Clinical Trial Results:
A Phase 3b/4 Randomized, Open-label, Efficacy Assessor Blinded Study, Comparing the Safety and Assessor Blinded Efficacy of Upadacitinib to Dupilumab in Subjects With Moderate to Severe Atopic Dermatitis (Level-Up)
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Summary
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EudraCT number |
2022-002482-15 |
Trial protocol |
ES HU SK SE FR PL IT PT DK NL GR BE BG HR |
Global end of trial date |
08 Aug 2024
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Results information
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Results version number |
v1(current) |
This version publication date |
09 Feb 2025
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First version publication date |
09 Feb 2025
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Other versions |
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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 |
M23-696
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT05601882 | ||
WHO universal trial number (UTN) |
- | ||
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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, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.com
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Scientific contact |
Global Medical Services, AbbVie, 001 8006339110, 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 |
08 Aug 2024
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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 |
08 Aug 2024
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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 |
Atopic dermatitis (AD) is a skin condition that may cause a rash and itching due to inflammation of the skin. This study compares upadacitinib to dupilumab in adolescent and adult subjects with moderate to severe AD and inadequate response to systemic therapies. Adverse events and change in disease activity will be assessed.
The study is comprised of a 35-day Screening Period, a 16-week treatment Period 1 and a 16-week treatment Period 2. Subjects are randomly assigned to receive upadacitinib Dose A or dupilumab in Period 1. There is a 30-day or 12-week follow-up visit for those on upadacitinib or dupilumab respectively, who won’t enter Period 2. In Period 2, subjects will receive upadacitinib Dose A or Dose B for 16 weeks, followed by a 30-day follow-up visit. Approximately 880 adolescent and adult subjects ages 12 to 64 with moderate to severe AD who are candidates for systemic therapy will be enrolled at up to 330 sites worldwide.
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Protection of trial subjects |
Adult subjects ≥18 years of age at Screening Visit or their legally authorized representative must voluntarily sign and date an informed consent, approved by an independent ethics committee (IEC)/institutional review board (IRB), prior to the initiation of any screening or study-specific procedures and comply with the requirements of this study protocol.
For subjects ≥12 and < 18 years of age at Screening Visit: Parent or legal guardian, as required, has voluntarily signed and dated an informed consent form, approved by an IEC, after the nature of the study has been explained and the subject's parent or legal guardian has had the opportunity to ask questions. Subjects will be included in all discussions in order to obtain verbal/and or written assent. Parent/legal guardian and subject must comply with the requirements of this study protocol. If a subject becomes of legal age during the course of the study, that subject will need to be consented using the approved informed consent form.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
28 Nov 2022
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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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 |
Australia: 22
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Country: Number of subjects enrolled |
Belgium: 1
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Country: Number of subjects enrolled |
Bulgaria: 34
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Country: Number of subjects enrolled |
Canada: 67
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Country: Number of subjects enrolled |
China: 66
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Country: Number of subjects enrolled |
Croatia: 34
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Country: Number of subjects enrolled |
Denmark: 7
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Country: Number of subjects enrolled |
France: 4
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Country: Number of subjects enrolled |
Germany: 86
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Country: Number of subjects enrolled |
Greece: 1
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Country: Number of subjects enrolled |
Hungary: 51
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Country: Number of subjects enrolled |
Israel: 1
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Country: Number of subjects enrolled |
Italy: 23
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Country: Number of subjects enrolled |
Japan: 27
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Country: Number of subjects enrolled |
Korea, Republic of: 58
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Country: Number of subjects enrolled |
Mexico: 14
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Country: Number of subjects enrolled |
Netherlands: 4
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Country: Number of subjects enrolled |
Poland: 111
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Country: Number of subjects enrolled |
Portugal: 57
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Country: Number of subjects enrolled |
Puerto Rico: 15
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Country: Number of subjects enrolled |
Romania: 4
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Country: Number of subjects enrolled |
Slovakia: 16
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Country: Number of subjects enrolled |
South Africa: 23
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Country: Number of subjects enrolled |
Spain: 30
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Country: Number of subjects enrolled |
Sweden: 2
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Country: Number of subjects enrolled |
Switzerland: 3
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Country: Number of subjects enrolled |
Taiwan: 40
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Country: Number of subjects enrolled |
Türkiye: 8
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Country: Number of subjects enrolled |
United States: 111
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Worldwide total number of subjects |
920
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EEA total number of subjects |
465
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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) |
117
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Adults (18-64 years) |
803
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
- | |||||||||||||||||||||
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Pre-assignment
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Screening details |
Eligible subjects were randomized in a 1:1 ratio to receive either upadacitinib (Upa) 15 mg QD or dupilumab (Dup) in Period 1. At Week 16, those with a < EASI 75 response entered Period 2; those from the Dup arm were offered the option to receive Upa 15 mg QD while those from the Upa arm either continued or escalated to Upa 30 mg QD until Week 32. | |||||||||||||||||||||
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Period 1
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Period 1 title |
Period 1 (Baseline – Week 16)
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Is this the baseline period? |
Yes | |||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Dupilumab (Period 1) | |||||||||||||||||||||
Arm description |
Adult participants received a loading dose of 600 mg dupilumab by subcutaneous (SC) injection at the Baseline visit followed by 300 mg dupilumab SC every other week (EOW) until Week 16. Adolescents (12 to 17 years of age and weighing at least 40 kg) received treatment according to their body weight. Participants weighing 40 to < 60 kg received a loading dose of 400 mg dupilumab SC at the Baseline visit followed by 200 mg SC EOW until Week 16. Those weighing 60 kg or more received a loading dose of 600 mg dupilumab SC at the Baseline visit followed by 300 mg dupilumab SC EOW until Week 16. | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Dupilumab
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Investigational medicinal product code |
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Other name |
Dupixent®
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Pharmaceutical forms |
Solution for injection in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Dupilumab is administered as a subcutaneous (SC) injection.
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Arm title
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Upadacitinib (Period 1) | |||||||||||||||||||||
Arm description |
Participants received 15 mg upadacitinib orally once a day (QD) up to Week 16. Starting at Week 4, participants had their dose increased to 30 mg QD if they had a < 50% reduction from Baseline in Eczema Area and Severity Index (EASI 50) response or a < 4-point improvement from Baseline in Worst Pruritus Numerical Rating Scale (WP-NRS; weekly average). Starting at Week 8, participants had their dose increased to 30 mg QD if they had a < EASI 75 response. | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Upadacitinib
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Investigational medicinal product code |
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Other name |
ABT-494, 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 |
Extended-release tablet
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Period 2
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Period 2 title |
Period 2 (Week 16 - Week 32)
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Is this the baseline period? |
No | |||||||||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Dupilumab -> Upadacitinib (Period 2) | |||||||||||||||||||||
Arm description |
At Week 16, participants receiving dupilumab as per its label in Period 1 were reassigned based on their Eczema Area and Severity Index (EASI) response. Those with < EASI 75 were offered the option to receive oral doses of upadacitinib 15 mg QD in Period 2 up to Week 32. Those with ≥ EASI 75 completed the end of study procedures. Starting at Week 20, participants with < EASI 75 or a < 4-point improvement from Baseline in Worst Pruritus Numerical Rating Scale (WP-NRS; weekly average) had their dose increased to 30 mg QD up to Week 32. | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Upadacitinib
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Investigational medicinal product code |
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Other name |
ABT-494, 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 |
Extended-release tablet
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Arm title
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Upadacitinib -> Upadacitinib 30 mg (Period 2) | |||||||||||||||||||||
Arm description |
At Week 16, participants receiving upadacitinib in Period 1 were reassigned based on their Eczema Area and Severity Index (EASI) response. Those with < EASI 75 were allocated or continued to receive upadacitinib 30 mg QD in Period 2. Those with ≥ EASI 75 completed the end of study procedures. | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Upadacitinib
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Investigational medicinal product code |
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Other name |
ABT-494, 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 |
Extended-release tablet
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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: At Week 16, subjects from both treatment arms in Period 1 with a < EASI 75 response entered Period 2; subjects from the dupilumab arm were offered the option to receive upadacitinib 15 mg QD while subjects from the upadacitinib arm either continued (if already receiving 30 mg) or escalated to upadacitinib 30 mg QD (if receiving 15 mg QD) until Week 32. Those with ≥ EASI 75 completed the end of study procedures. |
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Baseline characteristics reporting groups
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Reporting group title |
Dupilumab (Period 1)
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Reporting group description |
Adult participants received a loading dose of 600 mg dupilumab by subcutaneous (SC) injection at the Baseline visit followed by 300 mg dupilumab SC every other week (EOW) until Week 16. Adolescents (12 to 17 years of age and weighing at least 40 kg) received treatment according to their body weight. Participants weighing 40 to < 60 kg received a loading dose of 400 mg dupilumab SC at the Baseline visit followed by 200 mg SC EOW until Week 16. Those weighing 60 kg or more received a loading dose of 600 mg dupilumab SC at the Baseline visit followed by 300 mg dupilumab SC EOW until Week 16. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Upadacitinib (Period 1)
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Reporting group description |
Participants received 15 mg upadacitinib orally once a day (QD) up to Week 16. Starting at Week 4, participants had their dose increased to 30 mg QD if they had a < 50% reduction from Baseline in Eczema Area and Severity Index (EASI 50) response or a < 4-point improvement from Baseline in Worst Pruritus Numerical Rating Scale (WP-NRS; weekly average). Starting at Week 8, participants had their dose increased to 30 mg QD if they had a < EASI 75 response. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Dupilumab (Period 1)
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Reporting group description |
Adult participants received a loading dose of 600 mg dupilumab by subcutaneous (SC) injection at the Baseline visit followed by 300 mg dupilumab SC every other week (EOW) until Week 16. Adolescents (12 to 17 years of age and weighing at least 40 kg) received treatment according to their body weight. Participants weighing 40 to < 60 kg received a loading dose of 400 mg dupilumab SC at the Baseline visit followed by 200 mg SC EOW until Week 16. Those weighing 60 kg or more received a loading dose of 600 mg dupilumab SC at the Baseline visit followed by 300 mg dupilumab SC EOW until Week 16. | ||
Reporting group title |
Upadacitinib (Period 1)
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Reporting group description |
Participants received 15 mg upadacitinib orally once a day (QD) up to Week 16. Starting at Week 4, participants had their dose increased to 30 mg QD if they had a < 50% reduction from Baseline in Eczema Area and Severity Index (EASI 50) response or a < 4-point improvement from Baseline in Worst Pruritus Numerical Rating Scale (WP-NRS; weekly average). Starting at Week 8, participants had their dose increased to 30 mg QD if they had a < EASI 75 response. | ||
Reporting group title |
Dupilumab -> Upadacitinib (Period 2)
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Reporting group description |
At Week 16, participants receiving dupilumab as per its label in Period 1 were reassigned based on their Eczema Area and Severity Index (EASI) response. Those with < EASI 75 were offered the option to receive oral doses of upadacitinib 15 mg QD in Period 2 up to Week 32. Those with ≥ EASI 75 completed the end of study procedures. Starting at Week 20, participants with < EASI 75 or a < 4-point improvement from Baseline in Worst Pruritus Numerical Rating Scale (WP-NRS; weekly average) had their dose increased to 30 mg QD up to Week 32. | ||
Reporting group title |
Upadacitinib -> Upadacitinib 30 mg (Period 2)
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Reporting group description |
At Week 16, participants receiving upadacitinib in Period 1 were reassigned based on their Eczema Area and Severity Index (EASI) response. Those with < EASI 75 were allocated or continued to receive upadacitinib 30 mg QD in Period 2. Those with ≥ EASI 75 completed the end of study procedures. | ||
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End point title |
Percentage of Participants Achieving a ≥ 90% Reduction From Baseline in Eczema Area and Severity Index Score (EASI 90) and Worst Pruritus Numerical Rating Scale of 0 or 1 (WP-NRS 0/1) at Week 16 | ||||||||||||
End point description |
The EASI is a composite index with scores ranging from 0 to 72. Four AD disease characteristics are assessed for severity on a scale of "0" (absent) through "3" (severe), and area of AD involvement is assessed as a percentage by body area of head, trunk, upper extremities, and lower extremities and converted to a score of 0 to 6. In each body region, the area is expressed as 0, 1 (1% to 9%), 2 (10% to 29%), 3 (30% to 49%), 4 (50% to 69%), 5 (70% to 89%), or 6 (90% to 100%).
The Worst Pruritus NRS was used to report intensity of pruritus during a 24- hour recall period using an electronic hand-held device. Subjects rated itch (pruritus) intensity at its worst on an 11-point scale from 0 (no itch) to 10 (worst imaginable itch).
Analysis population: subjects randomized at Baseline; non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or any other missing data that can be reasonably assumed to be Missing at Random (NRI-MI) was used.
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End point type |
Primary
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End point timeframe |
Baseline and Week 16
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Statistical analysis title |
Upadacitinib (Per. 1) vs Dupilumab (Per. 1) | ||||||||||||
Statistical analysis description |
Analyzed using Cochran-Mantel-Haenszel (CMH) test stratified by Validated Investigator's Global Assessment for Atopic Dermatitis categories [(vIGA-AD (moderate [3] versus severe [4])] and age (12 to < 18; 18 to < 40; ≥40 to < 64 years)
Response rate difference = Upadacitinib (Period 1) - Dupilumab (Period 1)
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Comparison groups |
Dupilumab (Period 1) v Upadacitinib (Period 1)
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Number of subjects included in analysis |
920
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Adjusted Response Rate Difference | ||||||||||||
Point estimate |
11
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
6.6 | ||||||||||||
upper limit |
15.5 | ||||||||||||
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End point title |
Percentage of Participants Achieving a ≥ 90% Reduction From Baseline in Eczema Area and Severity Index Score (EASI 90) at Week 16 | ||||||||||||
End point description |
The EASI is a composite index with scores ranging from 0 to 72. Four AD disease characteristics (erythema, thickness [induration, papulation, edema], scratching [excoriation], and lichenification) assessed for severity on a scale of "0" (absent) through "3" (severe). In addition, the area of AD involvement is assessed as a percentage by body area of head, trunk (including the genital area), upper extremities, and lower extremities (including the buttocks), and converted to a score of 0 to 6. In each body region, the area is expressed as 0, 1 (1% to 9%), 2 (10% to 29%), 3 (30% to 49%), 4 (50% to 69%), 5 (70% to 89%), or 6 (90% to 100%).
Analysis population: subjects randomized at Baseline; non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or any other missing data that can be reasonably assumed to be Missing at Random (NRI-MI) was used.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 16
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Statistical analysis title |
Upadacitinib (Per. 1) vs Dupilumab (Per. 1) | ||||||||||||
Statistical analysis description |
Analyzed using Cochran-Mantel-Haenszel (CMH) test stratified by Validated Investigator's Global Assessment for Atopic Dermatitis categories [(vIGA-AD (moderate [3] versus severe [4])] and age (12 to < 18; 18 to < 40; ≥40 to < 64 years)
Response rate difference = Upadacitinib (Period 1) - Dupilumab (Period 1)
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Comparison groups |
Dupilumab (Period 1) v Upadacitinib (Period 1)
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Number of subjects included in analysis |
920
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Adjusted Response Rate Difference | ||||||||||||
Point estimate |
18.4
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
12.5 | ||||||||||||
upper limit |
24.2 | ||||||||||||
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End point title |
Percentage of Participants Achieving a Worst Pruritus Numerical Rating Scale of 0 or 1 (WP-NRS 0/1) at Week 16 Among Participants With Baseline WP-NRS > 1 | ||||||||||||
End point description |
The Worst Pruritus NRS is an assessment tool that participants used to report the intensity of their pruritus during a 24- hour recall period using an electronic hand-held device. Participants rated itch (pruritus) intensity at its worst during the past 24 hours on an 11-point scale from 0 (no itch) to 10 (worst imaginable itch).
Analysis population: subjects randomized at Baseline; non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or any other missing data that can be reasonably assumed to be Missing at Random (NRI-MI) was used.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 16
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Statistical analysis title |
Upadacitinib (Per. 1) vs Dupilumab (Per. 1) | ||||||||||||
Statistical analysis description |
Analyzed using Cochran-Mantel-Haenszel (CMH) test stratified by Validated Investigator's Global Assessment for Atopic Dermatitis categories [(vIGA-AD (moderate [3] versus severe [4])] and age (12 to < 18; 18 to < 40; ≥40 to < 64 years)
Response rate difference = Upadacitinib (Period 1) - Dupilumab (Period 1)
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Comparison groups |
Dupilumab (Period 1) v Upadacitinib (Period 1)
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Number of subjects included in analysis |
913
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Adjusted Response Rate Difference | ||||||||||||
Point estimate |
14.7
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
9.4 | ||||||||||||
upper limit |
20 | ||||||||||||
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End point title |
Percentage of Participants Achieving an Improvement (Reduction) in Worst Pruritus Numerical Rating Scale (WP-NRS) ≥4 at Week 16 Among Those With Baseline WP-NRS ≥4 | ||||||||||||
End point description |
The Worst Pruritus NRS is an assessment tool that participants used to report the intensity of their pruritus during a 24- hour recall period using an electronic hand-held device. Participants rated itch (pruritus) intensity at its worst during the past 24 hours on an 11-point scale from 0 (no itch) to 10 (worst imaginable itch).
Analysis population: subjects randomized at Baseline; non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or any other missing data that can be reasonably assumed to be Missing at Random (NRI-MI) was used.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and Week 16
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Upadacitinib (Per. 1) vs Dupilumab (Per. 1) | ||||||||||||
Statistical analysis description |
Analyzed using Cochran-Mantel-Haenszel (CMH) test stratified by Validated Investigator's Global Assessment for Atopic Dermatitis categories [(vIGA-AD (moderate [3] versus severe [4])] and age (12 to < 18; 18 to < 40; ≥40 to < 64 years)
Response rate difference = Upadacitinib (Period 1) - Dupilumab (Period 1)
|
||||||||||||
Comparison groups |
Dupilumab (Period 1) v Upadacitinib (Period 1)
|
||||||||||||
Number of subjects included in analysis |
905
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Adjusted Response Rate Difference | ||||||||||||
Point estimate |
16.6
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
10.2 | ||||||||||||
upper limit |
23 | ||||||||||||
|
|||||||||||||
End point title |
Percentage of Participants Achieving a Worst Pruritus Numerical Rating Scale of 0 or 1 (WP-NRS 0/1) at Week 4 Among Participants With Baseline WP-NRS > 1 | ||||||||||||
End point description |
The Worst Pruritus NRS is an assessment tool that participants used to report the intensity of their pruritus during a 24-hour recall period using an electronic hand-held device. Participants rated itch (pruritus) intensity at its worst during the past 24 hours on an 11-point scale from 0 (no itch) to 10 (worst imaginable itch).
Analysis population: subjects randomized at Baseline; non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or any other missing data that can be reasonably assumed to be Missing at Random (NRI-MI) was used.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and Week 4
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Upadacitinib (Per. 1) vs Dupilumab (Per. 1) | ||||||||||||
Statistical analysis description |
Analyzed using Cochran-Mantel-Haenszel (CMH) test stratified by Validated Investigator's Global Assessment for Atopic Dermatitis categories [(vIGA-AD (moderate [3] versus severe [4])] and age (12 to < 18; 18 to < 40; ≥40 to < 64 years)
Response rate difference = Upadacitinib (Period 1) - Dupilumab (Period 1)
|
||||||||||||
Comparison groups |
Dupilumab (Period 1) v Upadacitinib (Period 1)
|
||||||||||||
Number of subjects included in analysis |
913
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Adjusted Response Rate Difference | ||||||||||||
Point estimate |
13.2
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
9.6 | ||||||||||||
upper limit |
16.9 | ||||||||||||
|
|||||||||||||
End point title |
Percentage of Participants Achieving a Worst Pruritus Numerical Rating Scale of 0 or 1 (WP-NRS 0/1) at Week 2 among Participants with Baseline WP-NRS > 1 | ||||||||||||
End point description |
The Worst Pruritus NRS is an assessment tool that participants used to report the intensity of their pruritus during a 24-hour recall period using an electronic hand-held device. Participants rated itch (pruritus) intensity at its worst during the past 24 hours on an 11-point scale from 0 (no itch) to 10 (worst imaginable itch).
Analysis population: subjects randomized at Baseline; non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or any other missing data that can be reasonably assumed to be Missing at Random (NRI-MI) was used.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and Week 2
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Upadacitinib (Per. 1) vs Dupilumab (Per. 1) | ||||||||||||
Statistical analysis description |
Analyzed using Cochran-Mantel-Haenszel (CMH) test stratified by Validated Investigator's Global Assessment for Atopic Dermatitis categories [(vIGA-AD (moderate [3] versus severe [4])] and age (12 to < 18; 18 to < 40; ≥40 to < 64 years)
Response rate difference = Upadacitinib (Period 1) - Dupilumab (Period 1)
|
||||||||||||
Comparison groups |
Dupilumab (Period 1) v Upadacitinib (Period 1)
|
||||||||||||
Number of subjects included in analysis |
913
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Adjusted Response Rate Difference | ||||||||||||
Point estimate |
6.4
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
3.8 | ||||||||||||
upper limit |
9.1 | ||||||||||||
|
|||||||||||||
End point title |
Percentage of Participants Achieving a ≥ 90% Reduction From Baseline in Eczema Area and Severity Index Score (EASI 90) at Week 4 | ||||||||||||
End point description |
The EASI is a composite index with scores ranging from 0 to 72. Four AD disease characteristics (erythema, thickness [induration, papulation, edema], scratching [excoriation], and lichenification) assessed for severity on a scale of "0" (absent) through "3" (severe). In addition, the area of AD involvement is assessed as a percentage by body area of head, trunk (including the genital area), upper extremities, and lower extremities (including the buttocks), and converted to a score of 0 to 6. In each body region, the area is expressed as 0, 1 (1% to 9%), 2 (10% to 29%), 3 (30% to 49%), 4 (50% to 69%), 5 (70% to 89%), or 6 (90% to 100%).
Analysis population: subjects randomized at Baseline; non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or any other missing data that can be reasonably assumed to be Missing at Random (NRI-MI) was used.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and Week 4
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Upadacitinib (Per. 1) vs Dupilumab (Per. 1) | ||||||||||||
Statistical analysis description |
Analyzed using Cochran-Mantel-Haenszel (CMH) test stratified by Validated Investigator's Global Assessment for Atopic Dermatitis categories [(vIGA-AD (moderate [3] versus severe [4])] and age (12 to < 18; 18 to < 40; ≥40 to < 64 years)
Response rate difference = Upadacitinib (Period 1) - Dupilumab (Period 1)
|
||||||||||||
Comparison groups |
Dupilumab (Period 1) v Upadacitinib (Period 1)
|
||||||||||||
Number of subjects included in analysis |
920
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Adjusted Response Rate Difference | ||||||||||||
Point estimate |
14.1
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
9.4 | ||||||||||||
upper limit |
18.8 | ||||||||||||
|
|||||||||||||
End point title |
Percentage of Participants Achieving a ≥ 75% Reduction From Baseline in Eczema Area and Severity Index Score (EASI 75) at Week 2 | ||||||||||||
End point description |
The EASI is a composite index with scores ranging from 0 to 72. Four AD disease characteristics (erythema, thickness [induration, papulation, edema], scratching [excoriation], and lichenification) assessed for severity on a scale of "0" (absent) through "3" (severe). In addition, the area of AD involvement is assessed as a percentage by body area of head, trunk (including the genital area), upper extremities, and lower extremities (including the buttocks), and converted to a score of 0 to 6. In each body region, the area is expressed as 0, 1 (1% to 9%), 2 (10% to 29%), 3 (30% to 49%), 4 (50% to 69%), 5 (70% to 89%), or 6 (90% to 100%).
Analysis population: subjects randomized at Baseline; non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or any other missing data that can be reasonably assumed to be Missing at Random (NRI-MI) was used.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and Week 2
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Upadacitinib (Per. 1) vs Dupilumab (Per. 1) | ||||||||||||
Statistical analysis description |
Analyzed using Cochran-Mantel-Haenszel (CMH) test stratified by Validated Investigator's Global Assessment for Atopic Dermatitis categories [(vIGA-AD (moderate [3] versus severe [4])] and age (12 to < 18; 18 to < 40; ≥40 to < 64 years)
Response rate difference = Upadacitinib (Period 1) - Dupilumab (Period 1)
|
||||||||||||
Comparison groups |
Dupilumab (Period 1) v Upadacitinib (Period 1)
|
||||||||||||
Number of subjects included in analysis |
920
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Adjusted Response Rate Difference | ||||||||||||
Point estimate |
18.6
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
13.9 | ||||||||||||
upper limit |
23.3 | ||||||||||||
|
|||||||||||||
End point title |
Percentage of Participants Achieving a 100% Reduction From Baseline in Eczema Area and Severity Index Score (EASI 100) at Week 16 | ||||||||||||
End point description |
The EASI is a composite index with scores ranging from 0 to 72. Four AD disease characteristics (erythema, thickness [induration, papulation, edema], scratching [excoriation], and lichenification) assessed for severity on a scale of "0" (absent) through "3" (severe). In addition, the area of AD involvement is assessed as a percentage by body area of head, trunk (including the genital area), upper extremities, and lower extremities (including the buttocks), and converted to a score of 0 to 6. In each body region, the area is expressed as 0, 1 (1% to 9%), 2 (10% to 29%), 3 (30% to 49%), 4 (50% to 69%), 5 (70% to 89%), or 6 (90% to 100%).
Analysis population: subjects randomized at Baseline; non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or any other missing data that can be reasonably assumed to be Missing at Random (NRI-MI) was used.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and Week 16
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Upadacitinib (Per. 1) vs Dupilumab (Per. 1) | ||||||||||||
Statistical analysis description |
Analyzed using Cochran-Mantel-Haenszel (CMH) test stratified by Validated Investigator's Global Assessment for Atopic Dermatitis categories [(vIGA-AD (moderate [3] versus severe [4])] and age (12 to < 18; 18 to < 40; ≥40 to < 64 years)
Response rate difference = Upadacitinib (Period 1) - Dupilumab (Period 1)
|
||||||||||||
Comparison groups |
Dupilumab (Period 1) v Upadacitinib (Period 1)
|
||||||||||||
Number of subjects included in analysis |
920
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Adjusted Response Rate Difference | ||||||||||||
Point estimate |
9.3
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
5.4 | ||||||||||||
upper limit |
13.1 | ||||||||||||
|
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|
Adverse events information
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
All-cause mortality and adverse events were collected from the time informed consent was signed through the end of the study.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Median time on follow-up was for 113 days for the Dupilumab (Period 1) group; 114 days for the Upadacitinib (Period 1) group; 225 days for the Dupilumab -> Upadacitinib (Period 2) group; and 224 days for the Upadacitinib -> Upadacitinib 30 mg (Period 2) group.
|
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
26.1
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Dupilumab (Period 1)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Adult participants received a loading dose of 600 mg dupilumab by subcutaneous (SC) injection at the Baseline visit followed by 300 mg dupilumab SC every other week (EOW) until Week 16. Adolescents (12 to 17 years of age and weighing at least 40 kg) received treatment according to their body weight. Participants weighing 40 to < 60 kg received a loading dose of 400 mg dupilumab SC at the Baseline visit followed by 200 mg SC EOW until Week 16. Those weighing 60 kg or more received a loading dose of 600 mg dupilumab SC at the Baseline visit followed by 300 mg dupilumab SC EOW until Week 16. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Upadacitinib -> Upadacitinib 30 mg (Period 2)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
At Week 16, participants receiving upadacitinib in Period 1 were reassigned based on their Eczema Area and Severity Index (EASI) response. Those with < EASI 75 were allocated or continued to receive upadacitinib 30 mg QD in Period 2. Those with ≥ EASI 75 completed the end of study procedures. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Dupilumab -> Upadacitinib (Period 2)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
At Week 16, participants receiving dupilumab as per its label in Period 1 were reassigned based on their Eczema Area and Severity Index (EASI) response. Those with < EASI 75 were offered the option to receive oral doses of upadacitinib 15 mg QD in Period 2 up to Week 32. Those with ≥ EASI 75 completed the end of study procedures. Starting at Week 20, participants with < EASI 75 or a < 4-point improvement from Baseline in Worst Pruritus Numerical Rating Scale (WP-NRS; weekly average) had their dose increased to 30 mg QD up to Week 32. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Upadacitinib (Period 1)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Participants received 15 mg upadacitinib orally once a day (QD) up to Week 16. Starting at Week 4, participants had their dose increased to 30 mg QD if they had a < 50% reduction from Baseline in Eczema Area and Severity Index (EASI 50) response or a < 4-point improvement from Baseline in Worst Pruritus Numerical Rating Scale (WP-NRS; weekly average). Starting at Week 8, participants had their dose increased to 30 mg QD if they had a < EASI 75 response. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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02 May 2023 |
Version 2.0/Amendment 1 clarified the following points:
● Estimand definition and the handling rule of the intercurrent events
● Clarified the primary endpoint
● Added additional details for safety assessments, and Tanner Stage assessments included for adolescent subjects required by regulatory agencies
● Included that the permanent discontinuation from the study will be mandatory in any subject who has been treated for at least 8 weeks with upadacitinib 30 mg QD and has not achieved an EASI 50 response from Baseline after rescue with TCS for at least 1 week per FDA request
● Clarified the eligibility criteria language to enroll subjects < 64 to ensure no subject 65 or older is enrolled and for laboratory values specific to pediatric studies
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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 | |||
