A Maintenance and Long-Term Extension Study of the Efficacy and Safety of Upadacitinib (ABT-494) in Participants With Crohn's Disease Who Completed the Studies M14-431 or M14-433

Study Overview
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Brief Summary
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A multicenter study to evaluate the efficacy and safety of maintenance and long-term treatment administration of upadacitinib, an orally administered Janus kinase 1 inhibitor, in adult participants with Crohn's Disease.

Official Title
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A Multicenter, Randomized, Double-Blind, Placebo-Controlled Maintenance and Long-Term Extension Study of the Efficacy and Safety of Upadacitinib (ABT-494) in Subjects With Crohn's Disease Who Completed the Studies M14-431 or M14-433

Conditions
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Crohn's Disease

Intervention / Treatment
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* Drug: Upadacitinib
* Drug: Placebo for Upadacitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For Substudy 1: Participant who achieve clinical response in Study M14-431 or Study M14-433. Participant completes study procedures in the parent study. The final endoscopy for Studies M14-431 or M14-433 may be missing, if the endoscopy cannot be performed during the COVID-19 pandemic. For Substudy 2: Participant completes Substudy 1. The Week 52 endoscopy may be missing, if the endoscopy cannot be performed during the COVID-19 pandemic. Participant who achieved clincal response at the time descibed in the protocol and completes study procedures in the parent study/ substudy. For Substudy 3: Participant is an ongoing participant in Substudy 2 for at least 12 months. Participant is in stable remission for at least 6 months defined as: CDAI < 150 CRP < 5 mg/L and FCP < 250 mg/kg AND Participant has not been on locally acting (rectal or suppository) or systemic corticosteroids for CD => 90 days prior to the entry of Substudy 3. Exclusion Criteria: For Substudies 1,2 and 3: Participant is considered by the investigator, for any reason, to be an unsuitable candidate for the study. Participant who has a known hypersensitivity to upadacitinib or its excipients, or had an adverse event during Studies M14-431 and M14-433 or Substudy 1 or 2 of Study M14-430 that in the investigator's judgment makes the participant unsuitable for this study. Participant at the final visit of M14-431 or M14-433 with any active or chronic recurring infections based on the investigator's assessment that makes the participant an unsuitable candidate for the study. Participants 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. Participants 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 (Week 52). 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 of Substudy 3. Received any new medication or increase of the dose of current concomitant medication for the treatment of CD in the past 3 months.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Substudy 1: Cohort 1 Upadacitinib Dose A<br>This is a maintenance group which includes participants who achieved clinical response to upadacitinib in studies M14-431 and M14-433 and will receive upadacitinib dose A for 52 weeks. | Drug: Upadacitinib<br>* Oral; Tablet<br>* Other names: RINVOQ;|
| Experimental: Substudy 1: Cohort 1 Upadacitinib Dose B<br>This is a maintenance group which includes participants who achieved clinical response to upadacitinib in studies M14-431 and M14-433 and will receive upadacitinib dose B for 52 weeks. | Drug: Upadacitinib<br>* Oral; Tablet<br>* Other names: RINVOQ;|
| Experimental: Substudy 1: Cohort 1 Placebo<br>This is a maintenance group which includes participants who achieved clinical response to upadacitinib in studies M14-431 and M14-433 and will receive placebo for 52 weeks. | Drug: Placebo for Upadacitinib<br>* Oral; Tablet<br>|
| Experimental: Substudy 1: Cohort 2 Placebo<br>This is a maintenance group which includes participants who received double-blind placebo in studies M14-431 and M14-433 and achieved clinical response will continue to receive blinded placebo for 52 Weeks. | Drug: Placebo for Upadacitinib<br>* Oral; Tablet<br>|
| Experimental: Substudy 1: Cohort 3 Upadacitinib Dose B<br>This is a maintenance group which includes participants who achieved clinical response to upadacitinib from the extended treatment period of studies M14-431 and M14-433 and will receive upadacitinib Dose B for 52 Weeks. | Drug: Upadacitinib<br>* Oral; Tablet<br>* Other names: RINVOQ;|
| Experimental: Substudy 2: Cohort 4 Upadacitinib Dose B<br>This is a long-term extension group which includes participants who achieved clinical response in the open-label extended treatment period of study M14-431 and will receive upadacitinib dose B for 240 weeks. | Drug: Upadacitinib<br>* Oral; Tablet<br>* Other names: RINVOQ;|
| Experimental: Substudy 2: Cohort 5 Upadacitinib Dose A<br>This is a long-term extension group which includes participants who complete Substudy 1 and will receive upadacitinib dose A for 240 weeks. | Drug: Upadacitinib<br>* Oral; Tablet<br>* Other names: RINVOQ;|
| Experimental: Substudy 2: Cohort 5 Upadacitinib Dose B<br>This is a long-term extension group which includes participants who complete Substudy 1 and will receive upadacitinib dose B for 240 weeks. | Drug: Upadacitinib<br>* Oral; Tablet<br>* Other names: RINVOQ;|
| Experimental: Substudy 2: Cohort 5 Placebo<br>This is a long-term extension group which includes participants who complete Substudy 1 and will receive placebo for 240 weeks. | Drug: Placebo for Upadacitinib<br>* Oral; Tablet<br>|
| Experimental: Substudy 3: Cohort 6 Upadacitinib Dose A<br>This is the dose optimization group which includes participants from Substudy 2 who meet the criteria of stable remission will receive open-label upadacitinib dose A for up to 48 weeks. | Drug: Upadacitinib<br>* Oral; Tablet<br>* Other names: RINVOQ;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sub-Study 1: Percentage of Participants with Clinical Remission per Crohn's Disease Activity Index (CDAI) | Clinical remission per CDAI is defined as CDAI <150. | Week 52 | 
| Sub-Study 1: Percentage of Participants with Endoscopic Response | Endoscopic response is defined as decrease in Simple Endoscopic Score for Crohn's Disease (SES-CD) from Baseline. | Week 52 | 
| Number of Participants with Adverse Events | An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. The investigator assessed the relationship of each event to the use of study drug as either probably related, possibly related, probably not related or not related. A serious adverse event (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. For more details on adverse events please see the Adverse Event section. | Through Week 240 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sub-Study 1: Percentage of Participants with Clinical Remission per Patient-Reported Outcomes (PROs) | Clinical remission is defined based on average daily stool frequency (SF) AND average daily abdominal pain (AP) score. | Week 52 | 
| Sub-Study 1: Percentage of Participants Achieving Clinical Response 100 (CR-100) | Decrease of at least 100 points in CDAI from Baseline. | Week 52 | 
| Sub-Study 1: Percentage of Participants with Endoscopic Remission | Endoscopic remission is defined per Simplified Endoscopic Score for Crohn's Disease (SES-CD). | Week 52 | 
| Sub-Study 1: Percentage of Participants without Corticosteroid use for Crohn's Disease Among All Participants | This is assessed in participants not taking corticosteroids at least 90 days prior to Week 52 and achieved clinical remission per CDAI. Clinical remission is defined as CDAI <150. | Week 52 | 
| Sub-Study 1: Percentage of Participants with Clinical Remission per CDAI and Endoscopic Remission | Clinical remission per CDAI is defined as CDAI <150. Endoscopic remission is defined per SES-CD. | Week 52 | 
| Sub-Study 1: Percentage of Participants with Clinical Remission per CDAI | Clinical remission per CDAI is defined as CDAI <150 (as measured by the percentage of participants with clinical remission at Week 52 among those with clinical remission at Week 0). | Through Week 52 | 
| Sub-Study 1: Percentage of Participants who Discontinue Corticosteroid Use for Crohn's Disease at Least 90 Days Prior to Week 52 and Achieve Clinical Remission, in Participants Taking Corticosteroids at Baseline. | This is assessed in participants taking corticosteroids at Baseline. Clinical remission is defined based on average daily stool frequency (SF) AND average daily abdominal pain (AP) score. | Week 52 | 
| Sub-Study 1: Change in Inflammatory Bowel Disease Questionnaire (IBDQ) | The IBDQ is used to assess the quality of life of patients with inflammatory bowel disease. | Baseline (Week 0) to Week 52 | 
| Sub-Study 1: Change in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) | The FACIT-F questionnaire was developed to assess fatigue. | Baseline (Week 0) to Week 52 | 
| Sub-Study 1: Percentage of Participants with Hospitalizations due to Crohn's Disease (CD) | This is assessed by reviewing participant's hospitalization data. | Up to Week 52 | 
| Sub-Study 1: Percentage of Participants with Resolution of Extra-Intestinal Manifestation (EIMs) , in Participants with EIMs at Baseline | EIMs are defined as manifestations of Crohn's disease in areas of the body other than the digestive tract, including eyes, skin, joints, mouth, and liver. | Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Upadacitinib, ABT-494, Extension Study, Efficacy, Safety, Crohn's Disease, Maintenance Study