Clinical Trial Results:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Induction Study to Evaluate the Efficacy and Safety of Upadacitinib (ABT-494) in Subjects with Moderately to Severely Active Ulcerative Colitis
Summary
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EudraCT number |
2016-000642-62 |
Trial protocol |
NL LV PT FI DE GR SE GB AT CZ LT IE BE HU ES SK PL FR HR NO IT RO |
Global end of trial date |
14 Jan 2021
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Results information
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Results version number |
v2(current) |
This version publication date |
27 Apr 2022
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First version publication date |
23 Jul 2021
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Other versions |
v1 |
Version creation reason |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
M14-675
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03653026 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
AbbVie Deutschland GmbH & Co. KG
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Sponsor organisation address |
AbbVie House, Vanwall Business Park, Vanwall Road,, Maidenhead, Berkshire, United Kingdom, SL6 4UB
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Public contact |
Global Medical Services, AbbViw, 001 800-633-9110, abbvieclinicaltrials@abbvie.com
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Scientific contact |
Global Medical Services, AbbViw, 001 800-633-9110, abbvieclinicaltrials@abbvie.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
14 Jan 2021
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
14 Jan 2021
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective of this study was to evaluate the efficacy and safety of upadacitinib 45 mg once daily (QD) compared to placebo in inducing clinical remission (per the Adapted Mayo score) in subjects with moderately to severely active ulcerative colitis (UC) who have demonstrated inadequate response, loss of response, or intolerance to oral aminosalicylates, immunosuppressants, corticosteroids, and/or biologic therapies.
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Protection of trial subjects |
Subject and/or legal guardian read and understood the information provided about the study and gave written permission.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
06 Dec 2018
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Argentina: 7
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Country: Number of subjects enrolled |
Australia: 4
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Country: Number of subjects enrolled |
Austria: 3
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Country: Number of subjects enrolled |
Belgium: 2
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Country: Number of subjects enrolled |
Bosnia and Herzegovina: 2
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Country: Number of subjects enrolled |
Brazil: 3
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Country: Number of subjects enrolled |
Canada: 37
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Country: Number of subjects enrolled |
Chile: 2
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Country: Number of subjects enrolled |
China: 13
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Country: Number of subjects enrolled |
Colombia: 2
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Country: Number of subjects enrolled |
Croatia: 3
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Country: Number of subjects enrolled |
Czechia: 8
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Country: Number of subjects enrolled |
Estonia: 13
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Country: Number of subjects enrolled |
France: 1
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Country: Number of subjects enrolled |
Germany: 2
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Country: Number of subjects enrolled |
Greece: 2
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Country: Number of subjects enrolled |
Hungary: 4
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Country: Number of subjects enrolled |
Israel: 2
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Country: Number of subjects enrolled |
Italy: 34
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Country: Number of subjects enrolled |
Japan: 81
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Country: Number of subjects enrolled |
Korea, Republic of: 5
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Country: Number of subjects enrolled |
Latvia: 4
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Country: Number of subjects enrolled |
Lithuania: 10
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Country: Number of subjects enrolled |
Malaysia: 2
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Country: Number of subjects enrolled |
Mexico: 7
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Country: Number of subjects enrolled |
Norway: 22
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Country: Number of subjects enrolled |
Poland: 24
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Country: Number of subjects enrolled |
Portugal: 8
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Country: Number of subjects enrolled |
Puerto Rico: 2
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Country: Number of subjects enrolled |
Russian Federation: 30
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Country: Number of subjects enrolled |
Serbia: 9
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Country: Number of subjects enrolled |
Singapore: 1
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Country: Number of subjects enrolled |
Slovakia: 10
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Country: Number of subjects enrolled |
South Africa: 9
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Country: Number of subjects enrolled |
Spain: 1
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Country: Number of subjects enrolled |
Switzerland: 9
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Country: Number of subjects enrolled |
Taiwan: 15
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Country: Number of subjects enrolled |
Turkey: 2
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Country: Number of subjects enrolled |
Ukraine: 6
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Country: Number of subjects enrolled |
United Kingdom: 4
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Country: Number of subjects enrolled |
United States: 117
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Worldwide total number of subjects |
522
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EEA total number of subjects |
151
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
9
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Adults (18-64 years) |
466
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From 65 to 84 years |
47
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85 years and over |
0
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Recruitment
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Recruitment details |
The study included a Screening Period of up to 5 weeks, Part 1, and Part 2. Part 1 was a randomized, double-blind, placebo-controlled 8-week induction period. Part 2 was an open-label, 8 week extended treatment period for clinical non-responders from Part 1. A total of 522 subjects were randomized at 204 sites in 41 countries. | ||||||||||||||||||||||||
Pre-assignment
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Screening details |
Participants were randomized in a 2:1 ratio to upadacitinib or placebo. Randomization was stratified by bio-IR status, corticosteroid use, and Adapted Mayo score at Baseline. Within bio-IR, randomization was further stratified by number of prior biologic treatments. Within non-bio-IR, randomization was further stratified by previous biologic use. | ||||||||||||||||||||||||
Period 1
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Period 1 title |
Part 1: Placebo-controlled Period
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Data analyst, Carer, Assessor | ||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Upadacitinib 45 mg | ||||||||||||||||||||||||
Arm description |
Participants received 45 mg upadacitinib once daily (QD) for 8 weeks. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Upadacitinib
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Investigational medicinal product code |
ABT-494
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Other name |
RINVOQ
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Upadacitinib 45 mg administered orally once daily.
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Arm title
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Placebo | ||||||||||||||||||||||||
Arm description |
Participants received placebo matching to upadacitinib once daily for 8 weeks. | ||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Administered orally once daily.
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Period 2
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Period 2 title |
Part 2: Open-label Extension
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Is this the baseline period? |
No | ||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Upadacitinib 45 mg / Upadacitinib 45 mg | ||||||||||||||||||||||||
Arm description |
Participants initially assigned to upadacitinib who did not achieve clinical response per Adapted Mayo score at Week 8 in Part 1 received upadacitinib 45 mg once daily for 8 additional weeks in the open-label extension period. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Upadacitinib
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Investigational medicinal product code |
ABT-494
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Other name |
RINVOQ
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Upadacitinib 45 mg administered orally once daily.
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Arm title
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Placebo / Upadacitinib 45 mg | ||||||||||||||||||||||||
Arm description |
Participants initially assigned to placebo who did not achieve clinical response per Adapted Mayo score at Week 8 in Part 1 received upadacitinib 45 mg once daily for 8 weeks in the open-label extension period. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Upadacitinib
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Investigational medicinal product code |
ABT-494
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Other name |
RINVOQ
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Upadacitinib 45 mg administered orally once daily.
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Notes [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period. Justification: Part 2 was an open label, 8-week extended treatment period for subjects who did not achieve clinical response per Adapted Mayo score at Week 8 in Part 1. |
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Baseline characteristics reporting groups
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Reporting group title |
Upadacitinib 45 mg
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Reporting group description |
Participants received 45 mg upadacitinib once daily (QD) for 8 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Participants received placebo matching to upadacitinib once daily for 8 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Upadacitinib 45 mg
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Reporting group description |
Participants received 45 mg upadacitinib once daily (QD) for 8 weeks. | ||
Reporting group title |
Placebo
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Reporting group description |
Participants received placebo matching to upadacitinib once daily for 8 weeks. | ||
Reporting group title |
Upadacitinib 45 mg / Upadacitinib 45 mg
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Reporting group description |
Participants initially assigned to upadacitinib who did not achieve clinical response per Adapted Mayo score at Week 8 in Part 1 received upadacitinib 45 mg once daily for 8 additional weeks in the open-label extension period. | ||
Reporting group title |
Placebo / Upadacitinib 45 mg
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Reporting group description |
Participants initially assigned to placebo who did not achieve clinical response per Adapted Mayo score at Week 8 in Part 1 received upadacitinib 45 mg once daily for 8 weeks in the open-label extension period. |
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End point title |
Percentage of Participants who Achieved Clinical Remission per Adapted Mayo Score at Week 8 | ||||||||||||
End point description |
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 Remission is defined as an Adapted Mayo score ≤ 2, with SFS ≤ 1 and not higher than Baseline, RBS of 0, and endoscopic subscore ≤ 1.
The Part 1 intent-to-treat population (ITT1) includes randomized subjects who received at least 1 dose of study drug in Part 1. The ITT1 population excludes 6 subjects from 1 site with non-compliance. Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 was used.
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End point type |
Primary
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End point timeframe |
Week 8
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Notes [1] - ITT1 population [2] - ITT1 population |
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Statistical analysis title |
Primary Analysis | ||||||||||||
Comparison groups |
Placebo v Upadacitinib 45 mg
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Number of subjects included in analysis |
515
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Analysis specification |
Pre-specified
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Analysis type |
superiority [3] | ||||||||||||
P-value |
< 0.001 [4] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Adjusted Response Rate Difference | ||||||||||||
Point estimate |
29
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
23.2 | ||||||||||||
upper limit |
34.7 | ||||||||||||
Notes [3] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided). [4] - Cochran-Mantel-Haenszel (CMH) test adjusted for strata (Baseline corticosteroid use (yes or no), Baseline Adapted Mayo score (≤ 7 or > 7), bio-IR status (bio-IR or non-bio-IR)) for the comparison of two treatment groups. |
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End point title |
Percentage of Participants with Endoscopic Improvement at Week 8 | ||||||||||||
End point description |
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).
The analysis was conducted in the ITT1 population; non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 was used.
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End point type |
Secondary
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End point timeframe |
Week 8
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Notes [5] - ITT1 population [6] - ITT1 population |
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Statistical analysis title |
Analysis of Endoscopic Improvement | ||||||||||||
Comparison groups |
Upadacitinib 45 mg v Placebo
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Number of subjects included in analysis |
515
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Analysis specification |
Pre-specified
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Analysis type |
superiority [7] | ||||||||||||
P-value |
< 0.001 [8] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Adjusted Response Rate Difference | ||||||||||||
Point estimate |
35.1
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
28.6 | ||||||||||||
upper limit |
41.6 | ||||||||||||
Notes [7] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided). [8] - Cochran-Mantel-Haenszel (CMH) test adjusted for strata (Baseline corticosteroid use (yes or no), Baseline Adapted Mayo score (≤ 7 or > 7), bio-IR status (bio-IR or non-bio-IR)) for the comparison of two treatment groups. |
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End point title |
Percentage of Participants with Endoscopic Remission at Week 8 | ||||||||||||
End point description |
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).
The analysis was conducted in the ITT1 population; non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 was used.
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End point type |
Secondary
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End point timeframe |
Week 8
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Notes [9] - ITT1 population [10] - ITT1 population |
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Statistical analysis title |
Analysis of Endoscopic Remission | ||||||||||||
Comparison groups |
Upadacitinib 45 mg v Placebo
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Number of subjects included in analysis |
515
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Analysis specification |
Pre-specified
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Analysis type |
superiority [11] | ||||||||||||
P-value |
< 0.001 [12] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Adjusted Response Rate Difference | ||||||||||||
Point estimate |
15.9
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
11.4 | ||||||||||||
upper limit |
20.3 | ||||||||||||
Notes [11] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided). [12] - Cochran-Mantel-Haenszel (CMH) test adjusted for strata (Baseline corticosteroid use (yes or no), Baseline Adapted Mayo score (≤ 7 or > 7), bio-IR status (bio-IR or non-bio-IR)) for the comparison of two treatment groups. |
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End point title |
Percentage of Participants Achieving Clinical Response per Adapted Mayo Score at Week 8 | ||||||||||||
End point description |
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 with spontaneous bleeding, ulceration).
The overall Adapted Mayo score ranges from 0 to 9 with higher scores representing more severe disease.
Clinical response per the Adapted Mayo Score is defined as a decrease in Adapted Mayo score ≥ 2 points and ≥ 30% from Baseline, plus a decrease in RBS ≥ 1 or an absolute RBS ≤ 1.
The analysis was conducted in the ITT1 population; non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 was used.
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End point type |
Secondary
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End point timeframe |
Week 8
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Notes [13] - ITT1 population [14] - ITT1 population |
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Statistical analysis title |
Analysis of Clinical Response | ||||||||||||
Comparison groups |
Placebo v Upadacitinib 45 mg
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Number of subjects included in analysis |
515
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Analysis specification |
Pre-specified
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Analysis type |
superiority [15] | ||||||||||||
P-value |
< 0.001 [16] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Adjusted Response Rate Difference | ||||||||||||
Point estimate |
49.4
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
41.7 | ||||||||||||
upper limit |
57.1 | ||||||||||||
Notes [15] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided). [16] - Cochran-Mantel-Haenszel (CMH) test adjusted for strata (Baseline corticosteroid use (yes or no), Baseline Adapted Mayo score (≤ 7 or > 7), bio-IR status (bio-IR or non-bio-IR)) for the comparison of two treatment groups. |
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End point title |
Percentage of Participants Achieving Clinical Response per Partial Adapted Mayo Score at Week 2 | ||||||||||||
End point description |
The Partial Adapted 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 Adapted Mayo score ranges from 0 to 6 with higher scores representing more severe disease.
Clinical response per Partial Adapted Mayo Score is defined as a decrease in Partial Adapted Mayo score ≥ 1 point and ≥ 30% from Baseline, plus a decrease in RBS ≥ 1 or an absolute RBS ≤ 1.
The analysis was conducted in the ITT1 population; non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 was used.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 2
|
||||||||||||
|
|||||||||||||
Notes [17] - ITT1 population [18] - ITT1 population |
|||||||||||||
Statistical analysis title |
Analysis of Clinical Response at Week 2 | ||||||||||||
Comparison groups |
Upadacitinib 45 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
515
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [19] | ||||||||||||
P-value |
< 0.001 [20] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Adjusted Response Rate Difference | ||||||||||||
Point estimate |
37
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
28.8 | ||||||||||||
upper limit |
45.1 | ||||||||||||
Notes [19] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided). [20] - Cochran-Mantel-Haenszel (CMH) test adjusted for strata (Baseline corticosteroid use (yes or no), Baseline Adapted Mayo score (≤ 7 or > 7), bio-IR status (bio-IR or non-bio-IR)) for the comparison of two treatment groups. |
|
|||||||||||||
End point title |
Percentage of Participants Who Achieved Histologic-Endoscopic Mucosal Improvement at Week 8 | ||||||||||||
End point description |
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.
The analysis was conducted in the ITT1 population; non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 was used.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 8
|
||||||||||||
|
|||||||||||||
Notes [21] - ITT1 population [22] - ITT1 population |
|||||||||||||
Statistical analysis title |
Analysis of Histologic-Endoscopic Improvement | ||||||||||||
Comparison groups |
Upadacitinib 45 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
515
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [23] | ||||||||||||
P-value |
< 0.001 [24] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Adjusted Response Rate Difference | ||||||||||||
Point estimate |
30.1
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
24.1 | ||||||||||||
upper limit |
36.2 | ||||||||||||
Notes [23] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided). [24] - Cochran-Mantel-Haenszel test adjusted for strata (Baseline corticosteroid use (yes or no), Baseline Adapted Mayo score (≤ 7 or > 7), bio-IR status (bio-IR or non-bio-IR)) for the comparison of two treatment groups. |
|
|||||||||||||
End point title |
Percentage of Participants who Reported No Bowel Urgency at Week 8 | ||||||||||||
End point description |
Bowel urgency was assessed by participants in a subject diary completed once a day.
The analysis was conducted in the ITT1 population; non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 was used.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 8
|
||||||||||||
|
|||||||||||||
Notes [25] - ITT1 population [26] - ITT1 population |
|||||||||||||
Statistical analysis title |
Analysis of Bowel Urgency | ||||||||||||
Comparison groups |
Upadacitinib 45 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
515
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [27] | ||||||||||||
P-value |
< 0.001 [28] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Adjusted Response Rate Difference | ||||||||||||
Point estimate |
27.1
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
19 | ||||||||||||
upper limit |
35.3 | ||||||||||||
Notes [27] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided). [28] - Cochran-Mantel-Haenszel (CMH) test adjusted for strata (Baseline corticosteroid use (yes or no), Baseline Adapted Mayo score (<= 7 or > 7), bio-IR status (bio-IR or non-bio-IR)) for the comparison of two treatment groups. |
|
|||||||||||||
End point title |
Percentage of Participants who Reported No Abdominal Pain at Week 8 | ||||||||||||
End point description |
Abdominal pain was assessed by participants in a subject diary completed once a day. The analysis was conducted in the ITT1 population; non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 was used.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 8
|
||||||||||||
|
|||||||||||||
Notes [29] - ITT1 population [30] - ITT1 population |
|||||||||||||
Statistical analysis title |
Analysis of Abdominal Pain | ||||||||||||
Comparison groups |
Upadacitinib 45 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
515
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [31] | ||||||||||||
P-value |
< 0.001 [32] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Adjusted Response Rate Difference | ||||||||||||
Point estimate |
29.1
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
20.9 | ||||||||||||
upper limit |
37.4 | ||||||||||||
Notes [31] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided). [32] - Cochran-Mantel-Haenszel (CMH) test adjusted for strata (Baseline corticosteroid use (yes or no), Baseline Adapted Mayo score (≤ 7 or > 7), bio-IR status (bio-IR or non-bio-IR)) for the comparison of two treatment groups. |
|
|||||||||||||
End point title |
Percentage of Participants Who Achieved Histologic Improvement at Week 8 | ||||||||||||
End point description |
Histologic improvement is defined as a decrease from Baseline in Geboes score.
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.
The analysis was conducted in the ITT1 population; non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 was used.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 8
|
||||||||||||
|
|||||||||||||
Notes [33] - ITT1 population [34] - ITT1 population |
|||||||||||||
Statistical analysis title |
Analysis of Histologic Improvement | ||||||||||||
Comparison groups |
Upadacitinib 45 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
515
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [35] | ||||||||||||
P-value |
< 0.001 [36] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Adjusted Response Rate Difference | ||||||||||||
Point estimate |
37.9
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
29.8 | ||||||||||||
upper limit |
46.1 | ||||||||||||
Notes [35] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided). [36] - Cochran-Mantel-Haenszel (CMH) test adjusted for strata (Baseline corticosteroid use (yes or no), Baseline Adapted Mayo score (≤ 7 or > 7), bio-IR status (bio-IR or non-bio-IR)) for the comparison of two treatment groups. |
|
|||||||||||||
End point title |
Change from Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Week 8 | ||||||||||||
End point description |
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.
The analysis was conducted in the 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.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and Week 8
|
||||||||||||
|
|||||||||||||
Notes [37] - ITT1 population with available data [38] - ITT1 population with available data |
|||||||||||||
Statistical analysis title |
Analysis of Change in IBDQ Total Score | ||||||||||||
Comparison groups |
Upadacitinib 45 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
471
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [39] | ||||||||||||
P-value |
< 0.001 [40] | ||||||||||||
Method |
Mixed-effect model repeated measurement | ||||||||||||
Parameter type |
Least Squares (LS) Mean Difference | ||||||||||||
Point estimate |
31.2
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
24.98 | ||||||||||||
upper limit |
37.36 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
3.15
|
||||||||||||
Notes [39] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided). [40] - Mixed-Effect Model Repeat Measurement with Baseline, treatment, visit, treatment by visit interaction, and strata (Baseline corticosteroid use, Baseline Adapted Mayo score, bio-IR status) in the model. |
|
|||||||||||||
End point title |
Percentage of Participants Who Achieved Mucosal Healing at Week 8 | ||||||||||||
End point description |
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.
The analysis was conducted in the ITT1 population; non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 was used.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 8
|
||||||||||||
|
|||||||||||||
Notes [41] - ITT1 population [42] - ITT1 population |
|||||||||||||
Statistical analysis title |
Analysis of Mucosal Healing | ||||||||||||
Comparison groups |
Upadacitinib 45 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
515
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [43] | ||||||||||||
P-value |
< 0.001 [44] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Adjusted Response Rate Difference | ||||||||||||
Point estimate |
11.3
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
7.2 | ||||||||||||
upper limit |
15.3 | ||||||||||||
Notes [43] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided). [44] - Cochran-Mantel-Haenszel (CMH) test adjusted for strata (Baseline corticosteroid use (yes or no), Baseline Adapted Mayo score (≤ 7 or > 7), bio-IR status (bio-IR or non-bio-IR)) for the comparison of two treatment groups. |
|
|||||||||||||
End point title |
Change from Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Week 8 | ||||||||||||
End point description |
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.
The analysis was conducted in the 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.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and Week 8
|
||||||||||||
|
|||||||||||||
Notes [45] - ITT1 population with available data [46] - ITT1 population with available data |
|||||||||||||
Statistical analysis title |
Analysis of Change in FACIT-F | ||||||||||||
Comparison groups |
Placebo v Upadacitinib 45 mg
|
||||||||||||
Number of subjects included in analysis |
467
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [47] | ||||||||||||
P-value |
< 0.001 [48] | ||||||||||||
Method |
Mixed-effect model repeated measurement | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
6
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
4.19 | ||||||||||||
upper limit |
7.73 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.9
|
||||||||||||
Notes [47] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided). [48] - Mixed-Effect Model Repeat Measurement with Baseline, treatment, visit, treatment by visit interaction, and strata (Baseline corticosteroid use, Baseline Adapted Mayo score, bio-IR status) in the model. |
|
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Adverse events information
|
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Timeframe for reporting adverse events |
Part 1: From first dose of study drug up to 30 days after the last dose or until first dose of study drug in Part 2 or first dose of study drug in M14-234 (maintenance study) or M14-533 (long term extension).
|
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Adverse event reporting additional description |
Time Frame for Part 2: From the first dose of study drug in Part 2 up to 30 days after last dose or until first dose of study drug in M14-234 (maintenance study) or the first dose date of study drug in M14-533 (long-term extension study).
|
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23.0
|
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Reporting groups
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Part 1: Upadacitinib 45 mg
|
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Reporting group description |
Participants received 45 mg upadacitinib once daily (QD) for 8 weeks. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Part 1: Placebo
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Reporting group description |
Participants received placebo matching to upadacitinib once daily for 8 weeks. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Part 2: Upadacitinib 45 mg / Upadacitinib 45 mg
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Reporting group description |
Participants initially assigned to upadacitinib who did not achieve clinical response per Adapted Mayo score at Week 8 in Part 1 received upadacitinib 45 mg once daily for 8 additional weeks in the open-label extension period. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Part 2: Placebo / Upadacitinib 45 mg
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Reporting group description |
Participants initially assigned to placebo who did not achieve clinical response per Adapted Mayo score at Week 8 in Part 1 received upadacitinib 45 mg once daily for 8 weeks in the open-label extension period. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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12 Sep 2018 |
Global amendment 1:
● Clarified the study objective to outline both the primary and secondary endpoints.
● Enhanced various sections of the protocol to clarify expectations and create better understanding of the content.
● Enhanced the description of the DMC review, the contacts list and signatories were updated to reflect changes in study team administration. |
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24 Apr 2019 |
Global amendment 2:
● Updating the study objective to include the secondary objectives.
● Updating the benefit risk language, modifying exclusion criterion #14 to allow for undetectable biologic levels to be measured via a commercially available assay as an alternative to the washout period, based on regulatory feedback.
● Adding the country-specific requirements in the inclusion/exclusion criteria (included 16 and 17-year-old subjects, where locally permitted).
● Adding, amending, and clarifying the study procedures.
● Adding justification for the use of placebo and further elaborating on the details of the DMC. |
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29 Apr 2020 |
Global amendment 3:
● Updated wording about re-testing of exclusionary laboratory values during the screening period.
● Clarified intervals for testing biologic drug levels.
● Updated the criteria of clinical response for entering extended treatment period for subjects with missing Week 8 endoscopy when endoscopies cannot be performed due to the COVID-19 pandemic.
● Moved non-ranked secondary efficacy variables to additional efficacy variables.
● Added criteria for failure of ustekinumab treatment, added wording to define borderline serum pregnancy test results, clarified that live vaccines should not be administered for at least 30 days prior to or after study drug administration.
● Excluded subjects with a history of gastrointestinal perforation (perforation due to mechanical injury should not exclude a subject from participation).
● Prohibited cytapheresis treatment for 60 days prior to screening.
● Excluded subjects with prior history of thrombotic events including deep vein thrombosis and pulmonary embolism or known inherited conditions that predispose to hypercoagulability.
● Added wording about gastric banding/segmentation to make clear that it is not an exclusion.
● Added wording to the washout requirements for all biologic therapies.
● Removed wording about women classified as non-childbearing potential.
● Updated ECG review requirements.
● Updated the type of QuantiFERON TB test used.
● Updated toxicity management for aspartate aminotransferase (AST) and alanine aminotransferase (ALT), thrombosis events, and herpes zoster |
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31 Jul 2020 |
Global amendment 4:
Updated information on the re-evaluation of the benefit and risk to subjects participating in the study, updated wording to allow for changes in visits and procedures affected by the COVID-19 pandemic and associated changes in global/local regulations. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |