be ranked but included under additional efficacy variables. -Updated toxicity management section. -Added management of missing date due to COVID-19.

24 Sep 2020

The following changes were implemented with Amendment 6: - Updated information on the re-evaluation of the benefit and risk to subjects participating in the study, updated wording to allow for changes in visits and procedures affected by COVID-19 pandemic and asocial changes in global/local regulations.

05 Mar 2021

The following changes were implemented with Amendment 7: -Updated protocol to decrease the sample size of Part 2 from approximately 150 subjects to approximately 130 subjects, and consequently the total sample size from 645 to 625 subjects. -Increased the maximum percentage of subjects enroled who have had inadequate response or intolerance to 3 or more biologics from 30% to 35%.

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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