| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
| CD is an inflamatory bowel disease affects the lining of the digestive tract, often spreads into the layers of affected bowel tissue, can lead to abdominal pain, severe diarrhea, fatigue, weight loss. |
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| 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 | 10011401 |
| E.1.2 | Term | Crohn's disease |
| 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 |
Substudy 1 (randomized, double-blind, placebo-controlled maintenance): To evaluate the efficacy and safety of two doses of upadacitinib versus placebo as maintenance therapy in subjects with moderately to severely active Crohn's disease (CD) who responded to upadacitinib induction treatment in Studies M14-431 or M14-433.
Substudy 2 (long-term extension [LTE]): To evaluate safety and efficacy of long-term administration of upadacitinib in subjects with moderately to severely active CD who participated in the Phase 3 upadacitinib induction and maintenance studies.
Substudy 3 (dose optimization): To evaluate the efficacy and safety of dose decrease of upadacitinib from 30 mg QD to 15 mg QD in subjects who are receiving open-label upadacitinib 30 mg QD and are in stable remission in Substudy 2.
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| E.2.2 | Secondary objectives of the trial |
| To evaluate improvements in several efficacy parameters, including steroid discontinuation, laboratory parameters and quality of life questionnaires. |
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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 |
Substudy 1 - 52-Week, Randomized, Double-Blind, Maintenance
Substudy 2 - 240-Week Long-Term-Extension
Substudy 3 - 48 weeks Dose optimization
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| E.3 | Principal inclusion criteria |
For Substudy 1:
- Subject who receive double-blind treatment in Study M14- 431 or Study M14-433 and achieve clinical response.
- Subject completes Week 12 or Week 24 study procedures in study M14-431 or study M14-433. The final endoscopy for studies M14-431 or M14-433 may be missing, if the endoscopy cannot be performed during the coronavirus SARS-CoV-2 pandemic.
For Substudy 2:
- Subject completes Substudy 1 of Study M14-430. The week 52 endoscopy may be missing, if the endoscopy cannot be performed during the coronavirus SARS-CoV-2 pandemic.
- Subject achieved clinical response at Week 24 and completed Week 24 visit and procedures in Part 3/Cohort 3 of Study M14-431.
For Substudy 3
-Subject is an ongoing subject in Substudy 2 for at least 12 months
-Subject has received open-label upadacitinib 30 mg QD for at least 6 months during Substudy 2
-Subject is in stable remission for at least 6 months defined as:
a.CDAI < 150 AND
b.CRP < 5 mg/L and FCP < 250 mg/kg AND
c.Subject has not been on locally acting (rectal or suppository) or systemic corticosteroids for CD ≥ 90 days prior to the entry of Substudy 3.
NOTE: Hematocrit for baseline CDAI calculation, CRP, and FCP should be assessed within 4 weeks prior to enrolment to confirm subjects are in stable remission at time of enrolment into the substudy and will serve as
Baseline (Week 0) results.
-In the past 3 months the subject has not received any new medication or increase of the dose of current concomitant medication for treatment of CD
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| E.4 | Principal exclusion criteria |
Substudy 1, 2 and 3
-Subject is considered by the investigator, for any reason, to be an unsuitable candidate for the study.
-Subject who has a known hypersensitivity to upadacitinib or its excipients, or had an AE during Studies M14-431, M14-433, or Substudy
1 or 2 of Study M14-430 that, in the investigator's judgment, makes the subject unsuitable for this study.
-Subjects who anticipate the need for any live vaccine during study participation including at least 30 days (or longer, if required locally after the last dose of study drug.
-Female subjects with a confirmed positive pregnancy test at the final visit in Studies M14-431, M14-433, or Substudy 1 of Study M14-430, or who is considering becoming pregnant during the study.
-Subject is not in compliance with prior and concomitant medication requirements throughout Studies M14-431, M14-433, or Substudy 1 or 2 of Study M14-430 per investigator assessment.
-Subject at the final visit of M14-431 or M14-433 with any active or chronic recurring infections based on the investigator's assessment makes the subject an unsuitable candidate for the study. Subjects with serious infections undergoing treatment may be enrolled BUT NOT dosed until the infection treatment has been completed, and the infection is resolved, based on the investigator's assessment. -Current evidence of active or untreated latent tuberculosis. -Subjects with high grade colonic dysplasia or malignancy diagnosed at the endoscopy performed at the final visit of Studies M14- 431, M14-433, or Substudy 1 or 2 of Study M14-430.
-Current or history of malignancy or lymphoproliferative disease, including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy and/or splenomegaly; except for successfully treated non-metastatic cutaneous squamous cell, basal cell carcinoma, and/or localized carcinoma in situ of the cervix.
-Subject with a poorly controlled medical condition, such as uncontrolled diabetes, unstable ischemic heart disease, moderate or severe congestive heart failure, recent cerebrovascular accidents, and any other condition which, in the opinion of the investigator or sponsor, would put the subject at risk by participation in this study.
-Laboratory values from the visit immediately prior to the Substudy 1 Week 0 Visit or the Substudy 2
Week 0 Visit (for those subjects enrolling into Cohort 4) meeting the following criteria:
• EJAST or ALT > 3 x upper limit of normal (ULN)
• EJTotal WBC count < 2,000/pL
• EJAbsolute neutrophil count (ANC) < 1,000/pL
• EJPlatelet count < 50,000/pL
• EJAbsolute lymphocyte count < 500/pL
• EJHemoglobin <8 g/dL
-For Substudy 3 only: Total SES-CD >4 and/or subscore >1 in any segment in the Substudy 2 annual ileo-colonoscopy, if performed within 6 months prior to Week 0 in Substudy 3, based on the local reader score.
-Enrollment in another interventional clinical study while participating in
this study.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Substudy 1, Cohort 1 (Upadacitinib vs Placebo)
Co-Primary Endpoints:
Proportion of subjects with clinical remission per PROs at Week 52, AND
Proportion of subjects with endoscopic response at Week 52
Substudy 2
Occurrence rate of subjects
with total hospitalizations (all-cause) over time
with CD-related hospitalizations over time
with surgeries over time
with CD-related surgeries over time
Substudy 3
Proportion of subjects with clinical remission per CDAI at Week 48 and
without changes in CD-related medications and without corticosteroids
during the 48-week period.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Substudy 1
1. Proportion of subjects with clinical remission per CDAI at Week 52
2. Proportion of subjects with endoscopic remission at Week 52
3. Change from Baseline in IBDQ at Week 52
4. Proportion of subjects achieving CR-100 at Week 52
5. Proportion of subjects who discontinued corticosteroid use for CD at least 90 days prior to Week 52 and achieved clinical remission per PROs at Week 52 in subjects taking corticosteroids for CD at Baseline of induction
6. Proportion of subjects with clinical remission per PROs at Week 0 and Week 52
7. Change from Baseline in FACIT-F at Week 52
8. Proportion of subjects with clinical remission per PROs and endoscopic remission at Week 52
9. Proportion of subjects with CD-related hospitalizations during the 52 Week double-blind maintenance period.
10. Proportion of subjects with resolution of EIMs at Week 52, in subjects with EIMs at Baseline
Substudy 2
Proportion of subjects
with clinical remission over time
with enhanced clinical response over time
with endoscopic remission at Week 0, and every 48 weeks thereafter
with endoscopic response at Week 0, and every 48 weeks thereafter
who discontinue corticosteroid use and achieve clinical remission over time among subjects taking steroids at Baseline (of induction)
with clinical remission over time who were in clinical remission at Week 0
achieving Inflammatory Bowel Disease Questionnaire (IBDQ) response (increase of IBDQ ≥ 16 over time)
Time loss of
enhanced clinical response
clinical remission
Substudy 3
1.Proportion of subjects who had Crohn's disease relapse at any time
during the first 48 weeks in Substudy 3
2.Time from week 0 to Crohn's disease relapse
3.Proportion of subjects in clinical remission per CDAI at every
scheduled visit
4.Proportion of subjects in clinical remission per PROs at every
scheduled visit
5.Proportion of subjects with normal hsCRP (< 5 mg/L) at every
scheduled visit
6.Proportion of subjects with normal FCP (< 250 mg/kg) at every
scheduled visit
7.Proportion of subjects in clinical remission per CDAI and normal CRP at
every scheduled visit
8.Proportion of subjects in clinical remission per CDAI and normal FCP
at every scheduled visit
Additional pre-specified endpoints are outlined in the protocol.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Substudy 1
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
Substudy 2
Over study duration
Substudy 3
48 weeks till study duration
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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 | No |
| 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) | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Substudy 1 and 2 Randomized Double Blind Open Label Substudy 3 Dose Optimization |
|
| 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 | 3 |
| 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 | 146 |
| 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 |
| Brazil |
| Canada |
| Chile |
| China |
| Colombia |
| Egypt |
| Israel |
| Japan |
| Malaysia |
| Mexico |
| Singapore |
| South Africa |
| United States |
| Switzerland |
| Bosnia and Herzegovina |
| Russian Federation |
| Turkey |
| Ukraine |
| Serbia |
| Hong Kong |
| Korea, Republic of |
| Puerto Rico |
| Taiwan |
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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 | 5 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 12 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 12 |
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