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 |
|
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 |
The objective of Study M14-675 (Phase 3 induction) is to evaluate the efficacy and safety of upadacitinib 45 mg once daily (QD) compared to placebo in inducing clinical remission (per Adapted Mayo score) in subjects with moderately to severely active ulcerative colitis. |
|
E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are to evaluate the efficacy of upadacitinib 45 mg QD comparing with placebo in ranked secondary endpoints of achieving endoscopic improvement, endoscopic remission, clinical response per Adapted Mayo Score ,clinical response per Partial Adapted Mayo score, no bowel urgency, no abdominal pain, histologic improvement, response in IBDQ Below symptom domain, mucosal healing, UC-related hospitalization, UC-related surgery, and response in IBDQ fatigue item |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female between 18 and 75 years of age at Baseline. 2. Diagnosis of UC 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. 3. Active UC with an Adapted Mayo score of 5 to 9 points and endoscopic subscore of 2 to 3 (confirmed by central reader). 4. Demonstrated an inadequate response, loss of response, or intolerance to at least one of the following including, oral aminosalicylates, corticosteroids, immunosuppressants, and/or biologic therapies, in the opinion of the investigator, as defined below: • Oral aminosalicylates (e.g., mesalamine, sulfasalazine, olsalazine, balsalazide) o Signs and symptoms of persistently active disease, in the opinion of the investigator, during a current or prior course of at least 4 weeks of treatment with 2.4 g/day mesalamine, 4 g/day sulfasalazine, 1 g/day olsalazine, or 6.75 g/day balsalazide. • Corticosteroids o Signs and symptoms of persistently active disease despite a history of at least one induction regimen that included a dose equivalent to prednisone ≥ 40 mg/day orally for 3 to 4 weeks or intravenously for 1 week, OR o Unable to taper corticosteroids to below a dose equivalent to prednisone 10 mg daily orally without recurrent active disease, OR o History of intolerance to corticosteroids (including, but not limited to Cushing's syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, infection). • Immunosuppressants o Signs and symptoms of persistently active disease despite a history of at least one 90 day regimen of oral azathioprine (≥ 1.5 mg/kg/day; for subjects in Japan, China, and Taiwan only: ≥ 1.0 mg/kg/day), 6-MP (≥ 1 mg/kg/day; [for subjects in Japan, China, and Taiwan only: ≥ 0.6 mg/kg/day, rounded to the nearest available tablet of half tablet formulation] or a documented 6-TGN level of 230 – 450 pmol/8 × 108 RBC or higher on the current dosing regimen), injectable MTX (≥ 15 mg/week subcutaneous [SC] or intramuscular), or tacrolimus (for subjects in Japan and Taiwan only: documented trough level of 5 – 10 ng/mL), OR o History of intolerance to at least one immunosuppressant (including, but not limited to nausea/vomiting, abdominal pain, pancreatitis, liver enzyme abnormalities, lymphopenia, infection) Note: Oral MTX use is allowed during the study, however prior or current use of oral MTX is not sufficient for inclusion into the study unless these subjects were previously treated with aminosalicylates, corticosteroids or immunosuppressants (azathioprine or 6-MP) and have inadequate response to, loss of response to or intolerance to the therapy as defined above. • Biologic Agents for UC o Signs and symptoms of persistently active disease despite a history of any of the following: o at least one 6-week induction regimen of infliximab (≥ 5 mg/kg IV at 0, 2, and 6 weeks), o at least one 4-week induction regimen of adalimumab (one 160 mg SC dose followed by one 80 mg SC dose [or one 80 mg SC dose in countries where this dosing regimen is allowed] followed by one 40 mg SC dose at least 2 weeks apart), o at least one 2-week induction regimen of golimumab (one 200 mg SC dose followed by one 100 mg SC dose at least 2 weeks apart), o at least one 6-week induction regimen of vedolizumab (300 mg IV at 0, 2, and 6 weeks), OR o Recurrence of symptoms during scheduled maintenance dosing following prior clinical benefit (discontinuation despite clinical benefit does not qualify), OR o History of intolerance to at least one biologic agent (including, but not limited to infusion-related reaction, demyelination, congestive heart failure, infection)
5. Female subjects of childbearing potential must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at the Baseline Visit. 6. If female, subject must meet the criteria as stated in Section 5.2.4 of this protocol: Contraception Recommendations.
|
|
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, or mycophenolate mofetil within 30 days prior to Baseline. 5. Subject who received azathioprine or 6-MP 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.g., tofacitinib, baricitinib, filgotinib, upadacitinib). 8. Screening laboratory and other analyses show any of the following abnormal results: • Serum Aspartate Transaminase (AST) or Alanine Transaminase (ALT) > 2.0 × upper limit of the reference range (ULN); • Estimated glomerular filtration rate by simplified 4-variable Modification of Diet in Renal Disease (MDRD) formula < 30 mL/min/1.73 m2; • Total White Blood Cell (WBC) count < 2500/µL; • Absolute neutrophil count (ANC) < 1,200/µL; • Platelet count < 100,000/µL; • Absolute lymphocytes count < 750/µL; • Hemoglobin < 9g/dL. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint for Study M14-675 is the proportion of subjects who achieve clinical remission per Adapted Mayo score (defined as SFS ≤ 1, RBS of 0, and endoscopic sub score ≤ 1) at Week 8. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part 1: Week 8 and Part 2: Week 16 (Extended Treatment Period; as applicable) |
|
E.5.2 | Secondary end point(s) |
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 who reported no bowel urgency at Week 8 6. Proportion of subjects who reported no abdominal pain at Week 8 7. Proportion of subjects who achieved histologic improvement (defined as decrease from Baseline in Geboes score) at Week 8 8. Proportion of subjects achieving response in IBDQ Bowel Symptom domain (increase of IBDQ bowel symptom domain score ≥6) at Week 8 9. Proportion of subjects with mucosal healing (endoscopic and histologic remission) at Week 8 10. Proportion of subjects with UC-related hospitalizations through Week 8 11. Proportion of subjects with UC-related surgeries through Week 8 12. Proportion of subjects achieving response in IBDQ fatigue item (increase of IBDQ fatigue item score ≥1) at Week 8.
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
For points 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12 - week 8 For point 4 - Week 2 |
|
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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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) | No |
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 | 2 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 175 |
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 |
Argentina |
Australia |
Belarus |
Bosnia and Herzegovina |
Brazil |
Canada |
Chile |
China |
Colombia |
Israel |
Japan |
Korea, Republic of |
Malaysia |
Mexico |
Puerto Rico |
Russian Federation |
Serbia |
Singapore |
South Africa |
Taiwan |
Turkey |
Ukraine |
United States |
Croatia |
Norway |
Switzerland |
|
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 23 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 23 |
E.8.9.2 | In all countries concerned by the trial days | 0 |