Trial Outcomes & Findings for A Study of the Efficacy and Safety of Upadacitinib in Participants With Moderately to Severely Active Crohn's Disease Who Have Inadequately Responded to or Are Intolerant to Conventional and/or Biologic Therapies (NCT NCT03345849)

Last Updated: 2022-11-23

Results Overview

The co-primary endpoint for United States (US)/Food and Drug Administration (FDA) regulatory purposes was clinical remission based on CDAI at Week 12. CDAI is a composite instrument that includes participant symptoms evaluated over 7 days (abdominal pain, stool frequency and general well-being), as well as presence of complications (arthritis/arthralgia, iritis/uveitis, erythema nodosum/pyoderma gangrenosum/aphthous stomatitis, anal fissure/fistula/abscess, other fistula, and fever), the use of antidiarrheal medicines, presence of an abdominal mass, hematocrit, and body weight. These items are scored individually, weighted, and do not contribute equally to the overall score. The CDAI is derived from summing up the weighted individual scores of eight items. CDAI approximately ranges from 0 to 600 with higher scores indicating more severe disease. Clinical remission is defined as a CDAI score less than 150.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

526 participants

Primary outcome timeframe

Week 12

Results posted on

2022-11-23

Participant Flow

Eligible participants with moderately to severely active Crohn's disease (CD) were randomized at 209 sites in 42 countries. The study consisted of a 12-week double-blind induction treatment period, and a 12-week extended treatment period for participants who did not achieve clinical response at the end of the induction treatment period.

In Part 1 participants were randomly assigned in a 2:1 ratio to receive upadacitinib 45 mg or placebo, with randomization stratified by Baseline corticosteroid use (yes or no), endoscopic disease severity (Simple Endoscopic Score for Crohn's disease \[SES-CD\] \< 15 and ≥ 15), and the number of previously failed biologic therapies (0, 1, and \>1).

Participant milestones

Participant milestones
Measure	Part 1: Placebo Participants received placebo once daily for 12 weeks in Part 1.	Part 1: Upadacitinib 45 mg Participants received 45 mg upadacitinib once daily for 12 weeks in Part 1.	Part 2: Placebo / Upadacitinib 45 mg Participants who received placebo during Part 1 and did not achieve clinical response at Week 12 received induction treatment with 45 mg upadacitinib once daily from Week 12 to Week 24.	Part 2: Upadacitinib 45 mg / Upadacitinib 30 mg Participants who received upadacitinib during Part 1 and did not achieve clinical response at Week 12 received 30 mg upadacitinib once daily from Week 12 to Week 24.
Part 1: Induction Period (Weeks 1-12) STARTED	176	350	0	0
Part 1: Induction Period (Weeks 1-12) Received Study Drug	176	350	0	0
Part 1: Induction Period (Weeks 1-12) COMPLETED	154	330	0	0
Part 1: Induction Period (Weeks 1-12) NOT COMPLETED	22	20	0	0
Part 2: Extended Treatment (Weeks 12-24) STARTED	0	0	57	59
Part 2: Extended Treatment (Weeks 12-24) COMPLETED	0	0	49	49
Part 2: Extended Treatment (Weeks 12-24) NOT COMPLETED	0	0	8	10

Reasons for withdrawal

Reasons for withdrawal
Measure	Part 1: Placebo Participants received placebo once daily for 12 weeks in Part 1.	Part 1: Upadacitinib 45 mg Participants received 45 mg upadacitinib once daily for 12 weeks in Part 1.	Part 2: Placebo / Upadacitinib 45 mg Participants who received placebo during Part 1 and did not achieve clinical response at Week 12 received induction treatment with 45 mg upadacitinib once daily from Week 12 to Week 24.	Part 2: Upadacitinib 45 mg / Upadacitinib 30 mg Participants who received upadacitinib during Part 1 and did not achieve clinical response at Week 12 received 30 mg upadacitinib once daily from Week 12 to Week 24.
Part 1: Induction Period (Weeks 1-12) Adverse Event	8	12	0	0
Part 1: Induction Period (Weeks 1-12) Withdrawal by Subject	6	3	0	0
Part 1: Induction Period (Weeks 1-12) Lost to Follow-up	0	1	0	0
Part 1: Induction Period (Weeks 1-12) Lack of Efficacy	8	3	0	0
Part 1: Induction Period (Weeks 1-12) Other	0	1	0	0
Part 2: Extended Treatment (Weeks 12-24) Adverse Event	0	0	2	2
Part 2: Extended Treatment (Weeks 12-24) Withdrawal by Subject	0	0	3	1
Part 2: Extended Treatment (Weeks 12-24) Lack of Efficacy	0	0	1	5
Part 2: Extended Treatment (Weeks 12-24) Coronavirus Disease-2019 (COVID-19) Infection	0	0	0	1
Part 2: Extended Treatment (Weeks 12-24) COVID-19 Logistical Restrictions	0	0	1	0
Part 2: Extended Treatment (Weeks 12-24) Other	0	0	1	1

Baseline Characteristics

Participants with available data

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=176 Participants Participants received placebo once daily for 12 weeks in Part 1.	Upadacitinib 45 mg n=350 Participants Participants received 45 mg upadacitinib once daily for 12 weeks in Part 1.	Total n=526 Participants Total of all reporting groups
Age, Continuous	39.3 years STANDARD_DEVIATION 13.63 • n=176 Participants	39.7 years STANDARD_DEVIATION 13.71 • n=350 Participants	39.6 years STANDARD_DEVIATION 13.67 • n=526 Participants
Age, Customized 18 years - < 40 years	91 Participants n=176 Participants	193 Participants n=350 Participants	284 Participants n=526 Participants
Age, Customized 40 years - < 65 years	80 Participants n=176 Participants	142 Participants n=350 Participants	222 Participants n=526 Participants
Age, Customized ≥ 65 years	5 Participants n=176 Participants	15 Participants n=350 Participants	20 Participants n=526 Participants
Sex: Female, Male Female	82 Participants n=176 Participants	161 Participants n=350 Participants	243 Participants n=526 Participants
Sex: Female, Male Male	94 Participants n=176 Participants	189 Participants n=350 Participants	283 Participants n=526 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	8 Participants n=176 Participants	27 Participants n=350 Participants	35 Participants n=526 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	168 Participants n=176 Participants	323 Participants n=350 Participants	491 Participants n=526 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=176 Participants	0 Participants n=350 Participants	0 Participants n=526 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=176 Participants	0 Participants n=350 Participants	0 Participants n=526 Participants
Race (NIH/OMB) Asian	36 Participants n=176 Participants	73 Participants n=350 Participants	109 Participants n=526 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=176 Participants	0 Participants n=350 Participants	0 Participants n=526 Participants
Race (NIH/OMB) Black or African American	4 Participants n=176 Participants	17 Participants n=350 Participants	21 Participants n=526 Participants
Race (NIH/OMB) White	130 Participants n=176 Participants	258 Participants n=350 Participants	388 Participants n=526 Participants
Race (NIH/OMB) More than one race	6 Participants n=176 Participants	2 Participants n=350 Participants	8 Participants n=526 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=176 Participants	0 Participants n=350 Participants	0 Participants n=526 Participants
Baseline Corticosteroid Use Yes	64 Participants n=176 Participants	126 Participants n=350 Participants	190 Participants n=526 Participants
Baseline Corticosteroid Use No	112 Participants n=176 Participants	224 Participants n=350 Participants	336 Participants n=526 Participants
Number of Previously Failed Biologics Zero	98 Participants n=176 Participants	189 Participants n=350 Participants	287 Participants n=526 Participants
Number of Previously Failed Biologics One	28 Participants n=176 Participants	58 Participants n=350 Participants	86 Participants n=526 Participants
Number of Previously Failed Biologics More than one	50 Participants n=176 Participants	103 Participants n=350 Participants	153 Participants n=526 Participants
Endoscopic Disease Severity SES-CD < 15	110 Participants n=176 Participants	218 Participants n=350 Participants	328 Participants n=526 Participants
Endoscopic Disease Severity SES-CD ≥ 15	66 Participants n=176 Participants	132 Participants n=350 Participants	198 Participants n=526 Participants
Duration of Crohn's Disease	8.1005 years STANDARD_DEVIATION 7.9901 • n=176 Participants	9.2993 years STANDARD_DEVIATION 9.4684 • n=350 Participants	8.8982 years STANDARD_DEVIATION 9.0110 • n=526 Participants
Crohn's Disease Activity Index (CDAI) Score	293.85 score on a scale STANDARD_DEVIATION 85.378 • n=176 Participants • Participants with available data	292.42 score on a scale STANDARD_DEVIATION 81.250 • n=349 Participants • Participants with available data	292.90 score on a scale STANDARD_DEVIATION 82.578 • n=525 Participants • Participants with available data
Average Daily Abdominal Pain Score	1.9064 score on a scale STANDARD_DEVIATION 0.6942 • n=176 Participants	1.8917 score on a scale STANDARD_DEVIATION 0.6795 • n=350 Participants	1.8966 score on a scale STANDARD_DEVIATION 0.6839 • n=526 Participants
Average Daily Very Soft or Liquid Stool Frequency	5.0857 stools/day STANDARD_DEVIATION 2.8366 • n=176 Participants	5.1864 stools/day STANDARD_DEVIATION 2.6130 • n=350 Participants	5.1527 stools/day STANDARD_DEVIATION 2.6876 • n=526 Participants

PRIMARY outcome

Timeframe: Week 12

Population: Randomized participants who received at least one dose of double-blind study drug during Part 1 (intention-to-treat population). Participants with missing data or who withdrew prior to Week 12 were counted as non-responders (non-responder imputation); missing data due to COVID-19 infection or logistical restriction were handled by multiple imputation.

Outcome measures

Outcome measures
Measure	Placebo n=176 Participants Participants received placebo once daily for 12 weeks in Part 1.	Upadacitinib 45 mg QD n=350 Participants Participants received 45 mg upadacitinib once daily (QD) for 12 weeks in Part 1.
Percentage of Participants With Clinical Remission Per Crohn's Disease Activity Index (CDAI) at Week 12	29.1 percentage of participants Interval 22.4 to 35.8	49.5 percentage of participants Interval 44.2 to 54.8

PRIMARY outcome

Timeframe: Week 12

The co-primary endpoint for European Union (EU)/European Medicines Agency (EMA) regulatory purposes was clinical remission defined based on two patient reported outcomes, average daily stool frequency (SF) and average daily abdominal pain score (APS). Clinical remission per PROs was defined as average daily very soft or liquid SF ≤ 2.8 and average daily APS ≤ 1.0 and neither worse than Baseline. Participants recorded APS and the number of very soft or liquid SF daily in an electronic diary. Abdominal pain was rated on a scale from 0 (none) to 3 (severe). The average daily very soft or liquid SF and APS were calculated using the 4-7 most recent useable days of patient-report outcomes (i.e., excluding days with missing entries or associated with endoscopy procedures) out of the last 14 days prior to the Week 12 visit.

Outcome measures

Outcome measures
Measure	Placebo n=176 Participants Participants received placebo once daily for 12 weeks in Part 1.	Upadacitinib 45 mg QD n=350 Participants Participants received 45 mg upadacitinib once daily (QD) for 12 weeks in Part 1.
Percentage of Participants With Clinical Remission Per Patient-Reported Outcomes (PROs) at Week 12	22.2 percentage of participants Interval 16.0 to 28.3	50.7 percentage of participants Interval 45.5 to 56.0

PRIMARY outcome

Timeframe: Baseline and Week 12

Endoscopic response at Week 12 was a co-primary endpoint for both the US/FDA and EU/EMA regulatory purposes. 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, at least a 2-point reduction from Baseline), as scored by independent external and blinded central readers. The SES-CD evaluates 4 endoscopic variables (ulcer size, ulcerated surface, affected surface, and narrowing, each on a scale from 0 (none) to 3 in 5 segments assessed during ileocolonoscopy (ileum, right colon, transverse colon, sigmoid and left colon, and rectum). The total score is the sum of the 4 endoscopic variable scores and ranges from 0 to 56, where higher scores indicate more severe disease.

Outcome measures

Outcome measures
Measure	Placebo n=176 Participants Participants received placebo once daily for 12 weeks in Part 1.	Upadacitinib 45 mg QD n=350 Participants Participants received 45 mg upadacitinib once daily (QD) for 12 weeks in Part 1.
Percentage of Participants With Endoscopic Response at Week 12	13.1 percentage of participants Interval 8.1 to 18.0	45.5 percentage of participants Interval 40.3 to 50.8

SECONDARY outcome

Timeframe: Baseline and Week 12

Endoscopic remission is defined as an SES-CD ≤ 4 and at least 2 point reduction from Baseline and no subscore \> 1 in any individual variable,as scored by independent external and blinded central readers. The SES-CD evaluates 4 endoscopic variables (ulcer size, ulcerated surface, affected surface, and narrowing, each on a scale from 0 (none) to 3 in 5 segments assessed during ileocolonoscopy (ileum, right colon, transverse colon, sigmoid and left colon, and rectum). The total score is the sum of the 4 endoscopic variable scores and ranges from 0 to 56, where higher scores indicate more severe disease.

Outcome measures

Outcome measures
Measure	Placebo n=176 Participants Participants received placebo once daily for 12 weeks in Part 1.	Upadacitinib 45 mg QD n=350 Participants Participants received 45 mg upadacitinib once daily (QD) for 12 weeks in Part 1.
Percentage of Participants With Endoscopic Remission at Week 12	7.4 percentage of participants Interval 3.5 to 11.3	28.9 percentage of participants Interval 24.2 to 33.7

SECONDARY outcome

Timeframe: Week 12

Population: Randomized participants who received at least one dose of double-blind study drug during Part 1 (intention-to-treat population) who were taking corticosteroids for Crohn's disease at Baseline. Participants with missing data or who withdrew prior to Week 12 were counted as non-responders (non-responder imputation); missing data due to COVID-19 infection or logistical restriction were handled by multiple imputation.

Corticosteroid-free clinical remission is defined as participants who discontinued corticosteroid use for CD and achieved clinical remission per CDAI at Week 12, assessed for participants taking corticosteroids for CD at Baseline. CDAI is a composite instrument that includes participant symptoms evaluated over 7 days (abdominal pain, stool frequency and general well-being), as well as presence of complications (arthritis/arthralgia, iritis/uveitis, erythema nodosum/pyoderma gangrenosum/aphthous stomatitis, anal fissure/fistula/abscess, other fistula, and fever), the use of antidiarrheal medicines, presence of an abdominal mass, hematocrit, and body weight. These items are scored individually, weighted, and do not contribute equally to the overall score. The CDAI is derived from summing up the weighted individual scores of eight items. CDAI approximately ranges from 0 to 600 with higher scores indicating more severe disease. Clinical remission is defined as CDAI score less than 150.

Outcome measures

Outcome measures
Measure	Placebo n=64 Participants Participants received placebo once daily for 12 weeks in Part 1.	Upadacitinib 45 mg QD n=126 Participants Participants received 45 mg upadacitinib once daily (QD) for 12 weeks in Part 1.
Percentage of Participants Who Discontinued Corticosteroid Use for Crohn's Disease and Achieved Clinical Remission Per CDAI at Week 12	15.7 percentage of participants Interval 6.8 to 24.7	42.9 percentage of participants Interval 34.2 to 51.5

SECONDARY outcome

Timeframe: Baseline and Week 12

Population: Randomized participants who received at least one dose of double-blind study drug during Part 1 (intention-to-treat population); missing data were handled using a mixed-effect model with repeated measurements (MMRM). The Overall Number of Participants Analyzed presented below is based on the number of participants with non-missing Baseline and Week 12 values.

The FACIT-Fatigue questionnaire is a self-administered patient questionnaire that consists of 13 questions designed to measure the degree of fatigue experienced by participants in the previous 7 days, including physical fatigue (e.g., I feel tired), functional fatigue (e.g., trouble finishing things), emotional fatigue (e.g., frustration), and social consequences of fatigue (e.g., limits social activity). Participants respond to the questions on a scale from 0 (not at all) to 4 (very much). The FACIT-Fatigue score is computed by summing the item scores, after reversing those items that are worded in the negative direction. The FACIT-Fatigue score ranges from 0 to 52, where higher scores represent less fatigue. A positive change from Baseline indicates improvement.

Outcome measures

Outcome measures
Measure	Placebo n=133 Participants Participants received placebo once daily for 12 weeks in Part 1.	Upadacitinib 45 mg QD n=304 Participants Participants received 45 mg upadacitinib once daily (QD) for 12 weeks in Part 1.
Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) at Week 12	5.0 score on a scale Interval 3.2 to 6.8	11.3 score on a scale Interval 10.0 to 12.5

SECONDARY outcome

Timeframe: Baseline and Week 12

The Inflammatory Bowel Disease Questionnaire (IBDQ) is used to assess health-related quality of life (HRQoL) in patients with inflammatory bowel disease. It consists of 32 questions evaluating bowel and systemic symptoms, as well as emotional and social functions. Each question is answered on a scale from 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.

Outcome measures

Outcome measures
Measure	Placebo n=134 Participants Participants received placebo once daily for 12 weeks in Part 1.	Upadacitinib 45 mg QD n=304 Participants Participants received 45 mg upadacitinib once daily (QD) for 12 weeks in Part 1.
Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Week 12	24.423 score on a scale Interval 19.007 to 29.84	46.265 score on a scale Interval 42.495 to 50.035

SECONDARY outcome

Timeframe: Baseline and Week 2

Population: Randomized participants who received at least one dose of double-blind study drug during Part 1 (intention-to-treat population). Participants with missing data or who withdrew prior to Week 2 were counted as non-responders (non-responder imputation); missing data due to COVID-19 infection or logistical restriction were handled by multiple imputation.

Clinical response 100 (CR-100) is defined as a decrease of at least 100 points in CDAI from Baseline. CDAI is a composite instrument that includes participant symptoms evaluated over 7 days (abdominal pain, stool frequency and general well-being), as well as presence of complications (arthritis/arthralgia, iritis/uveitis, erythema nodosum/pyoderma gangrenosum/aphthous stomatitis, anal fissure/fistula/abscess, other fistula, and fever), the use of antidiarrheal medicines, presence of an abdominal mass, hematocrit, and body weight. These items are scored individually, weighted, and do not contribute equally to the overall score. The CDAI is derived from summing up the weighted individual scores of eight items. CDAI approximately ranges from 0 to 600 with higher scores indicating more severe disease.

Outcome measures

Outcome measures
Measure	Placebo n=176 Participants Participants received placebo once daily for 12 weeks in Part 1.	Upadacitinib 45 mg QD n=350 Participants Participants received 45 mg upadacitinib once daily (QD) for 12 weeks in Part 1.
Percentage of Participants Achieving Clinical Response 100 (CR-100) at Week 2	20.4 percentage of participants Interval 14.4 to 26.5	32.2 percentage of participants Interval 27.3 to 37.1

SECONDARY outcome

Timeframe: Baseline and Week 12

Outcome measures

Outcome measures
Measure	Placebo n=176 Participants Participants received placebo once daily for 12 weeks in Part 1.	Upadacitinib 45 mg QD n=350 Participants Participants received 45 mg upadacitinib once daily (QD) for 12 weeks in Part 1.
Percentage of Participants Achieving Clinical Response 100 (CR-100) at Week 12	37.3 percentage of participants Interval 30.1 to 44.5	56.6 percentage of participants Interval 51.4 to 61.8

SECONDARY outcome

Timeframe: Week 4

Population: Randomized participants who received at least one dose of double-blind study drug during Part 1 (intention-to-treat population). Participants with missing data or who withdrew prior to Week 4 were counted as non-responders (non-responder imputation); missing data due to COVID-19 infection or logistical restriction were handled by multiple imputation.

CDAI is a composite instrument that includes participant symptoms evaluated over 7 days (abdominal pain, stool frequency and general well-being), as well as presence of complications (arthritis/arthralgia, iritis/uveitis, erythema nodosum/pyoderma gangrenosum/aphthous stomatitis, anal fissure/fistula/abscess, other fistula, and fever), the use of antidiarrheal medicines, presence of an abdominal mass, hematocrit, and body weight. These items are scored individually, weighted, and do not contribute equally to the overall score. The CDAI is derived from summing up the weighted individual scores of eight items. CDAI approximately ranges from 0 to 600 with higher scores indicating more severe disease. Clinical remission is defined as CDAI score less than 150.

Outcome measures

Outcome measures
Measure	Placebo n=176 Participants Participants received placebo once daily for 12 weeks in Part 1.	Upadacitinib 45 mg QD n=350 Participants Participants received 45 mg upadacitinib once daily (QD) for 12 weeks in Part 1.
Percentage of Participants With Clinical Remission Per CDAI at Week 4	26.7 percentage of participants Interval 20.2 to 33.3	37.1 percentage of participants Interval 32.1 to 42.2

SECONDARY outcome

Timeframe: 12 weeks

Population: Randomized participants who received at least one dose of double-blind study drug during Part 1 (intention-to-treat population).

This was assessed by reviewing participant's hospitalization data.

Outcome measures

Outcome measures
Measure	Placebo n=176 Participants Participants received placebo once daily for 12 weeks in Part 1.	Upadacitinib 45 mg QD n=350 Participants Participants received 45 mg upadacitinib once daily (QD) for 12 weeks in Part 1.
Percentage of Participants With Hospitalizations Due to Crohn's Disease (CD) During the 12-Week Induction Period	5.1 percentage of participants Interval 1.9 to 8.4	3.7 percentage of participants Interval 1.7 to 5.7

SECONDARY outcome

Timeframe: Week 12

Population: Randomized participants who received at least one dose of double-blind study drug during Part 1 (intention-to-treat population) with any EIM at Baseline.

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. Only participants with any EIM present at Baseline were included in the analysis of resolution of EIMs. Resolution of EIMs was defined as absence of all EIMs at the Week 12 visit.

Outcome measures

Outcome measures
Measure	Placebo n=78 Participants Participants received placebo once daily for 12 weeks in Part 1.	Upadacitinib 45 mg QD n=151 Participants Participants received 45 mg upadacitinib once daily (QD) for 12 weeks in Part 1.
Percentage of Participants With Resolution of Extra-Intestinal Manifestation (EIMs) at Week 12	20.9 percentage of participants Interval 11.8 to 30.1	28.5 percentage of participants Interval 21.3 to 35.7

SECONDARY outcome

Timeframe: Week 4

Population: Randomized participants who received at least one dose of double-blind study drug during Part 1 (intention-to-treat population). Participants with missing data or who withdrew prior to Week 4 were counted as non-responders (non-responder imputation); missing data due to COVID-19 infection or logistical restriction were handled by multiple imputation.

Clinical remission per PROs was defined as average daily very soft or liquid SF ≤ 2.8 and average daily APS ≤ 1.0 and neither worse than Baseline. Participants recorded APS and the number of liquid or very soft SF daily in an electronic diary. Abdominal pain was rated on a scale from 0 (none) to 3 (severe). The average daily very soft or liquid SF and APS were calculated using the 4-7 most recent useable days of patient-reported outcomes (i.e., excluding days with missing entries or associated with endoscopy procedures) out of the last 14 days prior to the Week 4 visit.

Outcome measures

Outcome measures
Measure	Placebo n=176 Participants Participants received placebo once daily for 12 weeks in Part 1.	Upadacitinib 45 mg QD n=350 Participants Participants received 45 mg upadacitinib once daily (QD) for 12 weeks in Part 1.
Percentage of Participants With Clinical Remission Per PROs at Week 4	14.8 percentage of participants Interval 9.5 to 20.0	35.7 percentage of participants Interval 30.7 to 40.7

SECONDARY outcome

Timeframe: Week 12

Corticosteroid-free clinical remission is defined as participants who discontinued corticosteroid use for CD and achieved clinical remission per PROs at Week 12, assessed for participants taking corticosteroids for CD at Baseline. Clinical remission per PROs was defined as average daily very soft or liquid stool frequency (SF) ≤ 2.8 and average daily APS ≤ 1.0 and neither worse than Baseline. Participants recorded APS and the number of liquid or very soft SF daily in an electronic diary. Abdominal pain was rated on a scale from 0 (none) to 3 (severe). The average daily liquid or very soft SF and APS were calculated using the 4-7 most recent useable days of patient-reported outcomes (i.e., excluding days with missing entries or associated with endoscopy procedures) out of the last 14 days prior to the Week 12 visit.

Outcome measures

Outcome measures
Measure	Placebo n=64 Participants Participants received placebo once daily for 12 weeks in Part 1.	Upadacitinib 45 mg QD n=126 Participants Participants received 45 mg upadacitinib once daily (QD) for 12 weeks in Part 1.
Percentage of Participants Who Discontinued Corticosteroid Use for Crohn's Disease and Achieved Clinical Remission Per PROs at Week 12	12.5 percentage of participants Interval 4.4 to 20.6	44.4 percentage of participants Interval 35.8 to 53.1

Adverse Events

Part 1: Placebo

Serious events: 12 serious events

Other events: 37 other events

Deaths: 0 deaths

Part 1: Upadacitinib 45 mg

Serious events: 24 serious events

Other events: 92 other events

Deaths: 0 deaths

Part 2: Placebo / Upadacitinib 45 mg

Serious events: 4 serious events

Other events: 14 other events

Deaths: 0 deaths

Part 2: Upadacitinib 45 mg / Upadacitinib 30 mg

Serious events: 6 serious events

Other events: 13 other events

Deaths: 1 deaths

Serious adverse events

Serious adverse events
Measure	Part 1: Placebo n=176 participants at risk Participants received placebo once daily for 12 weeks in Part 1.	Part 1: Upadacitinib 45 mg n=350 participants at risk Participants received 45 mg upadacitinib once daily for 12 weeks in Part 1.	Part 2: Placebo / Upadacitinib 45 mg n=57 participants at risk Participants who received placebo during Part 1 and did not achieve clinical response at Week 12 received induction treatment with 45 mg upadacitinib once daily from Week 12 to Week 24.	Part 2: Upadacitinib 45 mg / Upadacitinib 30 mg n=59 participants at risk Participants who received upadacitinib during Part 1 and did not achieve clinical response at Week 12 received 30 mg upadacitinib once daily from Week 12 to Week 24.
Blood and lymphatic system disorders ANAEMIA	0.00% 0/176 • Part 1: 12 weeks Part 2: 12 weeks	0.29% 1/350 • Number of events 2 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/57 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/59 • Part 1: 12 weeks Part 2: 12 weeks
Blood and lymphatic system disorders IRON DEFICIENCY ANAEMIA	0.00% 0/176 • Part 1: 12 weeks Part 2: 12 weeks	0.29% 1/350 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/57 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/59 • Part 1: 12 weeks Part 2: 12 weeks
Gastrointestinal disorders ABDOMINAL PAIN	0.00% 0/176 • Part 1: 12 weeks Part 2: 12 weeks	0.29% 1/350 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/57 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/59 • Part 1: 12 weeks Part 2: 12 weeks
Gastrointestinal disorders ANAL FISTULA	0.57% 1/176 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/350 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/57 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/59 • Part 1: 12 weeks Part 2: 12 weeks
Gastrointestinal disorders CONSTIPATION	0.00% 0/176 • Part 1: 12 weeks Part 2: 12 weeks	0.29% 1/350 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/57 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/59 • Part 1: 12 weeks Part 2: 12 weeks
Gastrointestinal disorders CROHN'S DISEASE	2.8% 5/176 • Number of events 5 • Part 1: 12 weeks Part 2: 12 weeks	2.0% 7/350 • Number of events 8 • Part 1: 12 weeks Part 2: 12 weeks	1.8% 1/57 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks	3.4% 2/59 • Number of events 2 • Part 1: 12 weeks Part 2: 12 weeks
Gastrointestinal disorders ENTERITIS	0.00% 0/176 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/350 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/57 • Part 1: 12 weeks Part 2: 12 weeks	1.7% 1/59 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks
Gastrointestinal disorders ILEAL STENOSIS	0.00% 0/176 • Part 1: 12 weeks Part 2: 12 weeks	0.29% 1/350 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/57 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/59 • Part 1: 12 weeks Part 2: 12 weeks
Gastrointestinal disorders ILEUS	0.00% 0/176 • Part 1: 12 weeks Part 2: 12 weeks	0.29% 1/350 • Number of events 2 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/57 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/59 • Part 1: 12 weeks Part 2: 12 weeks
Gastrointestinal disorders INTESTINAL OBSTRUCTION	0.00% 0/176 • Part 1: 12 weeks Part 2: 12 weeks	0.57% 2/350 • Number of events 2 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/57 • Part 1: 12 weeks Part 2: 12 weeks	1.7% 1/59 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks
Gastrointestinal disorders INTESTINAL PERFORATION	0.00% 0/176 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/350 • Part 1: 12 weeks Part 2: 12 weeks	1.8% 1/57 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/59 • Part 1: 12 weeks Part 2: 12 weeks
Gastrointestinal disorders LARGE INTESTINAL STENOSIS	0.00% 0/176 • Part 1: 12 weeks Part 2: 12 weeks	0.29% 1/350 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/57 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/59 • Part 1: 12 weeks Part 2: 12 weeks
Gastrointestinal disorders LARGE INTESTINE PERFORATION	0.57% 1/176 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/350 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/57 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/59 • Part 1: 12 weeks Part 2: 12 weeks
Gastrointestinal disorders LOWER GASTROINTESTINAL HAEMORRHAGE	0.00% 0/176 • Part 1: 12 weeks Part 2: 12 weeks	0.29% 1/350 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/57 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/59 • Part 1: 12 weeks Part 2: 12 weeks
Gastrointestinal disorders SMALL INTESTINAL OBSTRUCTION	0.57% 1/176 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/350 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/57 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/59 • Part 1: 12 weeks Part 2: 12 weeks
General disorders PYREXIA	0.00% 0/176 • Part 1: 12 weeks Part 2: 12 weeks	0.29% 1/350 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/57 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/59 • Part 1: 12 weeks Part 2: 12 weeks
Hepatobiliary disorders CHOLECYSTITIS ACUTE	0.00% 0/176 • Part 1: 12 weeks Part 2: 12 weeks	0.29% 1/350 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/57 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/59 • Part 1: 12 weeks Part 2: 12 weeks
Infections and infestations ANAL ABSCESS	0.57% 1/176 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/350 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/57 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/59 • Part 1: 12 weeks Part 2: 12 weeks
Infections and infestations APPENDICITIS	0.00% 0/176 • Part 1: 12 weeks Part 2: 12 weeks	0.29% 1/350 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/57 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/59 • Part 1: 12 weeks Part 2: 12 weeks
Infections and infestations COVID-19	0.00% 0/176 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/350 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/57 • Part 1: 12 weeks Part 2: 12 weeks	1.7% 1/59 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks
Infections and infestations COVID-19 PNEUMONIA	0.57% 1/176 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/350 • Part 1: 12 weeks Part 2: 12 weeks	1.8% 1/57 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/59 • Part 1: 12 weeks Part 2: 12 weeks
Infections and infestations GASTROENTERITIS ROTAVIRUS	0.00% 0/176 • Part 1: 12 weeks Part 2: 12 weeks	0.29% 1/350 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/57 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/59 • Part 1: 12 weeks Part 2: 12 weeks
Infections and infestations GASTROENTERITIS VIRAL	0.00% 0/176 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/350 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/57 • Part 1: 12 weeks Part 2: 12 weeks	1.7% 1/59 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks
Infections and infestations OSTEOMYELITIS	0.57% 1/176 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/350 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/57 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/59 • Part 1: 12 weeks Part 2: 12 weeks
Infections and infestations PNEUMONIA	0.00% 0/176 • Part 1: 12 weeks Part 2: 12 weeks	0.29% 1/350 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/57 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/59 • Part 1: 12 weeks Part 2: 12 weeks
Infections and infestations RECTAL ABSCESS	0.00% 0/176 • Part 1: 12 weeks Part 2: 12 weeks	0.29% 1/350 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/57 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/59 • Part 1: 12 weeks Part 2: 12 weeks
Infections and infestations UPPER RESPIRATORY TRACT INFECTION	0.00% 0/176 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/350 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/57 • Part 1: 12 weeks Part 2: 12 weeks	1.7% 1/59 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks
Injury, poisoning and procedural complications FALL	0.00% 0/176 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/350 • Part 1: 12 weeks Part 2: 12 weeks	1.8% 1/57 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/59 • Part 1: 12 weeks Part 2: 12 weeks
Injury, poisoning and procedural complications FEMORAL NECK FRACTURE	0.00% 0/176 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/350 • Part 1: 12 weeks Part 2: 12 weeks	1.8% 1/57 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/59 • Part 1: 12 weeks Part 2: 12 weeks
Metabolism and nutrition disorders HYPOKALAEMIA	0.00% 0/176 • Part 1: 12 weeks Part 2: 12 weeks	0.29% 1/350 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/57 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/59 • Part 1: 12 weeks Part 2: 12 weeks
Musculoskeletal and connective tissue disorders FLANK PAIN	0.57% 1/176 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/350 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/57 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/59 • Part 1: 12 weeks Part 2: 12 weeks
Nervous system disorders CEREBROVASCULAR ACCIDENT	0.57% 1/176 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/350 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/57 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/59 • Part 1: 12 weeks Part 2: 12 weeks
Nervous system disorders PARAESTHESIA	0.00% 0/176 • Part 1: 12 weeks Part 2: 12 weeks	0.29% 1/350 • Number of events 2 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/57 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/59 • Part 1: 12 weeks Part 2: 12 weeks
Nervous system disorders SEIZURE	0.00% 0/176 • Part 1: 12 weeks Part 2: 12 weeks	0.29% 1/350 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/57 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/59 • Part 1: 12 weeks Part 2: 12 weeks
Renal and urinary disorders ACUTE KIDNEY INJURY	0.00% 0/176 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/350 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/57 • Part 1: 12 weeks Part 2: 12 weeks	1.7% 1/59 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks
Renal and urinary disorders NEPHROLITHIASIS	0.00% 0/176 • Part 1: 12 weeks Part 2: 12 weeks	0.29% 1/350 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/57 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/59 • Part 1: 12 weeks Part 2: 12 weeks
Respiratory, thoracic and mediastinal disorders ACUTE RESPIRATORY FAILURE	0.00% 0/176 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/350 • Part 1: 12 weeks Part 2: 12 weeks	1.8% 1/57 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/59 • Part 1: 12 weeks Part 2: 12 weeks
Skin and subcutaneous tissue disorders METASTATIC CUTANEOUS CROHN'S DISEASE	0.00% 0/176 • Part 1: 12 weeks Part 2: 12 weeks	0.29% 1/350 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/57 • Part 1: 12 weeks Part 2: 12 weeks	0.00% 0/59 • Part 1: 12 weeks Part 2: 12 weeks

Other adverse events

Other adverse events
Measure	Part 1: Placebo n=176 participants at risk Participants received placebo once daily for 12 weeks in Part 1.	Part 1: Upadacitinib 45 mg n=350 participants at risk Participants received 45 mg upadacitinib once daily for 12 weeks in Part 1.	Part 2: Placebo / Upadacitinib 45 mg n=57 participants at risk Participants who received placebo during Part 1 and did not achieve clinical response at Week 12 received induction treatment with 45 mg upadacitinib once daily from Week 12 to Week 24.	Part 2: Upadacitinib 45 mg / Upadacitinib 30 mg n=59 participants at risk Participants who received upadacitinib during Part 1 and did not achieve clinical response at Week 12 received 30 mg upadacitinib once daily from Week 12 to Week 24.
Blood and lymphatic system disorders ANAEMIA	4.5% 8/176 • Number of events 8 • Part 1: 12 weeks Part 2: 12 weeks	6.0% 21/350 • Number of events 23 • Part 1: 12 weeks Part 2: 12 weeks	5.3% 3/57 • Number of events 3 • Part 1: 12 weeks Part 2: 12 weeks	3.4% 2/59 • Number of events 2 • Part 1: 12 weeks Part 2: 12 weeks
Gastrointestinal disorders CROHN'S DISEASE	7.4% 13/176 • Number of events 13 • Part 1: 12 weeks Part 2: 12 weeks	1.4% 5/350 • Number of events 5 • Part 1: 12 weeks Part 2: 12 weeks	1.8% 1/57 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks	5.1% 3/59 • Number of events 3 • Part 1: 12 weeks Part 2: 12 weeks
General disorders PYREXIA	1.1% 2/176 • Number of events 2 • Part 1: 12 weeks Part 2: 12 weeks	4.0% 14/350 • Number of events 15 • Part 1: 12 weeks Part 2: 12 weeks	1.8% 1/57 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks	5.1% 3/59 • Number of events 3 • Part 1: 12 weeks Part 2: 12 weeks
Infections and infestations COVID-19	0.00% 0/176 • Part 1: 12 weeks Part 2: 12 weeks	0.86% 3/350 • Number of events 3 • Part 1: 12 weeks Part 2: 12 weeks	5.3% 3/57 • Number of events 3 • Part 1: 12 weeks Part 2: 12 weeks	1.7% 1/59 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks
Infections and infestations NASOPHARYNGITIS	3.4% 6/176 • Number of events 6 • Part 1: 12 weeks Part 2: 12 weeks	4.6% 16/350 • Number of events 16 • Part 1: 12 weeks Part 2: 12 weeks	3.5% 2/57 • Number of events 2 • Part 1: 12 weeks Part 2: 12 weeks	6.8% 4/59 • Number of events 4 • Part 1: 12 weeks Part 2: 12 weeks
Musculoskeletal and connective tissue disorders ARTHRALGIA	4.5% 8/176 • Number of events 9 • Part 1: 12 weeks Part 2: 12 weeks	2.6% 9/350 • Number of events 10 • Part 1: 12 weeks Part 2: 12 weeks	5.3% 3/57 • Number of events 3 • Part 1: 12 weeks Part 2: 12 weeks	1.7% 1/59 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks
Skin and subcutaneous tissue disorders ACNE	0.57% 1/176 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks	6.9% 24/350 • Number of events 24 • Part 1: 12 weeks Part 2: 12 weeks	5.3% 3/57 • Number of events 3 • Part 1: 12 weeks Part 2: 12 weeks	1.7% 1/59 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks
Skin and subcutaneous tissue disorders RASH	2.3% 4/176 • Number of events 4 • Part 1: 12 weeks Part 2: 12 weeks	3.7% 13/350 • Number of events 14 • Part 1: 12 weeks Part 2: 12 weeks	5.3% 3/57 • Number of events 3 • Part 1: 12 weeks Part 2: 12 weeks	1.7% 1/59 • Number of events 1 • Part 1: 12 weeks Part 2: 12 weeks

Additional Information

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