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

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.

Time frame: 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.

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.

Time frame: 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.

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.

Time frame: 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). 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.

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.

Time frame: 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 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.

Time frame: 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.

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.

Time frame: 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). 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.

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.

Time frame: 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.

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.

Time frame: 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 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.

Time frame: 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.

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.

Time frame: 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.

Time frame: 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.

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.

Time frame: 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). 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.

This was assessed by reviewing participant's hospitalization data.

Time frame: 12 weeks

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

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.

Time frame: 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.