| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10009900 |
| E.1.2 | Term | Colitis ulcerative |
| E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Main objective of SS1 (Ph2b induction) is to characterize dose-response, efficacy, and safety of upadacitinib compared to placebo in inducing clinical remission defined by Adapted Mayo score in subjects with moderately to severely active ulcerative colitis (UC) in order to identify the induction dose of upadacitinib for further evaluation in Phase 3 studies, SS1 has closed enrollment and all subjects have completed the induction phase.
Main objective of SS2 (Ph3 induction) is to evaluate efficacy and safety
of upadacitinib 45 mg once daily (QD) compared to placebo in inducing
clinical remission in subjects with moderately to severely active UC.
Main objective of SS3 (Ph3 maintenance) is to evaluate efficacy and safety of upadacitinib 15 mg QD and 30 mg QD compared to placebo in achieving clinical remission in subjects with moderately to severely active UC who achieved clinical response following induction with upadacitinib in M14-234 SS1 or 2 or M14-675.
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| E.2.2 | Secondary objectives of the trial |
evaluate the efficacy of upadacitinib as an induction and maintenance
therapy in ranked 2nd endpoints |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
This is a Phase IIb/III, multicenter, randomized, double-blind, placebo-controlled study consisting of the following Substudies:
Substudy 1 is a Phase IIb dose-ranging study designed to evaluate the efficacy, safety, and pharmacokinetics of oral administration of multiple different doses of Upadacitinib compared to placebo as induction therapy for 8 weeks in subjects with moderately to severely active ulcerative colitis (UC).
Substudy 2 is a Phase III dose-confirming study designed to evaluate the efficacy and safety of oral administration of one dose of Upadacitinib, based on the dose identified from Substudy 1, compared to placebo as induction therapy for 8 weeks in subjects with moderately to severely active UC.
Substudy 3 is a Phase III study designed to evaluate the efficacy and safety of oral administration of two doses of Upadacitinib compared to placebo as maintenance therapy for 52 weeks in subjects with moderately to severely active ulcerative colitis who achieved response following induction with Upadacitinib in Substudy 1 or 2 or study M14-675. |
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| E.3 | Principal inclusion criteria |
1. Male or female between 16 and 75 years of age at Baseline.
- Adolescent subjects at the age of 16 and 17 years old will be enrolled if
approved by the country or regulatory/health authority. If these
approvals have not been granted, only subjects ≥ 18 years old will be
enrolled.
- Adolescent subjects at the age of 16 and 17 years old must weigh ≥ 40
kg and meet the definition of Tanner Stage 5 (refer to Appendix J) at the
screening Visit.
2. Diagnosis of ulcerative colitis for 90 days or greater prior to Baseline, confirmed by colonoscopy
3. Moderately to severely active ulcerative colitis
4. Demonstrated an inadequate response to, loss of response to, or intolerance to immunosuppressants, corticosteroids or biologic therapies
5. Negative pregnancy test for female subjects of childbearing potential |
|
| E.4 | Principal exclusion criteria |
1. Subject with current diagnosis of Crohn's disease (CD) or diagnosis of indeterminate colitis (IC).
2. Current diagnosis of fulminant colitis and/or toxic megacolon.
3. Subject with disease limited to the rectum (ulcerative proctitis) during the screening endoscopy.
4. Received cyclosporine, tacrolimus, mycophenolate mofetil, or thalidomide within 30 days prior to Baseline.
5. Subject who received azathioprine or 6-mercaptopurine within 10 days of Baseline.
6. Received intravenous corticosteroids within 14 days prior to Screening or during the Screening Period.
7. Subject with previous exposure to JAK inhibitor. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint for Phase 2b Induction (Substudy 1) is the proportion of subjects who achieve clinical remission per Adapted Mayo score (defined as SFS ≤ 1, RBS of 0, and endoscopic subscore ≤ 1) at Week 8.
The primary endpoint for Phase 3 Induction (Substudy 2) is the
proportion of subjects who achieve clinical remission per Adapted Mayo score (defined as SFS ≤ 1 and not greater than Baseline, RBS of 0, and endoscopic subscore ≤ 1) at Week 8. Note: in Substudy 2, evidence of friability during endoscopy in subjects with otherwise "mild" endoscopic activity will confer an endoscopic subscore of 2.
The primary endpoint for Phase 3 maintenance (Substudy 3) is the proportion of subjects who achieve clinical remission per Adapted Mayo score (definition same as definition in Substudy 2) at Week 52.
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|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Substudy 1: Week 8
Substudy 2: Week 8
Substudy 3: Week 52
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|
| E.5.2 | Secondary end point(s) |
Substudy 1:
1. Proportion of subjects with endoscopic improvement (defined as an endoscopic subscore ≤ 1) at Week 8
2. Proportion of subjects achieving clinical remission per Full Mayo score (defined as a Full Mayo score ≤ 2 with no subscore > 1) at Week 8
3. Proportion of subjects achieving clinical response per Adapted Mayo score (defined as decrease from baseline in the Adapted Mayo score ≥ 2 points and ≥ 30% from baseline, PLUS a decrease in rectal bleeding subscore (RBS) ≥ 1 or an absolute RBS ≤ 1) at Week 8
4. Proportion of subjects achieving clinical response per Partial Mayo score (using the Mayo Scoring System for Assessment of Ulcerative Colitis Activity, excluding endoscopic subscore; clinical response defined as decrease from baseline in the Partial Mayo score ≥ 2 points and ≥ 30% from baseline, PLUS a decrease in rectal bleeding subscore (RBS) ≥ 1 or an absolute RBS ≤ 1) at Week 2
5. Change in Full Mayo score from Baseline to Week 8
6. Proportion of subjects with endoscopic remission (defined as an endoscopic subscore of 0) at Week 8
7. Proportion of subjects who achieved histologic improvement (defined as decrease from baseline in Geboes score) at Week 8
Substudy 2:
1. Proportion of subjects with endoscopic improvement at Week 8
2. Proportion of subjects with endoscopic remission at Week 8
3. Proportion of subjects achieving clinical response per Adapted Mayo
Score at Week 8
4. Proportion of subjects achieving clinical response per Partial Adapted
Mayo score (defined as decrease from Baseline ≥ 1 points and ≥ 30%
from Baseline, PLUS a decrease in RBS ≥ 1 or an absolute RBS ≤ 1) at
Week 2
5. Proportion of subjects achieving histologic-endoscopic mucosal
improvement at Week 8
6. Proportion of subjects who reported no bowel urgency at Week 8
7. Proportion of subjects who reported no abdominal pain at Week 8
8. Proportion of subjects who achieved histologic improvement at Week 8
9. Change from Baseline in IBDQ total score at Week 8
10. Proportion of subjects with mucosal healing at Week 8
11. Change from Baseline in FACIT-F score at Week 8
Substudy 3:
1. Proportion of subjects with endoscopic improvement
2. Proportion of subjects who maintain clinical remission per Adapted
Mayo score among subjects who achieved clinical remission per Adapted
Mayo score in Study M14-234 (Substudy 1 or 2) or Study M14-675
3. Proportion of subjects who achieved clinical remission at Week 52 per adapted Mayo score and were corticosteroid free for ≥ 90 days among subjects in clinical remission in the end of the induction treatment in Study M14-234 (Substudy 1 or 2) or Study M14-675.
4. Proportion of subjects with endoscopic improvement among subjects with endoscopic improvement in Study M14-234 (Substudy 1 or 2) or Study M14-675
5. Proportion of subjects with endoscopic remission
6. Proportion of subjects maintain clinical response per Adapted Mayo score
7. Proportion of subjects with histologic-endoscopic mucosal improvement
8. Change from Baseline in IBDQ total score
9. Proportion of subjects with mucosal healing
10. Proportion of subjects who reported no bowel urgency
11. Proportion of subjects who reported no abdominal pain
12. Change from Baseline in FACIT-F score |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Substudy 1:
1. Week 8
2. Week 8
3. Week 8
4. Week 2
5. Week 8
6. Week 8
7. Week 8
Substudy 2:
1. Week 8
2. Week 8
3. Week 8
4. Week 2
5. Week 8
6. Week 8
7. Week 8
8. Week 8
9. Week 8
10. Week 8
11. Week 8
Substudy 3:
1. Week 52
2. Week 52
3. Week 52
4. Week 52
5. Week 52
6. Week 52
7. Week 52
8. Week 52
9. Week 52
10. Week 52
11. Week 52
12. Week 52
13. Week 52
14. Week 52
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|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 130 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Bosnia and Herzegovina |
| Chile |
| Colombia |
| Egypt |
| Kazakhstan |
| Mexico |
| Puerto Rico |
| Saudi Arabia |
| Serbia |
| Singapore |
| South Africa |
| European Union |
| Argentina |
| Belarus |
| Brazil |
| Canada |
| China |
| Israel |
| Japan |
| Korea, Republic of |
| Malaysia |
| New Zealand |
| Norway |
| Russian Federation |
| Switzerland |
| Taiwan |
| Ukraine |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 5 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 5 |
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