Ulcerative Colitis (UC)
Conditions
Keywords
Upadacitinib (ABT-494), Moderately to Severely Active UC, RINVOQ
Brief summary
This study was comprised of three substudies. The objective of Substudy 1 was to characterize the dose-response, efficacy, and safety of upadacitinib compared to placebo in inducing clinical remission to identify the induction dose of upadacitinib for further evaluation in Substudy 2. The objective of Substudy 2 was to evaluate the efficacy and safety of upadacitinib compared to placebo in inducing clinical remission in participants. The objective of Substudy 3 was to evaluate the efficacy and safety of upadacitinib compared to placebo in achieving clinical remission in participants who had a response following induction with upadacitinib.
Detailed description
Substudy 1 was a Phase 2b dose-ranging study designed to evaluate the efficacy and safety of different oral doses of upadacitinib compared to placebo as 8-week induction therapy in participants with moderately to severely active UC. Approximately 250 participants were planned to be randomized 1:1:1:1:1 to the placebo group and 4 upadacitinib doses (7.5, 15, 30, and 45 mg). Randomization was stratified by previous biologic therapy use (yes/no), Baseline corticosteroid use (yes/no), and Baseline Adapted Mayo score (≤ 7 or \> 7). The study duration included a Screening Period of up to 5 weeks and an 8-week double-blind (DB) Induction Period. After all randomized participants completed the 8-week induction, a dose-selection analysis of efficacy and safety (selected laboratory parameters) of upadacitinib versus placebo was performed. Based on this dose-selection analysis, one induction dose (upadacitinib 45 mg) was identified for further evaluation in two Phase 3 induction studies, M14-234 Substudy 2 and M14-675 (NCT03653026). During the analysis period, 132 additional participants were randomized into Groups 3 and 4 of Substudy 1 (upadacitinib 30 mg and 45 mg dose groups; approximately 66 participants per dose group). The objectives of enrolling these additional participants were to avoid interrupting the study activities during the analysis period and to support a sufficient number of participants with clinical response to be re-randomized into the maintenance portion in Substudy 3. Substudy 1 main participants are defined as those first 250 randomized 250, and additional participants are defined as those who were randomized after the main participants. Substudy 2 was a two-part Phase 3 dose-confirming study designed to evaluate the efficacy and safety of oral administration of upadacitinib 45 mg compared to placebo as induction therapy for up to 16 weeks in participants with moderately to severely active UC. Substudy 2 included a Screening Period of up to 5 weeks, Part 1, and Part 2. Part 1 was a randomized, DB, placebo-controlled 8-week induction period. Part 2 was an open-label, 8-week extended treatment period for clinical non-responders from Part 1 of Substudy 2. Part 1 was planned to enroll 462 subjects; actual enrollment was 474 subjects. Eligible participants were randomized in a 2:1 ratio to one of the two treatment groups (DB upadacitinib 45 mg or matching placebo) for 8 weeks. The randomization was stratified by bio-IR status (Biologic inadequate responders \[bio-IR\] vs Non-biologic-inadequate responders \[non-bio-IR\], corticosteroid use (yes or no), and Adapted Mayo score (≤ 7 or \> 7) at Baseline. Within bio-IR, the randomization was further stratified by number of prior biologic treatments (≤ 1 or \> 1). Within non-bio-IR, the randomization was further stratified by previous biologic use (yes or no). Part 2 was an open label, 8-week Extended Treatment Period for those who did not achieve clinical response per Adapted Mayo score at Week 8 in Part 1. All participants received upadacitinib 45 mg. Substudy 3 was a Phase 3 maintenance study designed to evaluate the efficacy and safety of upadacitinib 15 and 30 mg once daily (QD) compared to placebo in achieving clinical remission per Adapted Mayo score in participants with moderately to severely active UC who achieved clinical response per Adapted Mayo score following induction therapy from Substudy 1, Substudy 2, or Study M14-675. A total of 1,046 subjects who achieved clinical response per Adapted Mayo score after completion of induction treatment or Extended Treatment Period in Study M14-234 Substudy 1, Substudy 2, or Study M14-675 entered Substudy 3, and 1,044 were treated with a blinded treatment assignment for up to 52 weeks. Substudy 3 included 4 cohorts. Cohort 1: 847 participants who achieved clinical response in Substudy 1, Substudy 2, or Study M14-675 at either Week 8 or Week 16, and received upadacitinib 15, 30, or 45 mg QD. The treatment groups in Cohort 1 were Group 1: upadacitinib 15 mg QD; Group 2: upadacitinib 30 mg QD; and Group 3: placebo QD. Those who achieved clinical response and received upadacitinib 15 mg QD in Substudy 1 were re-randomized 1:1 to only receive upadacitinib 15 mg QD or placebo QD (treatment Group 1 or 3). Cohort 2: 104 participants who received double-blind placebo QD treatment for 8 weeks during Substudy 1, Substudy 2 Part 1, or Study M14-675 Part 1 and achieved clinical response at Week 8 continued to receive blinded placebo QD in Substudy 3. Cohort 3: 75 participants who received upadacitinib 45 mg QD in Induction Phase and did not achieve clinical response and received upadacitinib 45 mg QD in Extended Treatment in Substudy 2 Part 2 or in Study M14-675 Part 2 and achieved clinical response at Week 16 were re-randomized 1:1 and received blinded upadacitinib 30 mg QD or upadacitinib 15 mg QD in Substudy 3. Cohort 4: 20 participants who received double-blinded treatment of upadacitinib 7.5 mg QD for 8 weeks during Substudy 1 and achieved clinical response at Week 8 continued to receive blinded treatment of upadacitinib 7.5 mg QD in Substudy 3.
Interventions
DRUGPlacebo
Film-coated tablet for oral administration
DRUGUpadacitinib
Film-coated tablet for oral administration
Sponsors
AbbVie
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
16 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Note: Adolescent participants who are 16 or 17 years old will be eligible to participate if approved by the country or regulatory/health authority. If approval has not been granted, only participants ≥18 years old will be enrolled. Adolescents must weigh ≥ 40 kilograms and meet the definition of Tanner Stage 5 at Screening Visit. * Diagnosis of ulcerative colitis for 90 days or greater prior to Baseline, confirmed by colonoscopy during the Screening Period, with exclusion of current infection, colonic dysplasia and/or malignancy. Appropriate documentation of biopsy results consistent with the diagnosis of UC, in the assessment of the Investigator, must be available. * Active ulcerative colitis with an Adapted Mayo score of 5 to 9 points and endoscopic sub score of 2 to 3 (confirmed by central reader). * Demonstrated an inadequate response to, loss of response to, or intolerance to at least one of the following treatments including: oral aminosalicylates, corticosteroids, immunosuppressants, and/or biologic therapies in the opinion of the investigator. Note: Participants who have had inadequate response, loss of response to conventional therapy, but have not failed biologic therapy (Non-bio-IR) and have received a prior biologic for up to 1 year may be enrolled, however they must have discontinued the biologic for reasons other than inadequate response or intolerance (e.g., change of insurance, well controlled disease) and must meet criteria for inadequate response, loss of response or intolerance to aminosalicylates, corticosteroids, and/or immunosuppressants as defined above. * If female, participant must meet the criteria for Contraception Recommendations * Female participants of childbearing potential must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at the Baseline Visit prior to study drug dosing.
Exclusion criteria
* Participant with current diagnosis of Crohn's disease (CD) or diagnosis of indeterminate colitis (IC) * Current diagnosis of fulminant colitis and/or toxic megacolon * Participant with disease limited to the rectum (ulcerative proctitis) during the screening endoscopy * Received cyclosporine, tacrolimus, mycophenolate mofetil, or thalidomide within 30 days prior to Baseline * Participant on azathioprine or 6-mercaptopurine within 10 days of Baseline * Received intravenous corticosteroids within 14 days prior to Screening or during the Screening Period. * Participant with previous exposure to Janus Activated Kinase (JAK) inhibitor (e.g., tofacitinib, baricitinib, filgotinib, upadacitinib). * Screening laboratory and other analyses show any abnormal results meeting the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Substudy 1: Percentage Of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Week 8 | At Week 8 | The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal) 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed) 3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration) The overall Adapted Mayo score ranges from 0 to 9 where higher scores represent more severe disease. For Substudy 1, clinical remission is defined as SFS ≤ 1, RBS of 0, and endoscopic subscore ≤ 1. |
| Substudy 2: Percentage Of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Week 8 | At Week 8 | The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal) 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed) 3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration) The overall Adapted Mayo score ranges from 0 to 9 where higher scores represent more severe disease. For Substudy 2, clinical remission is defined as SFS ≤ 1 and not greater than Baseline, RBS of 0, and endoscopic subscore ≤ 1. In Substudy 2, evidence of friability during endoscopy in participants with otherwise mild endoscopic activity conferred an endoscopic subscore of 2. |
| Substudy 3: Percentage Of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Week 52 | At Week 52 | The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). 3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration). The overall Adapted Mayo score ranges from 0 to 9 where higher scores represent more severe disease. For Substudy 3, clinical remission is defined as SFS ≤ 1 and not greater than Baseline, RBS of 0, and endoscopic subscore ≤ 1. In addition, evidence of friability during endoscopy in participants with otherwise mild endoscopic activity conferred an endoscopic subscore of 2. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Substudy 1: Percentage Of Participants Achieving Clinical Response Per Partial Mayo Score at Week 2 | At Week 2 | The Partial Mayo Score is a composite score of UC disease activity based on the following 2 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). The overall Partial Mayo score ranges from 0 to 6 with higher scores representing more severe disease. Clinical response per Partial Mayo Score is defined as a decrease in Partial Adapted Mayo score ≥ 2 points and ≥ 30% from Baseline, plus a decrease in RBS ≥ 1 or an absolute RBS ≤ 1. |
| Substudy 1: Change in Full Mayo Score From Baseline to Week 8 | Baseline (Week 0), Week 8 | The Mayo score is a tool designed to measure disease activity for ulcerative colitis. The Full Mayo score (FMS) ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy \[confirmed by a central reader\], and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). Negative changes indicate improvement. Clinical remission per FMS is defined as Mayo Score ≤ 2 and no individual subscore \> 1. |
| Substudy 1: Percentage Of Participants With Endoscopic Remission at Week 8 | At Week 8 | Endoscopic remission is defined as an endoscopic subscore of 0. Endoscopies were assessed by a blinded central reader and scored according to the following scale: 0 = Normal or inactive disease; 1 = Mild disease (erythema, decreased vascular pattern); 2 = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions); 3 = Severe disease (spontaneous bleeding, ulceration). |
| Substudy 1: Percentage Of Participants Who Achieved Histologic Improvement at Week 8 | At Week 8 | The Geboes histologic index includes seven histological features (architectural change, chronic inflammatory infiltrate, lamina propria neutrophils and eosinophils, neutrophils in epithelium, crypt destruction and erosion or ulcers). The Geboes score has 6 grades, each with 3-5 subgrades: Grade 0, structural change only; Grade 1, chronic inflammation; Grade 2, lamina propria neutrophils and eosinophils; Grade 3, neutrophils in epithelium; Grade 4, crypt destruction; and Grade 5, erosions or ulceration. Histologic improvement was defined as decrease from baseline in Geboes score. |
| Substudy 2: Percentage Of Participants With Endoscopic Improvement at Week 8 | At Week 8 | Endoscopic improvement is defined as an endoscopic subscore of 0 or 1. Endoscopies were assessed by a blinded central reader and scored according to the following scale: 0 = Normal or inactive disease; 1 = Mild disease (erythema, decreased vascular pattern); 2 = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions); 3 = Severe disease (spontaneous bleeding, ulceration). |
| Substudy 2: Percentage Of Participants With Endoscopic Remission at Week 8 | At Week 8 | Endoscopic remission is defined as an endoscopic subscore of 0. Endoscopies were assessed by a blinded central reader and scored according to the following scale: 0 = Normal or inactive disease; 1 = Mild disease (erythema, decreased vascular pattern); 2 = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions); 3 = Severe disease (spontaneous bleeding, ulceration). |
| Substudy 2: Percentage Of Participants Achieving Clinical Response Per Adapted Mayo Score at Week 8 | At Week 8 | The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). 3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration). The overall Adapted Mayo score ranges from 0 to 9 where higher scores represent more severe disease. Clinical response is defined as a decrease from baseline in the Adapted Mayo score ≥ 2 points and ≥ 30% from baseline, and a decrease in RBS ≥ 1 or an absolute RBS ≤ 1). |
| Substudy 2: Percentage Of Participants Achieving Clinical Response Per Partial Mayo Score at Week 2 | At Week 2 | The Partial Mayo Score is a composite score of UC disease activity based on the following 2 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). The overall Partial Mayo score ranges from 0 to 6 with higher scores representing more severe disease. Clinical response per Partial Mayo Score is defined as a decrease from Baseline ≥ 1 point and ≥ 30% from Baseline, plus a decrease in RBS ≥ 1 or an absolute RBS ≤ 1. |
| Substudy 2: Percentage Of Participants Who Achieved Histologic-Endoscopic Mucosal Improvement at Week 8 | At Week 8 | Histologic-endoscopic mucosal improvement is defined as an endoscopic subscore of 0 or 1 and a Geboes score ≤ 3.1. The endoscopic subscore ranges from 0 (normal or inactive disease) to 3 (severe disease with spontaneous bleeding, ulceration). The Geboes histologic index includes seven histological features (architectural change, chronic inflammatory infiltrate, lamina propria neutrophils and eosinophils, neutrophils in epithelium, crypt destruction and erosion or ulcers). The Geboes score has 6 grades, each with 3-5 subgrades: Grade 0, structural change only; Grade 1, chronic inflammation; Grade 2, lamina propria neutrophils and eosinophils; Grade 3, neutrophils in epithelium; Grade 4, crypt destruction; and Grade 5, erosions or ulceration. |
| Substudy 2: Percentage Of Participants Who Report No Bowel Urgency at Week 8 | At Week 8 | Bowel urgency was assessed by participants in a subject diary completed once a day. |
| Substudy 2: Percentage Of Participants Who Reported No Abdominal Pain at Week 8 | At Week 8 | Abdominal pain was assessed by participants in a subject diary completed once a day. |
| Substudy 2: Percentage Of Participants Who Achieved Histologic Improvement at Week 8 | At Week 8 | The Geboes histologic index includes seven histological features (architectural change, chronic inflammatory infiltrate, lamina propria neutrophils and eosinophils, neutrophils in epithelium, crypt destruction and erosion or ulcers). The Geboes score has 6 grades, each with 3-5 subgrades: Grade 0, structural change only; Grade 1, chronic inflammation; Grade 2, lamina propria neutrophils and eosinophils; Grade 3, neutrophils in epithelium; Grade 4, crypt destruction; and Grade 5, erosions or ulceration. Histologic improvement was defined as decrease from baseline in Geboes score. |
| Substudy 2: Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Week 8 | Baseline (Week 0), Week 8 | The Inflammatory Bowel Disease Questionnaire (IBDQ) is used to assess health-related quality of life (HRQoL) in patients with ulcerative colitis. 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. |
| Substudy 1: Percentage Of Participants With Endoscopic Improvement at Week 8 | At Week 8 | Endoscopic improvement is defined as an endoscopic subscore of 0 or 1. Endoscopies were assessed by a blinded central reader and scored according to the following scale: 0 = Normal or inactive disease; 1 = Mild disease (erythema, decreased vascular pattern); 2 = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions); 3 = Severe disease (spontaneous bleeding, ulceration). |
| Substudy 2: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Week 8 | Baseline (Week 0), Week 8 | The FACIT fatigue questionnaire was developed to assess fatigue associated with anemia. It consists of 13 fatigue-related questions. Each question is answered on a 5-point Likert scale: 0 (not at all); 1 (a little bit); 2 (somewhat); 3 (quite a bit); and 4 (very much). The total score ranges from 0 to 52, where higher scores represent less fatigue, and a positive change from Baseline indicates improvement. |
| Substudy 3: Percentage Of Participants With Endoscopic Improvement at Week 52 | At Week 52 | Endoscopic improvement is defined as an endoscopic subscore of 0 or 1. Endoscopies were assessed by a blinded central reader and scored according to the following scale: 0 = Normal or inactive disease; 1 = Mild disease (erythema, decreased vascular pattern); 2 = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions); 3 = Severe disease (spontaneous bleeding, ulceration). |
| Substudy 3: Percentage of Participants With Clinical Remission Per Adapted Mayo Score at Week 52 Among Those Who Achieved Clinical Remission at the End of the Induction Treatment | At Week 52 | The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). 3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration). The overall Adapted Mayo score ranges from 0 to 9 where higher scores represent more severe disease. For Substudy 3, clinical remission is defined as SFS ≤ 1 and not greater than Baseline, RBS of 0, and endoscopic subscore ≤ 1. In addition, evidence of friability during endoscopy in participants with otherwise mild endoscopic activity conferred an endoscopic subscore of 2. |
| Substudy 3: Percentage of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Wk 52 and Were Corticosteroid Free for ≥ 90 Days Immediately Preceding Wk 52 Among Those Who Achieved Clinical Remission at the End of the Induction Treatment | At Week 52 | The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). 3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration). The overall Adapted Mayo score ranges from 0 to 9 where higher scores represent more severe disease. For Substudy 3, clinical remission is defined as SFS ≤ 1 and not greater than Baseline, RBS of 0, and endoscopic subscore ≤ 1. In addition, evidence of friability during endoscopy in participants with otherwise mild endoscopic activity conferred an endoscopic subscore of 2. |
| Substudy 3: Percentage of Participants With Endoscopic Improvement at Wk 52 Among Those Who Achieved Endoscopic Improvement at the End of the Induction Treatment | At Week 52 | Endoscopic improvement is defined as an endoscopic subscore of 0 or 1. Endoscopies were assessed by a blinded central reader and scored according to the following scale: 0 = Normal or inactive disease; 1 = Mild disease (erythema, decreased vascular pattern); 2 = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions); 3 = Severe disease (spontaneous bleeding, ulceration). |
| Substudy 3: Percentage Of Participants With Endoscopic Remission At Week 52 | At Week 52 | Endoscopic remission is defined as an endoscopic subscore of 0. Endoscopies were assessed by a blinded central reader and scored according to the following scale: 0 = Normal or inactive disease; 1 = Mild disease (erythema, decreased vascular pattern); 2 = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions); 3 = Severe disease (spontaneous bleeding, ulceration). |
| Substudy 3: Percentage Of Participants Who Maintained Clinical Response Per Adapted Mayo Score at Wk 52 Among Those Who Achieved Clinical Response at the End of the Induction Treatment | At Week 52 | The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). 3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration). The overall Adapted Mayo score ranges from 0 to 9 where higher scores represent more severe disease. Clinical response is defined as a decrease from baseline in the Adapted Mayo score ≥ 2 points and ≥ 30% from baseline, and a decrease in RBS ≥ 1 or an absolute RBS ≤ 1). |
| Substudy 3: Percentage Of Participants Who Achieved Histologic-Endoscopic Mucosal Improvement at Week 52 | At Week 52 | Histologic-endoscopic mucosal improvement is defined as an endoscopic subscore of 0 or 1 and a Geboes score ≤ 3.1. The endoscopic subscore ranges from 0 (normal or inactive disease) to 3 (severe disease with spontaneous bleeding, ulceration). The Geboes histologic index includes seven histological features (architectural change, chronic inflammatory infiltrate, lamina propria neutrophils and eosinophils, neutrophils in epithelium, crypt destruction and erosion or ulcers). The Geboes score has 6 grades, each with 3-5 subgrades: Grade 0, structural change only; Grade 1, chronic inflammation; Grade 2, lamina propria neutrophils and eosinophils; Grade 3, neutrophils in epithelium; Grade 4, crypt destruction; and Grade 5, erosions or ulceration. |
| Substudy 3: Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Week 52 | Baseline (Week 0), Week 52 | The Inflammatory Bowel Disease Questionnaire (IBDQ) is used to assess health-related quality of life (HRQoL) in patients with ulcerative colitis. 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. |
| Substudy 3: Percentage Of Participants With Mucosal Healing at Week 52 | At Week 52 | Mucosal healing is defined as an endoscopic score of 0 and Geboes score \< 2.0. The endoscopic subscore ranges from 0 (normal or inactive disease) to 3 (severe disease with spontaneous bleeding, ulceration). The Geboes histologic index includes seven histological features (architectural change, chronic inflammatory infiltrate, lamina propria neutrophils and eosinophils, neutrophils in epithelium, crypt destruction and erosion or ulcers). The Geboes score has 6 grades, each with 3-5 subgrades: Grade 0, structural change only; Grade 1, chronic inflammation; Grade 2, lamina propria neutrophils and eosinophils; Grade 3, neutrophils in epithelium; Grade 4, crypt destruction; and Grade 5, erosions or ulceration. |
| Substudy 3: Percentage Of Participants Who Reported No Bowel Urgency at Week 52 | At Week 52 | Bowel urgency was assessed by participants in a subject diary completed once a day. |
| Substudy 3: Percentage Of Participants Who Reported No Abdominal Pain at Week 52 | At Week 52 | Abdominal pain was assessed by participants in a subject diary completed once a day. |
| Substudy 3: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Week 52 | Baseline (Week 0), Week 52 | The FACIT fatigue questionnaire was developed to assess fatigue associated with anemia. It consists of 13 fatigue-related questions. Each question is answered on a 5-point Likert scale: 0 (not at all); 1 (a little bit); 2 (somewhat); 3 (quite a bit); and 4 (very much). The total score ranges from 0 to 52, where higher scores represent less fatigue, and a positive change from Baseline indicates improvement. |
| Substudy 2: Percentage Of Participants With Mucosal Healing at Week 8 | At Week 8 | Mucosal healing is defined as an endoscopic score of 0 and Geboes score \< 2.0. The endoscopic subscore ranges from 0 (normal or inactive disease) to 3 (severe disease with spontaneous bleeding, ulceration). The Geboes histologic index includes seven histological features (architectural change, chronic inflammatory infiltrate, lamina propria neutrophils and eosinophils, neutrophils in epithelium, crypt destruction and erosion or ulcers). The Geboes score has 6 grades, each with 3-5 subgrades: Grade 0, structural change only; Grade 1, chronic inflammation; Grade 2, lamina propria neutrophils and eosinophils; Grade 3, neutrophils in epithelium; Grade 4, crypt destruction; and Grade 5, erosions or ulceration. |
| Substudy 1: Percentage Of Participants Achieving Clinical Remission Per Full Mayo Score at Week 8 | At Week 8 | The Mayo score is a tool designed to measure disease activity for ulcerative colitis. The Full Mayo score (FMS) ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy \[confirmed by a central reader\], and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). Negative changes indicate improvement. Clinical remission per FMS is defined as Mayo Score ≤ 2 and no individual subscore \> 1. |
| Substudy 1: Percentage Of Participants Achieving Clinical Response Per Adapted Mayo Score at Week 8 | At Week 8 | The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). 3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration). The overall Adapted Mayo score ranges from 0 to 9 where higher scores represent more severe disease. Clinical response is defined as a decrease from baseline in the Adapted Mayo score ≥ 2 points and ≥ 30% from baseline, and a decrease in RBS ≥ 1 or an absolute RBS ≤ 1). |
Countries
Argentina, Australia, Austria, Belarus, Belgium, Bosnia and Herzegovina, Brazil, Canada, Chile, China, Colombia, Croatia, Czechia, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Israel, Italy, Japan, Latvia, Lithuania, Malaysia, Mexico, Netherlands, Norway, Poland, Portugal, Puerto Rico, Russia, Serbia, Singapore, Slovakia, South Africa, South Korea, Spain, Sweden, Switzerland, Taiwan, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Pre-assignment details
Intent-to-treat (ITT) analysis set: Substudy 1 (all randomized participants who received at least one dose of study drug in Substudy 1); Substudy 2 (all randomized participants who received at least one dose of doubleblinded study drug in Part 1 and all participants who received at least one dose of upadacitinib 45 mg in Part 2); Substudy 3 (all participants who received at least one dose of study drug in Substudy 3)
Participants by arm
| Arm | Count |
|---|---|
| SS1: Placebo During the 8-week induction phase in Substudy 1, participants received placebo for upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. | 46 |
| SS1: Upadacitinib 7.5 mg During the 8-week induction phase in Substudy 1, participants received 7.5 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. | 47 |
| SS1: Upadacitinib 15 mg During the 8-week induction phase in Substudy 1, participants received 15 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. | 49 |
| SS1: Upadacitinib 30 mg During the 8-week induction phase in Substudy 1, participants received 30 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. Additional participants were enrolled during the Substudy 1 analysis period and received 30 mg upadacitinib film-coated tablets once daily by mouth (QD) for 4 weeks. | 117 |
| SS1: Upadacitinib 45 mg During the 8-week induction phase in Substudy 1, participants received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. Additional participants were enrolled during the Substudy 1 analysis period and received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for 4 weeks. | 123 |
| SS2: Placebo/Upadacitinib 45 mg During the Substudy 2 Part 1 induction period, participants received placebo for upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. Participants who did not achieve clinical response at Week 8 of Part 1 were enrolled in an open-label extended treatment period and received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for an additional 8 weeks. | 155 |
| SS2: Upadacitinib 45 mg/Upadacitinib 45 mg During the Substudy 2 Part 1 induction period, participants received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. Participants who did not achieve clinical response at Week 8 of Part 1 were enrolled in an open-label expended treatment period and received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for an additional 8 weeks. | 319 |
| SS3: M14-675 Clinical Responders Participants in Study M14-675 (NCT03653026) who achieved clinical response defined by Adapted Mayo Score at Week 8 or Week 16 in that study and did not meet any study discontinuation criteria were eligible to enroll into Substudy 3. Participants were treated with a blinded treatment assignment (15 mg upadacitinib film-coated tablets once daily by mouth \[QD\], or 30 mg upadacitinib film-coated tablets QD, or placebo for upadacitinib film-coated tablets QD) for up to 52 weeks. | 446 |
| Total | 1,302 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Substudy 1 and Substudy 2, Part 1 | Adverse Event | 3 | 1 | 3 | 5 | 4 | 9 | 6 | 0 | 0 | 0 | 0 | 0 |
| Substudy 1 and Substudy 2, Part 1 | COVID-19 Logistical Restrictions | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Substudy 1 and Substudy 2, Part 1 | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 |
| Substudy 1 and Substudy 2, Part 1 | Other, not specified | 2 | 1 | 1 | 7 | 5 | 7 | 3 | 0 | 0 | 0 | 0 | 0 |
| Substudy 1 and Substudy 2, Part 1 | Withdrew consent | 0 | 0 | 0 | 0 | 1 | 3 | 2 | 0 | 0 | 0 | 0 | 0 |
| Substudy 2, Part 2 | Adverse Event | 0 | 0 | 0 | 0 | 0 | 4 | 0 | 0 | 0 | 0 | 0 | 0 |
| Substudy 2, Part 2 | COVID-19 Logistical Restrictions | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 |
| Substudy 2, Part 2 | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Substudy 2, Part 2 | Other, not specified | 0 | 0 | 0 | 0 | 0 | 4 | 8 | 0 | 0 | 0 | 0 | 0 |
| Substudy 2, Part 2 | Withdrew consent | 0 | 0 | 0 | 0 | 0 | 3 | 1 | 0 | 0 | 0 | 0 | 0 |
| Substudy 3 | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 32 | 3 | 12 | 18 |
| Substudy 3 | COVID-19 Logistical Restrictions | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Substudy 3 | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 1 |
| Substudy 3 | Other, not specified | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 202 | 5 | 89 | 39 |
| Substudy 3 | Withdrew consent | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 11 | 1 | 4 | 9 |
Baseline characteristics
| Characteristic | SS1: Upadacitinib 15 mg | SS1: Upadacitinib 30 mg | SS1: Upadacitinib 45 mg | SS2: Placebo/Upadacitinib 45 mg | SS2: Upadacitinib 45 mg/Upadacitinib 45 mg | SS3: M14-675 Clinical Responders | Total | SS1: Upadacitinib 7.5 mg | SS1: Placebo |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 46.0 years STANDARD_DEVIATION 13.58 | 42.9 years STANDARD_DEVIATION 14.44 | 41.6 years STANDARD_DEVIATION 14.19 | 44.3 years STANDARD_DEVIATION 14.64 | 43.6 years STANDARD_DEVIATION 14.04 | 42.1 years STANDARD_DEVIATION 14.42 | 42.9 years STANDARD_DEVIATION 14.27 | 41.7 years STANDARD_DEVIATION 14.58 | 42.3 years STANDARD_DEVIATION 13.29 |
| Average Endoscopy Subscore | 2.8 units on a scale STANDARD_DEVIATION 0.39 | 2.7 units on a scale STANDARD_DEVIATION 0.47 | 2.7 units on a scale STANDARD_DEVIATION 0.48 | 2.7 units on a scale STANDARD_DEVIATION 0.47 | 2.7 units on a scale STANDARD_DEVIATION 0.46 | 2.7 units on a scale STANDARD_DEVIATION 0.47 | 2.7 units on a scale STANDARD_DEVIATION 0.46 | 2.8 units on a scale STANDARD_DEVIATION 0.4 | 2.8 units on a scale STANDARD_DEVIATION 0.43 |
| Average Rectal Bleeding Subscore | 1.55 units on a scale STANDARD_DEVIATION 0.915 | 1.51 units on a scale STANDARD_DEVIATION 0.975 | 1.49 units on a scale STANDARD_DEVIATION 0.96 | 1.76 units on a scale STANDARD_DEVIATION 0.994 | 1.71 units on a scale STANDARD_DEVIATION 1.046 | 1.77 units on a scale STANDARD_DEVIATION 0.99 | 1.68 units on a scale STANDARD_DEVIATION 1.003 | 1.61 units on a scale STANDARD_DEVIATION 1.027 | 1.66 units on a scale STANDARD_DEVIATION 1.034 |
| Average Stool Frequency Subscore | 2.68 units on a scale STANDARD_DEVIATION 0.565 | 2.61 units on a scale STANDARD_DEVIATION 0.613 | 2.58 units on a scale STANDARD_DEVIATION 0.648 | 2.52 units on a scale STANDARD_DEVIATION 0.668 | 2.60 units on a scale STANDARD_DEVIATION 0.624 | 2.55 units on a scale STANDARD_DEVIATION 0.623 | 2.58 units on a scale STANDARD_DEVIATION 0.628 | 2.62 units on a scale STANDARD_DEVIATION 0.6 | 2.56 units on a scale STANDARD_DEVIATION 0.667 |
| Baseline Corticosteroid Use No | 22 Participants | 66 Participants | 70 Participants | 93 Participants | 195 Participants | 273 Participants | 762 Participants | 23 Participants | 20 Participants |
| Baseline Corticosteroid Use Yes | 27 Participants | 51 Participants | 53 Participants | 62 Participants | 124 Participants | 173 Participants | 540 Participants | 24 Participants | 26 Participants |
| Biologic-inadequate Responder (Bio-IR) Status Bio-IR | — | — | — | 79 Participants | 168 Participants | 221 Participants | 468 Participants | — | — |
| Biologic-inadequate Responder (Bio-IR) Status Non-Bio-IR | — | — | — | 76 Participants | 151 Participants | 225 Participants | 452 Participants | — | — |
| Previous Biologic Use No | 11 Participants | 30 Participants | 31 Participants | — | — | — | 94 Participants | 11 Participants | 11 Participants |
| Previous Biologic Use Yes | 38 Participants | 87 Participants | 92 Participants | — | — | — | 288 Participants | 36 Participants | 35 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 4 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 10 Participants | 23 Participants | 28 Participants | 46 Participants | 95 Participants | 124 Participants | 341 Participants | 7 Participants | 8 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 3 Participants | 2 Participants | 4 Participants | 12 Participants | 15 Participants | 40 Participants | 3 Participants | 0 Participants |
| Race/Ethnicity, Customized Multiple | 0 Participants | 2 Participants | 3 Participants | 2 Participants | 5 Participants | 3 Participants | 17 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 38 Participants | 88 Participants | 90 Participants | 101 Participants | 206 Participants | 302 Participants | 898 Participants | 36 Participants | 37 Participants |
| Sex: Female, Male Female | 19 Participants | 47 Participants | 44 Participants | 58 Participants | 121 Participants | 170 Participants | 500 Participants | 24 Participants | 17 Participants |
| Sex: Female, Male Male | 30 Participants | 70 Participants | 79 Participants | 97 Participants | 198 Participants | 276 Participants | 802 Participants | 23 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 46 | 0 / 47 | 0 / 49 | 0 / 117 | 0 / 123 | 0 / 155 | 0 / 319 | 0 / 85 | 0 / 59 | 0 / 385 | 0 / 20 | 0 / 323 | 0 / 316 |
| other Total, other adverse events | 27 / 46 | 18 / 47 | 22 / 49 | 58 / 117 | 50 / 123 | 62 / 155 | 121 / 319 | 36 / 85 | 17 / 59 | 216 / 385 | 18 / 20 | 181 / 323 | 166 / 316 |
| serious Total, serious adverse events | 5 / 46 | 0 / 47 | 2 / 49 | 5 / 117 | 6 / 123 | 9 / 155 | 8 / 319 | 2 / 85 | 2 / 59 | 32 / 385 | 0 / 20 | 24 / 323 | 25 / 316 |
Outcome results
Primary
Substudy 1: Percentage Of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Week 8
The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal) 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed) 3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration) The overall Adapted Mayo score ranges from 0 to 9 where higher scores represent more severe disease. For Substudy 1, clinical remission is defined as SFS ≤ 1, RBS of 0, and endoscopic subscore ≤ 1.
Time frame: At Week 8
Population: SS1 main population (ITT1A): those randomized to ≥1 dose of study drug during the initial part of SS1. Non-responder imputation (NRI) was used to impute missing values.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SS1: Placebo | Substudy 1: Percentage Of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Week 8 | 0 percentage of participants |
| SS1: Upadacitinib 7.5 mg | Substudy 1: Percentage Of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Week 8 | 8.5 percentage of participants |
| SS1: Upadacitinib 15 mg | Substudy 1: Percentage Of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Week 8 | 14.3 percentage of participants |
| SS1: Upadacitinib 30 mg | Substudy 1: Percentage Of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Week 8 | 13.5 percentage of participants |
| SS1: Upadacitinib 45 mg | Substudy 1: Percentage Of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Week 8 | 21.4 percentage of participants |
Comparison: Substudy 1: Upadacitinib 7.5 mg vs Placebop-value: 0.04995% CI: [0, 16.8]Cochran-Mantel-Haenszel
Comparison: Substudy 1: Upadacitinib 15 mg vs Placebop-value: 0.0195% CI: [3.3, 23.8]Cochran-Mantel-Haenszel
Comparison: Substudy 1: Upadacitinib 30 mg vs Placebop-value: 0.00795% CI: [3.8, 23.9]Cochran-Mantel-Haenszel
Comparison: Substudy 1: Upadacitinib 45 mg vs Placebop-value: <0.00195% CI: [8.6, 33.6]Cochran-Mantel-Haenszel
Primary
Substudy 2: Percentage Of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Week 8
The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal) 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed) 3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration) The overall Adapted Mayo score ranges from 0 to 9 where higher scores represent more severe disease. For Substudy 2, clinical remission is defined as SFS ≤ 1 and not greater than Baseline, RBS of 0, and endoscopic subscore ≤ 1. In Substudy 2, evidence of friability during endoscopy in participants with otherwise mild endoscopic activity conferred an endoscopic subscore of 2.
Time frame: At Week 8
Population: SS2, Part 1 population (ITT1): all randomized participants in the 8-week double-blind induction period who received ≥1 dose of study drug. NRI incorporating multiple imputation (MI) to handle missing data due to COVID-19 (NRI-C) was used for SS2, with participants analyzed according to treatment groups to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SS1: Placebo | Substudy 2: Percentage Of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Week 8 | 4.8 percentage of participants |
| SS1: Upadacitinib 7.5 mg | Substudy 2: Percentage Of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Week 8 | 26.1 percentage of participants |
Comparison: Substudy 2: Upadacitinib 45 mg vs Placebop-value: <0.00195% CI: [15.8, 27.4]Cochran-Mantel-Haenszel
Primary
Substudy 3: Percentage Of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Week 52
The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). 3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration). The overall Adapted Mayo score ranges from 0 to 9 where higher scores represent more severe disease. For Substudy 3, clinical remission is defined as SFS ≤ 1 and not greater than Baseline, RBS of 0, and endoscopic subscore ≤ 1. In addition, evidence of friability during endoscopy in participants with otherwise mild endoscopic activity conferred an endoscopic subscore of 2.
Time frame: At Week 52
Population: Substudy 3 ITT\_A population: the first 451 upadacitinib 45 mg 8-week induction responders who were enrolled under the protocol for 52-week maintenance treatment period in Cohort 1. Non-responder imputation incorporating multiple imputation (MI) to handle missing data due to COVID-19 (NRI-C) was used to handle missing data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SS1: Placebo | Substudy 3: Percentage Of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Week 52 | 12.1 percentage of participants |
| SS1: Upadacitinib 7.5 mg | Substudy 3: Percentage Of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Week 52 | 42.3 percentage of participants |
| SS1: Upadacitinib 15 mg | Substudy 3: Percentage Of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Week 52 | 51.7 percentage of participants |
Comparison: Substudy 3: Upadacitinib 15 mg vs Placebop-value: <0.00195% CI: [21.7, 39.8]Cochran-Mantel-Haenszel
Comparison: Substudy 3: Upadacitinib 30 mg vs Placebop-value: <0.00195% CI: [29.7, 48.2]Cochran-Mantel-Haenszel
Secondary
Substudy 1: Change in Full Mayo Score From Baseline to Week 8
The Mayo score is a tool designed to measure disease activity for ulcerative colitis. The Full Mayo score (FMS) ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy \[confirmed by a central reader\], and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). Negative changes indicate improvement. Clinical remission per FMS is defined as Mayo Score ≤ 2 and no individual subscore \> 1.
Time frame: Baseline (Week 0), Week 8
Population: The Substudy 1 main population (ITT1A) includes participants who were randomized to at least one dose (placebo or upadacitinib 7.5 mg, 15 mg, 30 mg, 45 mg) during the main (initial) part of Substudy 1. Last observation carried forward (LOCF) was used for missing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SS1: Placebo | Substudy 1: Change in Full Mayo Score From Baseline to Week 8 | -0.741 units on a scale | Standard Deviation 2.3302 |
| SS1: Upadacitinib 7.5 mg | Substudy 1: Change in Full Mayo Score From Baseline to Week 8 | -2.870 units on a scale | Standard Deviation 2.9685 |
| SS1: Upadacitinib 15 mg | Substudy 1: Change in Full Mayo Score From Baseline to Week 8 | -3.589 units on a scale | Standard Deviation 2.4984 |
| SS1: Upadacitinib 30 mg | Substudy 1: Change in Full Mayo Score From Baseline to Week 8 | -4.211 units on a scale | Standard Deviation 3.0886 |
| SS1: Upadacitinib 45 mg | Substudy 1: Change in Full Mayo Score From Baseline to Week 8 | -4.606 units on a scale | Standard Deviation 2.8976 |
Comparison: Substudy 1: Upadacitinib 7.5 mg vs Placebop-value: <0.00195% CI: [-3.2323, -1.052]ANCOVA
Comparison: Substudy 1: Upadacitinib 15 mg vs Placebop-value: <0.00195% CI: [-4.0284, -1.8478]ANCOVA
Comparison: Substudy 1: Upadacitinib 30 mg vs Placebop-value: <0.00195% CI: [-4.8247, -2.647]ANCOVA
Comparison: Substudy 1: Upadacitinib 45 mg vs Placebop-value: <0.00195% CI: [-5.1252, -2.9974]ANCOVA
Secondary
Substudy 1: Percentage Of Participants Achieving Clinical Remission Per Full Mayo Score at Week 8
The Mayo score is a tool designed to measure disease activity for ulcerative colitis. The Full Mayo score (FMS) ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy \[confirmed by a central reader\], and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). Negative changes indicate improvement. Clinical remission per FMS is defined as Mayo Score ≤ 2 and no individual subscore \> 1.
Time frame: At Week 8
Population: The Substudy 1 main population (ITT1A) includes participants who were randomized to at least one dose (placebo or upadacitinib 7.5 mg, 15 mg, 30 mg, 45 mg) during the main (initial) part of Substudy 1. Non-responder imputation (NRI) was used to impute missing values for the ITT1A population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SS1: Placebo | Substudy 1: Percentage Of Participants Achieving Clinical Remission Per Full Mayo Score at Week 8 | 0 percentage of participants |
| SS1: Upadacitinib 7.5 mg | Substudy 1: Percentage Of Participants Achieving Clinical Remission Per Full Mayo Score at Week 8 | 10.6 percentage of participants |
| SS1: Upadacitinib 15 mg | Substudy 1: Percentage Of Participants Achieving Clinical Remission Per Full Mayo Score at Week 8 | 10.2 percentage of participants |
| SS1: Upadacitinib 30 mg | Substudy 1: Percentage Of Participants Achieving Clinical Remission Per Full Mayo Score at Week 8 | 11.5 percentage of participants |
| SS1: Upadacitinib 45 mg | Substudy 1: Percentage Of Participants Achieving Clinical Remission Per Full Mayo Score at Week 8 | 19.6 percentage of participants |
Comparison: Substudy 1: Upadacitinib 7.5 mg vs Placebop-value: 0.02195% CI: [1.7, 20.4]Cochran-Mantel-Haenszel
Comparison: Substudy 1: Upadacitinib 15 mg vs Placebop-value: 0.02495% CI: [1.3, 18]Cochran-Mantel-Haenszel
Comparison: Substudy 1: Upadacitinib 30 mg vs Placebop-value: 0.01595% CI: [2.3, 22]Cochran-Mantel-Haenszel
Comparison: Substudy 1: Upadacitinib 45 mg vs Placebop-value: 0.00195% CI: [8, 32.1]Cochran-Mantel-Haenszel
Secondary
Substudy 1: Percentage Of Participants Achieving Clinical Response Per Adapted Mayo Score at Week 8
The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). 3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration). The overall Adapted Mayo score ranges from 0 to 9 where higher scores represent more severe disease. Clinical response is defined as a decrease from baseline in the Adapted Mayo score ≥ 2 points and ≥ 30% from baseline, and a decrease in RBS ≥ 1 or an absolute RBS ≤ 1).
Time frame: At Week 8
Population: The Substudy 1 main population (ITT1A) includes participants who were randomized to at least one dose (placebo or upadacitinib 7.5 mg, 15 mg, 30 mg, 45 mg) during the main (initial) part of Substudy 1. Non-responder imputation (NRI) was used to impute missing values for the ITT1A population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SS1: Placebo | Substudy 1: Percentage Of Participants Achieving Clinical Response Per Adapted Mayo Score at Week 8 | 13.0 percentage of participants |
| SS1: Upadacitinib 7.5 mg | Substudy 1: Percentage Of Participants Achieving Clinical Response Per Adapted Mayo Score at Week 8 | 29.8 percentage of participants |
| SS1: Upadacitinib 15 mg | Substudy 1: Percentage Of Participants Achieving Clinical Response Per Adapted Mayo Score at Week 8 | 49.0 percentage of participants |
| SS1: Upadacitinib 30 mg | Substudy 1: Percentage Of Participants Achieving Clinical Response Per Adapted Mayo Score at Week 8 | 46.2 percentage of participants |
| SS1: Upadacitinib 45 mg | Substudy 1: Percentage Of Participants Achieving Clinical Response Per Adapted Mayo Score at Week 8 | 55.4 percentage of participants |
Comparison: Substudy 1: Upadacitinib 7.5 mg vs Placebop-value: 0.03895% CI: [0.9, 32.5]Cochran-Mantel-Haenszel
Comparison: Substudy 1: Upadacitinib 15 mg vs Placebop-value: <0.00195% CI: [17.5, 52.8]Cochran-Mantel-Haenszel
Comparison: Substudy 1: Upadacitinib 30 mg vs Placebop-value: <0.00195% CI: [16.3, 50.8]Cochran-Mantel-Haenszel
Comparison: Substudy 1: Upadacitinib 45 mg vs Placebop-value: <0.00195% CI: [26.2, 63.9]Cochran-Mantel-Haenszel
Secondary
Substudy 1: Percentage Of Participants Achieving Clinical Response Per Partial Mayo Score at Week 2
The Partial Mayo Score is a composite score of UC disease activity based on the following 2 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). The overall Partial Mayo score ranges from 0 to 6 with higher scores representing more severe disease. Clinical response per Partial Mayo Score is defined as a decrease in Partial Adapted Mayo score ≥ 2 points and ≥ 30% from Baseline, plus a decrease in RBS ≥ 1 or an absolute RBS ≤ 1.
Time frame: At Week 2
Population: The Substudy 1 main population (ITT1A) includes participants who were randomized to at least one dose (placebo or upadacitinib 7.5 mg, 15 mg, 30 mg, 45 mg) during the main (initial) part of Substudy 1. Non-responder imputation (NRI) was used to impute missing values for the ITT1A population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SS1: Placebo | Substudy 1: Percentage Of Participants Achieving Clinical Response Per Partial Mayo Score at Week 2 | 17.4 percentage of participants |
| SS1: Upadacitinib 7.5 mg | Substudy 1: Percentage Of Participants Achieving Clinical Response Per Partial Mayo Score at Week 2 | 23.4 percentage of participants |
| SS1: Upadacitinib 15 mg | Substudy 1: Percentage Of Participants Achieving Clinical Response Per Partial Mayo Score at Week 2 | 34.7 percentage of participants |
| SS1: Upadacitinib 30 mg | Substudy 1: Percentage Of Participants Achieving Clinical Response Per Partial Mayo Score at Week 2 | 36.5 percentage of participants |
| SS1: Upadacitinib 45 mg | Substudy 1: Percentage Of Participants Achieving Clinical Response Per Partial Mayo Score at Week 2 | 55.4 percentage of participants |
Comparison: Substudy 1: Upadacitinib 7.5 mg vs Placebop-value: 0.49595% CI: [-11.1, 22.9]Cochran-Mantel-Haenszel
Comparison: Substudy 1: Upadacitinib 15 mg vs Placebop-value: 0.07495% CI: [-1.6, 33.4]Cochran-Mantel-Haenszel
Comparison: Substudy 1: Upadacitinib 30 mg vs Placebop-value: 0.03395% CI: [1.6, 36.9]Cochran-Mantel-Haenszel
Comparison: Substudy 1: Upadacitinib 45 mg vs Placebop-value: <0.00195% CI: [20.5, 59.7]Cochran-Mantel-Haenszel
Secondary
Substudy 1: Percentage Of Participants Who Achieved Histologic Improvement at Week 8
The Geboes histologic index includes seven histological features (architectural change, chronic inflammatory infiltrate, lamina propria neutrophils and eosinophils, neutrophils in epithelium, crypt destruction and erosion or ulcers). The Geboes score has 6 grades, each with 3-5 subgrades: Grade 0, structural change only; Grade 1, chronic inflammation; Grade 2, lamina propria neutrophils and eosinophils; Grade 3, neutrophils in epithelium; Grade 4, crypt destruction; and Grade 5, erosions or ulceration. Histologic improvement was defined as decrease from baseline in Geboes score.
Time frame: At Week 8
Population: The Substudy 1 main population (ITT1A) includes participants who were randomized to at least one dose (placebo or upadacitinib 7.5 mg, 15 mg, 30 mg, 45 mg) during the main (initial) part of Substudy 1. Non-responder imputation (NRI) was used to impute missing values for the ITT1A population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SS1: Placebo | Substudy 1: Percentage Of Participants Who Achieved Histologic Improvement at Week 8 | 6.5 percentage of participants |
| SS1: Upadacitinib 7.5 mg | Substudy 1: Percentage Of Participants Who Achieved Histologic Improvement at Week 8 | 31.9 percentage of participants |
| SS1: Upadacitinib 15 mg | Substudy 1: Percentage Of Participants Who Achieved Histologic Improvement at Week 8 | 51.0 percentage of participants |
| SS1: Upadacitinib 30 mg | Substudy 1: Percentage Of Participants Who Achieved Histologic Improvement at Week 8 | 44.2 percentage of participants |
| SS1: Upadacitinib 45 mg | Substudy 1: Percentage Of Participants Who Achieved Histologic Improvement at Week 8 | 48.2 percentage of participants |
Comparison: Substudy 1: Upadacitinib 7.5 mg vs Placebop-value: 0.00395% CI: [8.9, 42.3]Cochran-Mantel-Haenszel
Comparison: Substudy 1: Upadacitinib 15 mg vs Placebop-value: <0.00195% CI: [25.4, 61.8]Cochran-Mantel-Haenszel
Comparison: Substudy 1: Upadacitinib 30 mg vs Placebop-value: <0.00195% CI: [21.3, 57.5]Cochran-Mantel-Haenszel
Comparison: Substudy 1: Upadacitinib 45 mg vs Placebop-value: <0.00195% CI: [24.4, 61.9]Cochran-Mantel-Haenszel
Secondary
Substudy 1: Percentage Of Participants With Endoscopic Improvement at Week 8
Endoscopic improvement is defined as an endoscopic subscore of 0 or 1. Endoscopies were assessed by a blinded central reader and scored according to the following scale: 0 = Normal or inactive disease; 1 = Mild disease (erythema, decreased vascular pattern); 2 = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions); 3 = Severe disease (spontaneous bleeding, ulceration).
Time frame: At Week 8
Population: The Substudy 1 main population (ITT1A) includes participants who were randomized to at least one dose (placebo or upadacitinib 7.5 mg, 15 mg, 30 mg, 45 mg) during the main (initial) part of Substudy 1. Non-responder imputation (NRI) was used to impute missing values for the ITT1A population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SS1: Placebo | Substudy 1: Percentage Of Participants With Endoscopic Improvement at Week 8 | 2.2 percentage of participants |
| SS1: Upadacitinib 7.5 mg | Substudy 1: Percentage Of Participants With Endoscopic Improvement at Week 8 | 14.9 percentage of participants |
| SS1: Upadacitinib 15 mg | Substudy 1: Percentage Of Participants With Endoscopic Improvement at Week 8 | 30.6 percentage of participants |
| SS1: Upadacitinib 30 mg | Substudy 1: Percentage Of Participants With Endoscopic Improvement at Week 8 | 26.9 percentage of participants |
| SS1: Upadacitinib 45 mg | Substudy 1: Percentage Of Participants With Endoscopic Improvement at Week 8 | 35.7 percentage of participants |
Comparison: Substudy 1: Upadacitinib 7.5 mg vs Placebop-value: 0.0395% CI: [1.2, 25]Cochran-Mantel-Haenszel
Comparison: Substudy 1: Upadacitinib 15 mg vs Placebop-value: <0.00195% CI: [13.1, 42.1]Cochran-Mantel-Haenszel
Comparison: Substudy 1: Upadacitinib 30 mg vs Placebop-value: <0.00195% CI: [12.3, 40.8]Cochran-Mantel-Haenszel
Comparison: Substudy 1: Upadacitinib 45 mg vs Placebop-value: <0.00195% CI: [19.2, 51.7]Cochran-Mantel-Haenszel
Secondary
Substudy 1: Percentage Of Participants With Endoscopic Remission at Week 8
Endoscopic remission is defined as an endoscopic subscore of 0. Endoscopies were assessed by a blinded central reader and scored according to the following scale: 0 = Normal or inactive disease; 1 = Mild disease (erythema, decreased vascular pattern); 2 = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions); 3 = Severe disease (spontaneous bleeding, ulceration).
Time frame: At Week 8
Population: The Substudy 1 main population (ITT1A) includes participants who were randomized to at least one dose (placebo or upadacitinib 7.5 mg, 15 mg, 30 mg, 45 mg) during the main (initial) part of Substudy 1. Non-responder imputation (NRI) was used to impute missing values for the ITT1A population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SS1: Placebo | Substudy 1: Percentage Of Participants With Endoscopic Remission at Week 8 | 0 percentage of participants |
| SS1: Upadacitinib 7.5 mg | Substudy 1: Percentage Of Participants With Endoscopic Remission at Week 8 | 6.4 percentage of participants |
| SS1: Upadacitinib 15 mg | Substudy 1: Percentage Of Participants With Endoscopic Remission at Week 8 | 4.1 percentage of participants |
| SS1: Upadacitinib 30 mg | Substudy 1: Percentage Of Participants With Endoscopic Remission at Week 8 | 9.6 percentage of participants |
| SS1: Upadacitinib 45 mg | Substudy 1: Percentage Of Participants With Endoscopic Remission at Week 8 | 17.9 percentage of participants |
Comparison: Substudy 1: Upadacitinib 30 mg vs Placebop-value: 0.01595% CI: [2.2, 20]Cochran-Mantel-Haenszel
Comparison: Substudy 1: Upadacitinib 45 mg vs Placebop-value: 0.00495% CI: [5.8, 29.9]Cochran-Mantel-Haenszel
Comparison: Substudy 1: Upadacitinib 7.5 mg vs Placebop-value: 0.07595% CI: [-0.7, 13.9]Cochran-Mantel-Haenszel
Comparison: Substudy 1: Upadacitinib 15 mg vs Placebop-value: 0.19995% CI: [-2, 9.6]Cochran-Mantel-Haenszel
Secondary
Substudy 2: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Week 8
The FACIT fatigue questionnaire was developed to assess fatigue associated with anemia. It consists of 13 fatigue-related questions. Each question is answered on a 5-point Likert scale: 0 (not at all); 1 (a little bit); 2 (somewhat); 3 (quite a bit); and 4 (very much). The total score ranges from 0 to 52, where higher scores represent less fatigue, and a positive change from Baseline indicates improvement.
Time frame: Baseline (Week 0), Week 8
Population: The Substudy 2, Part 1 ITT1 population with available data; a mixed effect model repeat measurement (MMRM) analysis with data from observed cases up to Week 8 was used except for measurements at or after the occurrence of UC-related corticosteroids intercurrent event were excluded
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| SS1: Placebo | Substudy 2: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Week 8 | 2.8 units on a scale |
| SS1: Upadacitinib 7.5 mg | Substudy 2: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Week 8 | 9.5 units on a scale |
Comparison: Substudy 2: Upadacitinib 45 mg vs Placebop-value: <0.00195% CI: [4.79, 8.59]Mixed-effect model repeated measurement
Secondary
Substudy 2: Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Week 8
The Inflammatory Bowel Disease Questionnaire (IBDQ) is used to assess health-related quality of life (HRQoL) in patients with ulcerative colitis. 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 (Week 0), Week 8
Population: The Substudy 2, Part 1 ITT1 population with available data; a mixed effect model repeat measurement (MMRM) analysis with data from observed cases up to Week 8 was used except for measurements at or after the occurrence of UC-related corticosteroids intercurrent event were excluded
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| SS1: Placebo | Substudy 2: Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Week 8 | 21.7 units on a scale |
| SS1: Upadacitinib 7.5 mg | Substudy 2: Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Week 8 | 55.3 units on a scale |
Comparison: Substudy 2: Upadacitinib 45 mg vs Placebop-value: <0.00195% CI: [27.02, 40.36]Mixed-effect model repeated measurement
Secondary
Substudy 2: Percentage Of Participants Achieving Clinical Response Per Adapted Mayo Score at Week 8
The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). 3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration). The overall Adapted Mayo score ranges from 0 to 9 where higher scores represent more severe disease. Clinical response is defined as a decrease from baseline in the Adapted Mayo score ≥ 2 points and ≥ 30% from baseline, and a decrease in RBS ≥ 1 or an absolute RBS ≤ 1).
Time frame: At Week 8
Population: The Substudy 2, Part 1 population (ITT1) includes all randomized participants in the 8-week double-blind induction period who received at least one dose of double-blinded study drug in Part 1; NRI incorporating multiple imputation (MI) to handle missing data due to COVID-19 (NRI-C) was used with participants analyzed according to treatment groups to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SS1: Placebo | Substudy 2: Percentage Of Participants Achieving Clinical Response Per Adapted Mayo Score at Week 8 | 27.3 percentage of participants |
| SS1: Upadacitinib 7.5 mg | Substudy 2: Percentage Of Participants Achieving Clinical Response Per Adapted Mayo Score at Week 8 | 72.6 percentage of participants |
Comparison: Substudy 2: Upadacitinib 45 mg vs Placebop-value: <0.00195% CI: [38.4, 54.2]Cochran-Mantel-Haenszel
Secondary
Substudy 2: Percentage Of Participants Achieving Clinical Response Per Partial Mayo Score at Week 2
The Partial Mayo Score is a composite score of UC disease activity based on the following 2 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). The overall Partial Mayo score ranges from 0 to 6 with higher scores representing more severe disease. Clinical response per Partial Mayo Score is defined as a decrease from Baseline ≥ 1 point and ≥ 30% from Baseline, plus a decrease in RBS ≥ 1 or an absolute RBS ≤ 1.
Time frame: At Week 2
Population: The Substudy 2, Part 1 population (ITT1) includes all randomized participants in the 8-week double-blind induction period who received at least one dose of double-blinded study drug in Part 1; NRI incorporating multiple imputation (MI) to handle missing data due to COVID-19 (NRI-C) was used with participants analyzed according to treatment groups to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SS1: Placebo | Substudy 2: Percentage Of Participants Achieving Clinical Response Per Partial Mayo Score at Week 2 | 27.3 percentage of participants |
| SS1: Upadacitinib 7.5 mg | Substudy 2: Percentage Of Participants Achieving Clinical Response Per Partial Mayo Score at Week 2 | 60.1 percentage of participants |
Comparison: Substudy 2: Upadacitinib 45 mg vs Placebop-value: <0.00195% CI: [24.8, 41.8]Cochran-Mantel-Haenszel
Secondary
Substudy 2: Percentage Of Participants Who Achieved Histologic-Endoscopic Mucosal Improvement at Week 8
Histologic-endoscopic mucosal improvement is defined as an endoscopic subscore of 0 or 1 and a Geboes score ≤ 3.1. The endoscopic subscore ranges from 0 (normal or inactive disease) to 3 (severe disease with spontaneous bleeding, ulceration). The Geboes histologic index includes seven histological features (architectural change, chronic inflammatory infiltrate, lamina propria neutrophils and eosinophils, neutrophils in epithelium, crypt destruction and erosion or ulcers). The Geboes score has 6 grades, each with 3-5 subgrades: Grade 0, structural change only; Grade 1, chronic inflammation; Grade 2, lamina propria neutrophils and eosinophils; Grade 3, neutrophils in epithelium; Grade 4, crypt destruction; and Grade 5, erosions or ulceration.
Time frame: At Week 8
Population: The Substudy 2, Part 1 population (ITT1) includes all randomized participants in the 8-week double-blind induction period who received at least one dose of double-blinded study drug in Part 1; NRI incorporating multiple imputation (MI) to handle missing data due to COVID-19 (NRI-C) was used with participants analyzed according to treatment groups to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SS1: Placebo | Substudy 2: Percentage Of Participants Who Achieved Histologic-Endoscopic Mucosal Improvement at Week 8 | 6.6 percentage of participants |
| SS1: Upadacitinib 7.5 mg | Substudy 2: Percentage Of Participants Who Achieved Histologic-Endoscopic Mucosal Improvement at Week 8 | 30.1 percentage of participants |
Comparison: Substudy 2: Upadacitinib 45 mg vs Placebop-value: <0.00195% CI: [17.5, 30]Cochran-Mantel-Haenszel
Secondary
Substudy 2: Percentage Of Participants Who Achieved Histologic Improvement at Week 8
The Geboes histologic index includes seven histological features (architectural change, chronic inflammatory infiltrate, lamina propria neutrophils and eosinophils, neutrophils in epithelium, crypt destruction and erosion or ulcers). The Geboes score has 6 grades, each with 3-5 subgrades: Grade 0, structural change only; Grade 1, chronic inflammation; Grade 2, lamina propria neutrophils and eosinophils; Grade 3, neutrophils in epithelium; Grade 4, crypt destruction; and Grade 5, erosions or ulceration. Histologic improvement was defined as decrease from baseline in Geboes score.
Time frame: At Week 8
Population: The Substudy 2, Part 1 population (ITT1) includes all randomized participants in the 8-week double-blind induction period who received at least one dose of double-blinded study drug in Part 1; NRI incorporating multiple imputation (MI) to handle missing data due to COVID-19 (NRI-C) was used with participants analyzed according to treatment groups to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SS1: Placebo | Substudy 2: Percentage Of Participants Who Achieved Histologic Improvement at Week 8 | 22.5 percentage of participants |
| SS1: Upadacitinib 7.5 mg | Substudy 2: Percentage Of Participants Who Achieved Histologic Improvement at Week 8 | 55.0 percentage of participants |
Comparison: Substudy 2: Upadacitinib 45 mg vs Placebop-value: <0.00195% CI: [23.8, 40.7]Cochran-Mantel-Haenszel
Secondary
Substudy 2: Percentage Of Participants Who Reported No Abdominal Pain at Week 8
Abdominal pain was assessed by participants in a subject diary completed once a day.
Time frame: At Week 8
Population: The Substudy 2, Part 1 population (ITT1) includes all randomized participants in the 8-week double-blind induction period who received at least one dose of double-blinded study drug in Part 1; NRI incorporating multiple imputation (MI) to handle missing data due to COVID-19 (NRI-C) was used with participants analyzed according to treatment groups to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SS1: Placebo | Substudy 2: Percentage Of Participants Who Reported No Abdominal Pain at Week 8 | 23.4 percentage of participants |
| SS1: Upadacitinib 7.5 mg | Substudy 2: Percentage Of Participants Who Reported No Abdominal Pain at Week 8 | 46.6 percentage of participants |
Comparison: Substudy 2: Upadacitinib 45 mg vs Placebop-value: <0.00195% CI: [15.1, 32.1]Cochran-Mantel-Haenszel
Secondary
Substudy 2: Percentage Of Participants Who Report No Bowel Urgency at Week 8
Bowel urgency was assessed by participants in a subject diary completed once a day.
Time frame: At Week 8
Population: The Substudy 2, Part 1 population (ITT1) includes all randomized participants in the 8-week double-blind induction period who received at least one dose of double-blinded study drug in Part 1; NRI incorporating multiple imputation (MI) to handle missing data due to COVID-19 (NRI-C) was used with participants analyzed according to treatment groups to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SS1: Placebo | Substudy 2: Percentage Of Participants Who Report No Bowel Urgency at Week 8 | 21.4 percentage of participants |
| SS1: Upadacitinib 7.5 mg | Substudy 2: Percentage Of Participants Who Report No Bowel Urgency at Week 8 | 48.4 percentage of participants |
Comparison: Substudy 2: Upadacitinib 45 mg vs Placebop-value: <0.00195% CI: [19.2, 35.6]Cochran-Mantel-Haenszel
Secondary
Substudy 2: Percentage Of Participants With Endoscopic Improvement at Week 8
Endoscopic improvement is defined as an endoscopic subscore of 0 or 1. Endoscopies were assessed by a blinded central reader and scored according to the following scale: 0 = Normal or inactive disease; 1 = Mild disease (erythema, decreased vascular pattern); 2 = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions); 3 = Severe disease (spontaneous bleeding, ulceration).
Time frame: At Week 8
Population: The Substudy 2, Part 1 population (ITT1) includes all randomized participants in the 8-week double-blind induction period who received at least one dose of double-blinded study drug in Part 1; NRI incorporating multiple imputation (MI) to handle missing data due to COVID-19 (NRI-C) was used with participants analyzed according to treatment groups to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SS1: Placebo | Substudy 2: Percentage Of Participants With Endoscopic Improvement at Week 8 | 7.4 percentage of participants |
| SS1: Upadacitinib 7.5 mg | Substudy 2: Percentage Of Participants With Endoscopic Improvement at Week 8 | 36.3 percentage of participants |
Comparison: Substudy 2: Upadacitinib 45 mg vs Placebop-value: <0.00195% CI: [22.6, 35.9]Cochran-Mantel-Haenszel
Secondary
Substudy 2: Percentage Of Participants With Endoscopic Remission at Week 8
Endoscopic remission is defined as an endoscopic subscore of 0. Endoscopies were assessed by a blinded central reader and scored according to the following scale: 0 = Normal or inactive disease; 1 = Mild disease (erythema, decreased vascular pattern); 2 = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions); 3 = Severe disease (spontaneous bleeding, ulceration).
Time frame: At Week 8
Population: The Substudy 2, Part 1 population (ITT1) includes all randomized participants in the 8-week double-blind induction period who received at least one dose of double-blinded study drug in Part 1; NRI incorporating multiple imputation (MI) to handle missing data due to COVID-19 (NRI-C) was used with participants analyzed according to treatment groups to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SS1: Placebo | Substudy 2: Percentage Of Participants With Endoscopic Remission at Week 8 | 1.3 percentage of participants |
| SS1: Upadacitinib 7.5 mg | Substudy 2: Percentage Of Participants With Endoscopic Remission at Week 8 | 13.7 percentage of participants |
Comparison: Substudy 2: Upadacitinib 45 mg vs Placebop-value: <0.00195% CI: [8.4, 17]Cochran-Mantel-Haenszel
Secondary
Substudy 2: Percentage Of Participants With Mucosal Healing at Week 8
Mucosal healing is defined as an endoscopic score of 0 and Geboes score \< 2.0. The endoscopic subscore ranges from 0 (normal or inactive disease) to 3 (severe disease with spontaneous bleeding, ulceration). The Geboes histologic index includes seven histological features (architectural change, chronic inflammatory infiltrate, lamina propria neutrophils and eosinophils, neutrophils in epithelium, crypt destruction and erosion or ulcers). The Geboes score has 6 grades, each with 3-5 subgrades: Grade 0, structural change only; Grade 1, chronic inflammation; Grade 2, lamina propria neutrophils and eosinophils; Grade 3, neutrophils in epithelium; Grade 4, crypt destruction; and Grade 5, erosions or ulceration.
Time frame: At Week 8
Population: The Substudy 2, Part 1 population (ITT1) includes all randomized participants in the 8-week double-blind induction period who received at least one dose of double-blinded study drug in Part 1; NRI incorporating multiple imputation (MI) to handle missing data due to COVID-19 (NRI-C) was used with participants analyzed according to treatment groups to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SS1: Placebo | Substudy 2: Percentage Of Participants With Mucosal Healing at Week 8 | 1.3 percentage of participants |
| SS1: Upadacitinib 7.5 mg | Substudy 2: Percentage Of Participants With Mucosal Healing at Week 8 | 10.7 percentage of participants |
Comparison: Substudy 2: Upadacitinib 45 mg vs Placebop-value: <0.00195% CI: [5.7, 13.7]Cochran-Mantel-Haenszel
Secondary
Substudy 3: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Week 52
The FACIT fatigue questionnaire was developed to assess fatigue associated with anemia. It consists of 13 fatigue-related questions. Each question is answered on a 5-point Likert scale: 0 (not at all); 1 (a little bit); 2 (somewhat); 3 (quite a bit); and 4 (very much). The total score ranges from 0 to 52, where higher scores represent less fatigue, and a positive change from Baseline indicates improvement.
Time frame: Baseline (Week 0), Week 52
Population: Substudy 3 ITT\_A population with available data: Baseline is defined as the last non-missing value prior to the first dose in Phase 2b Induction or Induction Studies. Multiple Imputation Incorporating Return-to-Baseline (RTB-MI) was used to handle missing data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| SS1: Placebo | Substudy 3: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Week 52 | 3.7 units on a scale |
| SS1: Upadacitinib 7.5 mg | Substudy 3: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Week 52 | 8.7 units on a scale |
| SS1: Upadacitinib 15 mg | Substudy 3: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Week 52 | 9.5 units on a scale |
Comparison: Substudy 3: Upadacitinib 15 mg vs Placebop-value: <0.00195% CI: [2.67, 7.52]ANCOVA
Comparison: Substudy 3: Upadacitinib 30 mg vs Placebop-value: <0.00195% CI: [3.44, 8.27]ANCOVA
Secondary
Substudy 3: Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Week 52
The Inflammatory Bowel Disease Questionnaire (IBDQ) is used to assess health-related quality of life (HRQoL) in patients with ulcerative colitis. 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 (Week 0), Week 52
Population: Substudy 3 ITT\_A population with available data: Baseline is defined as the last non-missing value prior to the first dose in Phase 2b Induction or Induction Studies. Multiple Imputation Incorporating Return-to-Baseline (RTB-MI) was used to handle missing data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| SS1: Placebo | Substudy 3: Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Week 52 | 17.9 units on a scale |
| SS1: Upadacitinib 7.5 mg | Substudy 3: Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Week 52 | 49.2 units on a scale |
| SS1: Upadacitinib 15 mg | Substudy 3: Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Week 52 | 58.9 units on a scale |
Comparison: Substudy 3: Upadacitinib 15 mg vs Placebop-value: <0.00195% CI: [21.98, 40.7]ANCOVA
Comparison: Substudy 3: Upadacitinib 30 mg vs Placebop-value: <0.00195% CI: [31.39, 50.55]ANCOVA
Secondary
Substudy 3: Percentage of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Wk 52 and Were Corticosteroid Free for ≥ 90 Days Immediately Preceding Wk 52 Among Those Who Achieved Clinical Remission at the End of the Induction Treatment
The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). 3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration). The overall Adapted Mayo score ranges from 0 to 9 where higher scores represent more severe disease. For Substudy 3, clinical remission is defined as SFS ≤ 1 and not greater than Baseline, RBS of 0, and endoscopic subscore ≤ 1. In addition, evidence of friability during endoscopy in participants with otherwise mild endoscopic activity conferred an endoscopic subscore of 2.
Time frame: At Week 52
Population: Substudy 3 ITT\_A population: the first 451 upadacitinib 45 mg 8-week induction responders who were enrolled under the protocol for 52-week maintenance treatment period in Cohort 1 and who achieved clinical remission per Adapted Mayo Score in Substudy 1, 2, or M14-675. Non-responder imputation incorporating multiple imputation (MI) to handle missing data due to COVID-19 (NRI-C) was used to handle missing data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SS1: Placebo | Substudy 3: Percentage of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Wk 52 and Were Corticosteroid Free for ≥ 90 Days Immediately Preceding Wk 52 Among Those Who Achieved Clinical Remission at the End of the Induction Treatment | 22.2 percentage of participants |
| SS1: Upadacitinib 7.5 mg | Substudy 3: Percentage of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Wk 52 and Were Corticosteroid Free for ≥ 90 Days Immediately Preceding Wk 52 Among Those Who Achieved Clinical Remission at the End of the Induction Treatment | 57.1 percentage of participants |
| SS1: Upadacitinib 15 mg | Substudy 3: Percentage of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Wk 52 and Were Corticosteroid Free for ≥ 90 Days Immediately Preceding Wk 52 Among Those Who Achieved Clinical Remission at the End of the Induction Treatment | 68.0 percentage of participants |
Comparison: Substudy 3: Upadacitinib 15 mg vs Placebop-value: <0.00195% CI: [18.2, 52.7]Cochran-Mantel-Haenszel
Comparison: Substudy 3: Upadacitinib 30 mg vs Placebop-value: <0.00195% CI: [28.7, 61.6]Cochran-Mantel-Haenszel
Secondary
Substudy 3: Percentage Of Participants Who Achieved Histologic-Endoscopic Mucosal Improvement at Week 52
Histologic-endoscopic mucosal improvement is defined as an endoscopic subscore of 0 or 1 and a Geboes score ≤ 3.1. The endoscopic subscore ranges from 0 (normal or inactive disease) to 3 (severe disease with spontaneous bleeding, ulceration). The Geboes histologic index includes seven histological features (architectural change, chronic inflammatory infiltrate, lamina propria neutrophils and eosinophils, neutrophils in epithelium, crypt destruction and erosion or ulcers). The Geboes score has 6 grades, each with 3-5 subgrades: Grade 0, structural change only; Grade 1, chronic inflammation; Grade 2, lamina propria neutrophils and eosinophils; Grade 3, neutrophils in epithelium; Grade 4, crypt destruction; and Grade 5, erosions or ulceration.
Time frame: At Week 52
Population: Substudy 3 ITT\_A population: the first 451 upadacitinib 45 mg 8-week induction responders who were enrolled under the protocol for 52-week maintenance treatment period in Cohort 1. Non-responder imputation incorporating multiple imputation (MI) to handle missing data due to COVID-19 (NRI-C) was used to handle missing data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SS1: Placebo | Substudy 3: Percentage Of Participants Who Achieved Histologic-Endoscopic Mucosal Improvement at Week 52 | 11.9 percentage of participants |
| SS1: Upadacitinib 7.5 mg | Substudy 3: Percentage Of Participants Who Achieved Histologic-Endoscopic Mucosal Improvement at Week 52 | 35.0 percentage of participants |
| SS1: Upadacitinib 15 mg | Substudy 3: Percentage Of Participants Who Achieved Histologic-Endoscopic Mucosal Improvement at Week 52 | 49.8 percentage of participants |
Comparison: Substudy 3: Upadacitinib 15 mg vs Placebop-value: <0.00195% CI: [14.8, 32.8]Cochran-Mantel-Haenszel
Comparison: Substudy 3: Upadacitinib 30 mg vs Placebop-value: <0.00195% CI: [27.8, 46.8]Cochran-Mantel-Haenszel
Secondary
Substudy 3: Percentage Of Participants Who Maintained Clinical Response Per Adapted Mayo Score at Wk 52 Among Those Who Achieved Clinical Response at the End of the Induction Treatment
The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). 3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration). The overall Adapted Mayo score ranges from 0 to 9 where higher scores represent more severe disease. Clinical response is defined as a decrease from baseline in the Adapted Mayo score ≥ 2 points and ≥ 30% from baseline, and a decrease in RBS ≥ 1 or an absolute RBS ≤ 1).
Time frame: At Week 52
Population: Substudy 3 ITT\_A population: the first 451 upadacitinib 45 mg 8-week induction responders who were enrolled under the protocol for 52-week maintenance treatment period in Cohort 1 and who achieved clinical response per Adapted Mayo Score in Substudy 1, 2, or M14-675. Non-responder imputation incorporating multiple imputation (MI) to handle missing data due to COVID-19 (NRI-C) was used to handle missing data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SS1: Placebo | Substudy 3: Percentage Of Participants Who Maintained Clinical Response Per Adapted Mayo Score at Wk 52 Among Those Who Achieved Clinical Response at the End of the Induction Treatment | 18.8 percentage of participants |
| SS1: Upadacitinib 7.5 mg | Substudy 3: Percentage Of Participants Who Maintained Clinical Response Per Adapted Mayo Score at Wk 52 Among Those Who Achieved Clinical Response at the End of the Induction Treatment | 63.0 percentage of participants |
| SS1: Upadacitinib 15 mg | Substudy 3: Percentage Of Participants Who Maintained Clinical Response Per Adapted Mayo Score at Wk 52 Among Those Who Achieved Clinical Response at the End of the Induction Treatment | 76.6 percentage of participants |
Comparison: Substudy 3: Upadacitinib 15 mg vs Placebop-value: <0.00195% CI: [34.5, 54.7]Cochran-Mantel-Haenszel
Comparison: Substudy 3: Upadacitinib 30 mg vs Placebop-value: <0.00195% CI: [47.2, 66]Cochran-Mantel-Haenszel
Secondary
Substudy 3: Percentage Of Participants Who Reported No Abdominal Pain at Week 52
Abdominal pain was assessed by participants in a subject diary completed once a day.
Time frame: At Week 52
Population: Substudy 3 ITT\_A population: the first 451 upadacitinib 45 mg 8-week induction responders who were enrolled under the protocol for 52-week maintenance treatment period in Cohort 1. Non-responder imputation incorporating multiple imputation (MI) to handle missing data due to COVID-19 (NRI-C) was used to handle missing data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SS1: Placebo | Substudy 3: Percentage Of Participants Who Reported No Abdominal Pain at Week 52 | 20.8 percentage of participants |
| SS1: Upadacitinib 7.5 mg | Substudy 3: Percentage Of Participants Who Reported No Abdominal Pain at Week 52 | 45.9 percentage of participants |
| SS1: Upadacitinib 15 mg | Substudy 3: Percentage Of Participants Who Reported No Abdominal Pain at Week 52 | 55.3 percentage of participants |
Comparison: Substudy 3: Upadacitinib 15 mg vs Placebop-value: <0.00195% CI: [14.2, 34.5]Cochran-Mantel-Haenszel
Comparison: Substudy 3: Upadacitinib 30 mg vs Placebop-value: <0.00195% CI: [23.6, 43.9]Cochran-Mantel-Haenszel
Secondary
Substudy 3: Percentage Of Participants Who Reported No Bowel Urgency at Week 52
Bowel urgency was assessed by participants in a subject diary completed once a day.
Time frame: At Week 52
Population: Substudy 3 ITT\_A population: the first 451 upadacitinib 45 mg 8-week induction responders who were enrolled under the protocol for 52-week maintenance treatment period in Cohort 1. Non-responder imputation incorporating multiple imputation (MI) to handle missing data due to COVID-19 (NRI-C) was used to handle missing data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SS1: Placebo | Substudy 3: Percentage Of Participants Who Reported No Bowel Urgency at Week 52 | 17.4 percentage of participants |
| SS1: Upadacitinib 7.5 mg | Substudy 3: Percentage Of Participants Who Reported No Bowel Urgency at Week 52 | 56.1 percentage of participants |
| SS1: Upadacitinib 15 mg | Substudy 3: Percentage Of Participants Who Reported No Bowel Urgency at Week 52 | 63.6 percentage of participants |
Comparison: Substudy 3: Upadacitinib 15 mg vs Placebop-value: <0.00195% CI: [28.9, 48.5]Cochran-Mantel-Haenszel
Comparison: Substudy 3: Upadacitinib 30 mg vs Placebop-value: <0.00195% CI: [35.5, 54.8]Cochran-Mantel-Haenszel
Secondary
Substudy 3: Percentage of Participants With Clinical Remission Per Adapted Mayo Score at Week 52 Among Those Who Achieved Clinical Remission at the End of the Induction Treatment
The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). 3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration). The overall Adapted Mayo score ranges from 0 to 9 where higher scores represent more severe disease. For Substudy 3, clinical remission is defined as SFS ≤ 1 and not greater than Baseline, RBS of 0, and endoscopic subscore ≤ 1. In addition, evidence of friability during endoscopy in participants with otherwise mild endoscopic activity conferred an endoscopic subscore of 2.
Time frame: At Week 52
Population: Substudy 3 ITT\_A population: the first 451 upadacitinib 45 mg 8-week induction responders who were enrolled under the protocol for 52-week maintenance treatment period in Cohort 1 and who achieved clinical remission per Adapted Mayo Score in Substudy 1, 2, or M14-675. Non-responder imputation incorporating multiple imputation (MI) to handle missing data due to COVID-19 (NRI-C) was used to handle missing data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SS1: Placebo | Substudy 3: Percentage of Participants With Clinical Remission Per Adapted Mayo Score at Week 52 Among Those Who Achieved Clinical Remission at the End of the Induction Treatment | 22.2 percentage of participants |
| SS1: Upadacitinib 7.5 mg | Substudy 3: Percentage of Participants With Clinical Remission Per Adapted Mayo Score at Week 52 Among Those Who Achieved Clinical Remission at the End of the Induction Treatment | 59.2 percentage of participants |
| SS1: Upadacitinib 15 mg | Substudy 3: Percentage of Participants With Clinical Remission Per Adapted Mayo Score at Week 52 Among Those Who Achieved Clinical Remission at the End of the Induction Treatment | 69.7 percentage of participants |
Comparison: Substudy 3: Upadacitinib 15 mg vs Placebop-value: <0.00195% CI: [20.3, 54.6]Cochran-Mantel-Haenszel
Comparison: Substudy 3: Upadacitinib 30 mg vs Placebop-value: <0.00195% CI: [30.7, 63.3]Cochran-Mantel-Haenszel
Secondary
Substudy 3: Percentage Of Participants With Endoscopic Improvement at Week 52
Endoscopic improvement is defined as an endoscopic subscore of 0 or 1. Endoscopies were assessed by a blinded central reader and scored according to the following scale: 0 = Normal or inactive disease; 1 = Mild disease (erythema, decreased vascular pattern); 2 = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions); 3 = Severe disease (spontaneous bleeding, ulceration).
Time frame: At Week 52
Population: Substudy 3 ITT\_A population: the first 451 upadacitinib 45 mg 8-week induction responders who were enrolled under the protocol for 52-week maintenance treatment period in Cohort 1. Non-responder imputation incorporating multiple imputation (MI) to handle missing data due to COVID-19 (NRI-C) was used to handle missing data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SS1: Placebo | Substudy 3: Percentage Of Participants With Endoscopic Improvement at Week 52 | 14.5 percentage of participants |
| SS1: Upadacitinib 7.5 mg | Substudy 3: Percentage Of Participants With Endoscopic Improvement at Week 52 | 48.7 percentage of participants |
| SS1: Upadacitinib 15 mg | Substudy 3: Percentage Of Participants With Endoscopic Improvement at Week 52 | 61.6 percentage of participants |
Comparison: Substudy 3: Upadacitinib 15 mg vs Placebop-value: <0.00195% CI: [25.1, 43.7]Cochran-Mantel-Haenszel
Comparison: Substudy 3: Upadacitinib 30 mg vs Placebop-value: <0.00195% CI: [36.7, 55.8]Cochran-Mantel-Haenszel
Secondary
Substudy 3: Percentage of Participants With Endoscopic Improvement at Wk 52 Among Those Who Achieved Endoscopic Improvement at the End of the Induction Treatment
Endoscopic improvement is defined as an endoscopic subscore of 0 or 1. Endoscopies were assessed by a blinded central reader and scored according to the following scale: 0 = Normal or inactive disease; 1 = Mild disease (erythema, decreased vascular pattern); 2 = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions); 3 = Severe disease (spontaneous bleeding, ulceration).
Time frame: At Week 52
Population: Substudy 3 ITT\_A population: the first 451 upadacitinib 45 mg 8-week induction responders who were enrolled under the protocol for 52-week maintenance treatment period in Cohort 1 and who achieved endoscopic improvement in Substudy 1, 2, or M14-675. Non-responder imputation incorporating multiple imputation (MI) to handle missing data due to COVID-19 (NRI-C) was used to handle missing data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SS1: Placebo | Substudy 3: Percentage of Participants With Endoscopic Improvement at Wk 52 Among Those Who Achieved Endoscopic Improvement at the End of the Induction Treatment | 19.2 percentage of participants |
| SS1: Upadacitinib 7.5 mg | Substudy 3: Percentage of Participants With Endoscopic Improvement at Wk 52 Among Those Who Achieved Endoscopic Improvement at the End of the Induction Treatment | 61.6 percentage of participants |
| SS1: Upadacitinib 15 mg | Substudy 3: Percentage of Participants With Endoscopic Improvement at Wk 52 Among Those Who Achieved Endoscopic Improvement at the End of the Induction Treatment | 69.5 percentage of participants |
Comparison: Substudy 3: Upadacitinib 15 mg vs Placebop-value: <0.00195% CI: [27.8, 56.2]Cochran-Mantel-Haenszel
Comparison: Substudy 3: Upadacitinib 30 mg vs Placebop-value: <0.00195% CI: [35.5, 61.7]Cochran-Mantel-Haenszel
Secondary
Substudy 3: Percentage Of Participants With Endoscopic Remission At Week 52
Endoscopic remission is defined as an endoscopic subscore of 0. Endoscopies were assessed by a blinded central reader and scored according to the following scale: 0 = Normal or inactive disease; 1 = Mild disease (erythema, decreased vascular pattern); 2 = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions); 3 = Severe disease (spontaneous bleeding, ulceration).
Time frame: At Week 52
Population: Substudy 3 ITT\_A population: the first 451 upadacitinib 45 mg 8-week induction responders who were enrolled under the protocol for 52-week maintenance treatment period in Cohort 1. Non-responder imputation incorporating multiple imputation (MI) to handle missing data due to COVID-19 (NRI-C) was used to handle missing data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SS1: Placebo | Substudy 3: Percentage Of Participants With Endoscopic Remission At Week 52 | 5.6 percentage of participants |
| SS1: Upadacitinib 7.5 mg | Substudy 3: Percentage Of Participants With Endoscopic Remission At Week 52 | 24.2 percentage of participants |
| SS1: Upadacitinib 15 mg | Substudy 3: Percentage Of Participants With Endoscopic Remission At Week 52 | 25.9 percentage of participants |
Comparison: Substudy 3: Upadacitinib 15 mg vs Placebop-value: <0.00195% CI: [11, 26.4]Cochran-Mantel-Haenszel
Comparison: Substudy 3: Upadacitinib 30 mg vs Placebop-value: <0.00195% CI: [11.7, 27.2]Cochran-Mantel-Haenszel
Secondary
Substudy 3: Percentage Of Participants With Mucosal Healing at Week 52
Mucosal healing is defined as an endoscopic score of 0 and Geboes score \< 2.0. The endoscopic subscore ranges from 0 (normal or inactive disease) to 3 (severe disease with spontaneous bleeding, ulceration). The Geboes histologic index includes seven histological features (architectural change, chronic inflammatory infiltrate, lamina propria neutrophils and eosinophils, neutrophils in epithelium, crypt destruction and erosion or ulcers). The Geboes score has 6 grades, each with 3-5 subgrades: Grade 0, structural change only; Grade 1, chronic inflammation; Grade 2, lamina propria neutrophils and eosinophils; Grade 3, neutrophils in epithelium; Grade 4, crypt destruction; and Grade 5, erosions or ulceration.
Time frame: At Week 52
Population: Substudy 3 ITT\_A population: the first 451 upadacitinib 45 mg 8-week induction responders who were enrolled under the protocol for 52-week maintenance treatment period in Cohort 1. Non-responder imputation incorporating multiple imputation (MI) to handle missing data due to COVID-19 (NRI-C) was used to handle missing data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SS1: Placebo | Substudy 3: Percentage Of Participants With Mucosal Healing at Week 52 | 4.7 percentage of participants |
| SS1: Upadacitinib 7.5 mg | Substudy 3: Percentage Of Participants With Mucosal Healing at Week 52 | 17.6 percentage of participants |
| SS1: Upadacitinib 15 mg | Substudy 3: Percentage Of Participants With Mucosal Healing at Week 52 | 19.0 percentage of participants |
Comparison: Substudy 3: Upadacitinib 15 mg vs Placebop-value: <0.00195% CI: [6, 20]Cochran-Mantel-Haenszel
Comparison: Substudy 3: Upadacitinib 30 mg vs Placebop-value: <0.00195% CI: [6.6, 20.6]Cochran-Mantel-Haenszel