A Study to Evaluate Upadacitinib in Combination With Topical Corticosteroids in Adolescent and Adult Participants With Moderate to Severe Atopic Dermatitis (AD Up)

• ClinicalTrials.gov Identifier: NCT03568318
• Recruitment Status: Active, not recruiting
• First Posted: June 26, 2018
• Results First Posted: March 31, 2022
• Last Update Posted: March 31, 2022
• Sponsor: AbbVie
• Information provided by (Responsible Party): AbbVie

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Atopic Dermatitis
• Interventions: Drug: Placebo; Drug: Upadacitinib; Drug: Topical corticosteroids (TCS)
• Enrollment: 968

Participant Flow

Recruitment Details

Participants were enrolled at 171 clinical sites in 22 countries in the Asia-Pacific region, Europe, Middle East, North America, and Oceania. The study included a 16-week double-blind treatment period followed by a blinded extension period (ongoing). The first 810 adults and adolescents enrolled constituted the Main Study; additional adolescents were enrolled in the Adolescent Substudy to ensure enrollment of a total of 180 adolescent participants overall. Results are reported up to Week 16.

Pre-assignment Details

Participants were randomized equally into 1 of 3 treatment groups, stratified by disease severity (validated Investigator Global Assessment Scale for Atopic Dermatitis [vIGA-AD] moderate [3] vs severe [4]), geographic region (US/Puerto Rico/Canada, Japan, China, and Other), and age (adolescent [ages 12 to 17] vs adult [ages 18 to 75]). Randomization for the adolescent substudy was stratified by disease severity (vIGA-AD 3 vs vIGA-AD 4) and geographic region (US/Puerto Rico/Canada vs Other).

Arm/Group Title	Adults: Placebo + Topical Corticosteroids	Adults: Upadacitinib 15 mg + Topical Corticosteroids	Adults: Upadacitinib 30 mg + Topical Corticosteroids	Adolescents: Placebo + Topical Corticosteroids	Adolescents: Upadacitinib 15 mg + Topical Corticosteroids	Adolescents: Upadacitinib 30 mg + Topical Corticosteroids
Arm/Group Description	Participants ≥ 18 years old received placebo orally once a day (QD) and topical corticosteroids (TCS) following a step-down regimen for 16 weeks in the double-blind treatment period.	Participants ≥ 18 years old received upadacitinib 15 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Participants ≥ 18 years old received upadacitinib 30 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Adolescent participants (12 - 17 years old) received placebo orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Adolescent participants received upadacitinib 15 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Adolescent participants received upadacitinib 30 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.
Period Title: Overall Study
Started [1]	264	261	260	63	60	60
Received Study Drug	264	261	260	62	60	60
Completed [2]	244	249	250	59	58	60
Not Completed	20	12	10	4	2	0
Reason Not Completed
Adverse Event	3	1	1	0	1	0
Withdrawal by Subject	6	5	2	1	0	0
Lost to Follow-up	3	2	2	2	1	0
Other	3	1	3	0	0	0
Ongoing at Time of Analysis	5	3	2	1	0	0
[1] Randomized into study; [2] Completed Week 16

Baseline Characteristics

Arm/Group Title		Adults: Placebo + Topical Corticosteroids	Adults: Upadacitinib 15 mg + Topical Corticosteroids	Adults: Upadacitinib 30 mg + Topical Corticosteroids	Adolescents: Placebo + Topical Corticosteroids	Adolescents: Upadacitinib 15 mg + Topical Corticosteroids	Adolescents: Upadacitinib 30 mg + Topical Corticosteroids	Total
Arm/Group Description		Participants ≥ 18 years old received placebo orally once a day (QD) and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Participants ≥ 18 years old received upadacitinib 15 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Participants ≥ 18 years old received upadacitinib 30 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Adolescent participants (12 - 17 years old) received placebo orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Adolescent participants received upadacitinib 15 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Adolescent participants received upadacitinib 30 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Total of all reporting groups
Overall Number of Baseline Participants		264	261	260	63	60	60	968
Baseline Analysis Population Description		All randomized participants
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	264 participants	261 participants	260 participants	63 participants	60 participants	60 participants	968 participants
		37.2 (14.08)	35.0 (13.29)	38.3 (14.82)	15.1 (1.85)	15.4 (1.65)	15.3 (1.86)	32.8 (15.29)
Age, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	264 participants	261 participants	260 participants	63 participants	60 participants	60 participants	968 participants
	12 - 14 years	0 0.0%	0 0.0%	0 0.0%	23 36.5%	14 23.3%	21 35.0%	58 6.0%
	15 - 17 years	0 0.0%	0 0.0%	0 0.0%	40 63.5%	46 76.7%	39 65.0%	125 12.9%
	18 - < 40 years	156 59.1%	176 67.4%	158 60.8%	0 0.0%	0 0.0%	0 0.0%	490 50.6%
	40 - < 65 years	94 35.6%	80 30.7%	85 32.7%	0 0.0%	0 0.0%	0 0.0%	259 26.8%
	≥ 65 years	14 5.3%	5 1.9%	17 6.5%	0 0.0%	0 0.0%	0 0.0%	36 3.7%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	264 participants	261 participants	260 participants	63 participants	60 participants	60 participants	968 participants
	Female	101 38.3%	104 39.8%	95 36.5%	36 57.1%	27 45.0%	25 41.7%	388 40.1%
	Male	163 61.7%	157 60.2%	165 63.5%	27 42.9%	33 55.0%	35 58.3%	580 59.9%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	264 participants	261 participants	260 participants	63 participants	60 participants	60 participants	968 participants
	Hispanic or Latino	15 5.7%	21 8.0%	14 5.4%	7 11.1%	8 13.3%	7 11.7%	72 7.4%
	Not Hispanic or Latino	249 94.3%	240 92.0%	246 94.6%	56 88.9%	52 86.7%	53 88.3%	896 92.6%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	264 participants	261 participants	260 participants	63 participants	60 participants	60 participants	968 participants
	American Indian or Alaska Native	1 0.4%	2 0.8%	3 1.2%	0 0.0%	0 0.0%	0 0.0%	6 0.6%
	Asian	52 19.7%	57 21.8%	58 22.3%	14 22.2%	13 21.7%	6 10.0%	200 20.7%
	Native Hawaiian or Other Pacific Islander	0 0.0%	3 1.1%	1 0.4%	0 0.0%	0 0.0%	0 0.0%	4 0.4%
	Black or African American	15 5.7%	15 5.7%	9 3.5%	5 7.9%	5 8.3%	6 10.0%	55 5.7%
	White	196 74.2%	177 67.8%	188 72.3%	44 69.8%	41 68.3%	46 76.7%	692 71.5%
	More than one race	0 0.0%	7 2.7%	1 0.4%	0 0.0%	1 1.7%	2 3.3%	11 1.1%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Study Enrollment; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	264 participants	261 participants	260 participants	63 participants	60 participants	60 participants	968 participants
	Main Study	264 100.0%	261 100.0%	260 100.0%	40 63.5%	39 65.0%	37 61.7%	901 93.1%
	Adolescent Substudy	0 0.0%	0 0.0%	0 0.0%	23 36.5%	21 35.0%	23 38.3%	67 6.9%
Geographic Region; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	264 participants	261 participants	260 participants	63 participants	60 participants	60 participants	968 participants
	US/Puerto Rico/Canada	90 34.1%	90 34.5%	89 34.2%	31 49.2%	31 51.7%	31 51.7%	362 37.4%
	Japan	18 6.8%	16 6.1%	17 6.5%	0 0.0%	0 0.0%	0 0.0%	51 5.3%
	China	16 6.1%	15 5.7%	15 5.8%	2 3.2%	2 3.3%	1 1.7%	51 5.3%
	Other	140 53.0%	140 53.6%	139 53.5%	30 47.6%	27 45.0%	28 46.7%	504 52.1%
Validated Investigator Global Assessment Scale for Atopic Dermatitis (vIGA-AD) [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	264 participants	261 participants	260 participants	63 participants	60 participants	60 participants	968 participants
	3 (Moderate)	123 46.6%	124 47.5%	123 47.3%	28 44.4%	29 48.3%	29 48.3%	456 47.1%
	4 (Severe)	141 53.4%	137 52.5%	137 52.7%	35 55.6%	31 51.7%	31 51.7%	512 52.9%
		[1] Measure Description: The vIGA-AD was used to assess the severity of atopic dermatitis based on lesion appearance on the following scale: 0-Clear: No inflammatory signs of AD;; 1-Almost clear: Barely perceptible erythema, induration/papulation and/or lichenification;; 2-Mild: Slight but definite erythema, induration/papulation and/or lichenification. No oozing or crusting;; 3-Moderate: Clearly perceptible erythema, induration/papulation and/or lichenification, oozing or crusting may be present;; 4-Severe: Marked erythema, induration/papulation and/or lichenification, oozing or crusting may be present.
Eczema Area and Severity Index (EASI) Score [1]; Mean (Standard Deviation); Unit of measure: Score on a scale
	Number Analyzed	264 participants	261 participants	260 participants	63 participants	60 participants	60 participants	968 participants
		30.06 (12.860)	29.03 (11.925)	29.68 (11.993)	30.25 (12.105)	29.59 (11.683)	28.68 (10.143)	29.58 (12.082)
		[1] Measure Description: EASI is a tool to measure the extent and severity of atopic eczema based on assessments of the head/neck, trunk, upper limbs and lower limbs. For each region the percentage of skin affected, and the severity of eczema (scored as none [0], mild [1], moderate [2], or severe [3]) for redness, thickness, scratching, and lichenification are assessed. The EASI score is the sum of the scores for each region and ranges from 0 to 72, where higher scores represent worse disease.
Disease Duration since Diagnosis [1]; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	264 participants	261 participants	260 participants	62 participants	60 participants	60 participants	967 participants
		25.986 (15.5650)	24.511 (14.0363)	24.617 (16.6107)	12.315 (4.2769)	11.370 (5.0674)	12.244 (3.9262)	22.584 (14.9374)
		[1] Measure Analysis Population Description: Participants with available data

Outcome Measures

1. Primary Outcome

Title	Main Study: Percentage of Participants Achieving at Least a 75% Reduction in Eczema Area and Severity Index Score (EASI 75) From Baseline at Week 16
Description	EASI is a tool used to measure the extent (area) and severity of atopic eczema based on assessments of the head/neck, trunk, upper limbs and lower limbs. For each region the area score is recorded as the percentage of skin affected by eczema. For each region, the severity score is calculated as the sum of the intensity scores (scored as none [0], mild [1], moderate [2], or severe [3]) for redness (erythema, inflammation), thickness (induration, papulation, swelling - acute eczema), scratching (excoriation), and lichenification (lined skin, prurigo nodules - chronic eczema). The total EASI score for each region is calculated by multiplying the severity score by the area score, with adjustment for the proportion of the body region to the whole body. The final EASI score is the sum of the 4 region scores and ranges from 0 to 72 where higher scores represent worse disease.
Time Frame	Baseline and Week 16

Outcome Measure Data

Analysis Population Description

The intent-to-treat population for the main study (ITT_M) includes all participants who were randomized in the main study (adults and adolescents). Non-responder imputation incorporating multiple imputation to handle missing data due to coronavirus disease 2019 pandemic (COVID-19) (NRI-C) was used.

The pre-specified primary analysis included participants enrolled in the main study only; Efficacy analyses of adolescent participants were conducted separately and are reported below.

Arm/Group Title	Placebo + Topical Corticosteroids	Upadacitinib 15 mg + Topical Corticosteroids	Upadacitinib 30 mg + Topical Corticosteroids
Arm/Group Description:	Participants received placebo orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Participants received upadacitinib 15 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Participants received upadacitinib 30 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.
Overall Number of Participants Analyzed	304	300	297
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	26.4; (21.5 to 31.4)	64.6; (59.1 to 70.0)	77.1; (72.3 to 81.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Topical Corticosteroids, Upadacitinib 30 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the coprimary and all key secondary endpoints for upadacitinib 30 mg was controlled at the 0.05 level using a graphical multiple testing procedure following a pre-specified α transfer path which includes downstream transfer along the endpoints sequence within each dose as well as cross-dose transfer.
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for strata (Baseline vIGA-AD categories and age [adolescent vs. adult])
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	50.6
	Confidence Interval	(2-Sided) 95%; 43.8 to 57.4
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + Topical Corticosteroids, Upadacitinib 15 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the coprimary and all key secondary endpoints for upadacitinib 15 mg was controlled at the 0.05 level using a graphical multiple testing procedure following a pre-specified α transfer path which includes downstream transfer along the endpoints sequence within each dose as well as cross-dose transfer.
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for strata (Baseline vIGA-AD categories and age [adolescent vs. adult])
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	38.1
	Confidence Interval	(2-Sided) 95%; 30.8 to 45.4
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

2. Primary Outcome

Title	Main Study: Percentage of Participants Achieving Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) of 0 or 1 With a Reduction From Baseline of ≥ 2 Points at Week 16
Description	The vIGA-AD is a validated assessment instrument to rate the severity of atopic dermatitis globally, based on the following scale: 0 - Clear: No inflammatory signs of AD;; 1 - Almost clear: Barely perceptible erythema, induration/papulation and/or lichenification;; 2 - Mild: Slight but definite erythema, induration/papulation and/or minimal lichenification. No oozing or crusting;; 3 - Moderate: Clearly perceptible erythema, induration/papulation and/or lichenification, oozing or crusting may be present;; 4 - Severe: Marked erythema, induration/papulation and/or lichenification; Oozing or crusting may be present.
Time Frame	Baseline and Week 16

Outcome Measure Data

Analysis Population Description

Intent-to-treat population for the main study; Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) was used.

Arm/Group Title	Placebo + Topical Corticosteroids	Upadacitinib 15 mg + Topical Corticosteroids	Upadacitinib 30 mg + Topical Corticosteroids
Arm/Group Description:	Participants received placebo orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Participants received upadacitinib 15 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Participants received upadacitinib 30 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.
Overall Number of Participants Analyzed	304	300	297
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	10.9; (7.4 to 14.4)	39.6; (34.1 to 45.2)	58.6; (53.0 to 64.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Topical Corticosteroids, Upadacitinib 30 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the coprimary and all key secondary endpoints for upadacitinib 30 mg was controlled at the 0.05 level using a graphical multiple testing procedure following a pre-specified α transfer path which includes downstream transfer along the endpoints sequence within each dose as well as cross-dose transfer.
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for strata (Baseline vIGA-AD categories and age [adolescent vs. adult])
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	47.6
	Confidence Interval	(2-Sided) 95%; 41.1 to 54.0
	Estimation Comments	Response rate difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + Topical Corticosteroids, Upadacitinib 15 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the coprimary and all key secondary endpoints for upadacitinib 15 mg was controlled at the 0.05 level using a graphical multiple testing procedure following a pre-specified α transfer path which includes downstream transfer along the endpoints sequence within each dose as well as cross-dose transfer.
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for strata (Baseline vIGA-AD categories and age [adolescent vs. adult])
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	28.5
	Confidence Interval	(2-Sided) 95%; 22.1 to 34.9
	Estimation Comments	Response rate difference = Upadacitinib - Placebo

3. Secondary Outcome

Title	Main Study: Percentage of Participants Achieving a Reduction of ≥ 4 Points From Baseline in Worst Pruritus Numerical Rating Scale (NRS) at Week 16
Description	Participants were asked to rate itch (pruritus) intensity at its worst during the past 24 hours on a daily basis using an 11-point scale from 0 (no itch) to 10 (worst imaginable itch). Pruritus NRS was analyzed based on weekly rolling averages of daily scores.
Time Frame	Baseline (last available rolling average before the first dose of study drug) and Week 16

Outcome Measure Data

Analysis Population Description

Intent-to-treat population for the main study with Worst Pruritus NRS (weekly average) ≥ 4 at Baseline; Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) was used.

Arm/Group Title	Placebo + Topical Corticosteroids	Upadacitinib 15 mg + Topical Corticosteroids	Upadacitinib 30 mg + Topical Corticosteroids
Arm/Group Description:	Participants received placebo orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Participants received upadacitinib 15 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Participants received upadacitinib 30 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.
Overall Number of Participants Analyzed	294	288	291
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	15.0; (10.9 to 19.0)	51.7; (46.0 to 57.5)	63.9; (58.4 to 69.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Topical Corticosteroids, Upadacitinib 30 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the coprimary and all key secondary endpoints for upadacitinib 30 mg was controlled at the 0.05 level using a graphical multiple testing procedure following a pre-specified α transfer path which includes downstream transfer along the endpoints sequence within each dose as well as cross-dose transfer.
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for strata (Baseline vIGA-AD categories and age [adolescent vs. adult])
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	48.8
	Confidence Interval	(2-Sided) 95%; 41.9 to 55.7
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + Topical Corticosteroids, Upadacitinib 15 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the coprimary and all key secondary endpoints for upadacitinib 15 mg was controlled at the 0.05 level using a graphical multiple testing procedure following a pre-specified α transfer path which includes downstream transfer along the endpoints sequence within each dose as well as cross-dose transfer.
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for strata (Baseline vIGA-AD categories and age [adolescent vs. adult])
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	36.8
	Confidence Interval	(2-Sided) 95%; 29.7 to 43.8
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

4. Secondary Outcome

Title	Main Study: Percentage of Participants Achieving a 90% Reduction From Baseline in EASI Score (EASI 90) at Week 16
Description	EASI is a tool used to measure the extent (area) and severity of atopic eczema based on assessments of the head/ neck, trunk, upper limbs and lower limbs. For each region the area score is recorded as the percentage of skin affected by eczema. For each region, the severity score is calculated as the sum of the intensity scores (scored as none [0], mild [1], moderate [2], or severe [3]) for redness (erythema, inflammation), thickness (induration, papulation, swelling - acute eczema), scratching (excoriation), and lichenification (lined skin, prurigo nodules - chronic eczema). The total EASI score for each region is calculated by multiplying the severity score by the area score, with adjustment for the proportion of the body region to the whole body. The final EASI score is the sum of the 4 region scores and ranges from 0 to 72 where higher scores represent worse disease.
Time Frame	Baseline and Week 16

Outcome Measure Data

Analysis Population Description

Intent-to-treat population for the main study; Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) was used.

Arm/Group Title	Placebo + Topical Corticosteroids	Upadacitinib 15 mg + Topical Corticosteroids	Upadacitinib 30 mg + Topical Corticosteroids
Arm/Group Description:	Participants received placebo orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Participants received upadacitinib 15 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Participants received upadacitinib 30 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.
Overall Number of Participants Analyzed	304	300	297
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	13.2; (9.4 to 17.0)	42.8; (37.2 to 48.4)	63.1; (57.6 to 68.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Topical Corticosteroids, Upadacitinib 30 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the coprimary and all key secondary endpoints for upadacitinib 30 mg was controlled at the 0.05 level using a graphical multiple testing procedure following a pre-specified α transfer path which includes downstream transfer along the endpoints sequence within each dose as well as cross-dose transfer.
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for strata (Baseline vIGA-AD categories and age [adolescent vs. adult])
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	49.9
	Confidence Interval	(2-Sided) 95%; 43.3 to 56.4
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + Topical Corticosteroids, Upadacitinib 15 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the coprimary and all key secondary endpoints for upadacitinib 15 mg was controlled at the 0.05 level using a graphical multiple testing procedure following a pre-specified α transfer path which includes downstream transfer along the endpoints sequence within each dose as well as cross-dose transfer.
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for strata (Baseline vIGA-AD categories and age [adolescent vs. adult])
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	29.5
	Confidence Interval	(2-Sided) 95%; 22.8 to 36.3
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

5. Secondary Outcome

Title	Main Study: Percentage of Participants Achieving a Reduction of ≥ 4 Points From Baseline in Worst Pruritus NRS at Week 4
Description	Participants were asked to rate itch (pruritus) intensity at its worst during the past 24 hours on a daily basis using an 11-point scale from 0 (no itch) to 10 (worst imaginable itch). Pruritus NRS was analyzed based on weekly rolling averages of daily scores.
Time Frame	Baseline (last available rolling average before the first dose of study drug) and Week 4

Outcome Measure Data

Analysis Population Description

Intent-to-treat population for the main study with Worst Pruritus NRS (weekly average) ≥ 4 at Baseline; Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) was used.

Arm/Group Title	Placebo + Topical Corticosteroids	Upadacitinib 15 mg + Topical Corticosteroids	Upadacitinib 30 mg + Topical Corticosteroids
Arm/Group Description:	Participants received placebo orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Participants received upadacitinib 15 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Participants received upadacitinib 30 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.
Overall Number of Participants Analyzed	294	288	291
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	15.0; (10.9 to 19.0)	52.4; (46.7 to 58.2)	65.6; (60.2 to 71.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Topical Corticosteroids, Upadacitinib 30 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the coprimary and all key secondary endpoints for upadacitinib 30 mg was controlled at the 0.05 level using a graphical multiple testing procedure following a pre-specified α transfer path which includes downstream transfer along the endpoints sequence within each dose as well as cross-dose transfer.
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for strata (Baseline vIGA-AD categories and age [adolescent vs. adult])
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	50.6
	Confidence Interval	(2-Sided) 95%; 43.8 to 57.3
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + Topical Corticosteroids, Upadacitinib 15 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the coprimary and all key secondary endpoints for upadacitinib 15 mg was controlled at the 0.05 level using a graphical multiple testing procedure following a pre-specified α transfer path which includes downstream transfer along the endpoints sequence within each dose as well as cross-dose transfer.
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for strata (Baseline vIGA-AD categories and age [adolescent vs. adult])
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	37.4
	Confidence Interval	(2-Sided) 95%; 30.4 to 44.3
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

6. Secondary Outcome

Title	Main Study: Percentage of Participants Achieving an EASI 75 Response at Week 4
Description	EASI is a tool used to measure the extent (area) and severity of atopic eczema based on assessments of the head/neck, trunk, upper limbs and lower limbs. For each region the area score is recorded as the percentage of skin affected by eczema. For each region, the severity score is calculated as the sum of the intensity scores (scored as none [0], mild [1], moderate [2], or severe [3]) for redness (erythema, inflammation), thickness (induration, papulation, swelling - acute eczema), scratching (excoriation), and lichenification (lined skin, prurigo nodules - chronic eczema). The total EASI score for each region is calculated by multiplying the severity score by the area score, with adjustment for the proportion of the body region to the whole body. The final EASI score is the sum of the 4 region scores and ranges from 0 to 72 where higher scores represent worse disease. An EASI 75 response is defined as at least a 75% reduction (improvement) from Baseline in EASI score.
Time Frame	Baseline and Week 4

Outcome Measure Data

Analysis Population Description

Intent-to-treat population for the main study; Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) was used.

Arm/Group Title	Placebo + Topical Corticosteroids	Upadacitinib 15 mg + Topical Corticosteroids	Upadacitinib 30 mg + Topical Corticosteroids
Arm/Group Description:	Participants received placebo orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Participants received upadacitinib 15 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Participants received upadacitinib 30 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.
Overall Number of Participants Analyzed	304	300	297
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	14.8; (10.8 to 18.8)	58.7; (53.1 to 64.2)	72.4; (67.3 to 77.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Topical Corticosteroids, Upadacitinib 30 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the coprimary and all key secondary endpoints for upadacitinib 30 mg was controlled at the 0.05 level using a graphical multiple testing procedure following a pre-specified α transfer path which includes downstream transfer along the endpoints sequence within each dose as well as cross-dose transfer.
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for strata (Baseline vIGA-AD categories and age [adolescent vs. adult])
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	57.6
	Confidence Interval	(2-Sided) 95%; 51.2 to 63.9
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + Topical Corticosteroids, Upadacitinib 15 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the coprimary and all key secondary endpoints for upadacitinib 15 mg was controlled at the 0.05 level using a graphical multiple testing procedure following a pre-specified α transfer path which includes downstream transfer along the endpoints sequence within each dose as well as cross-dose transfer.
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for strata (Baseline vIGA-AD categories and age [adolescent vs. adult])
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	43.8
	Confidence Interval	(2-Sided) 95%; 37.0 to 50.5
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

7. Secondary Outcome

Title	Main Study: Percentage of Participants Achieving an EASI 75 Response at Week 2
Description	EASI is a tool used to measure the extent (area) and severity of atopic eczema based on assessments of the head/neck, trunk, upper limbs and lower limbs. For each region the area score is recorded as the percentage of skin affected by eczema. For each region, the severity score is calculated as the sum of the intensity scores (scored as none [0], mild [1], moderate [2], or severe [3]) for redness (erythema, inflammation), thickness (induration, papulation, swelling - acute eczema), scratching (excoriation), and lichenification (lined skin, prurigo nodules - chronic eczema). The total EASI score for each region is calculated by multiplying the severity score by the area score, with adjustment for the proportion of the body region to the whole body. The final EASI score is the sum of the 4 region scores and ranges from 0 to 72 where higher scores represent worse disease. An EASI 75 response is defined as at least a 75% reduction (improvement) from Baseline in EASI score.
Time Frame	Baseline and Week 2

Outcome Measure Data

Analysis Population Description

Intent-to-treat population for the main study; Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) was used.

Arm/Group Title	Placebo + Topical Corticosteroids	Upadacitinib 15 mg + Topical Corticosteroids	Upadacitinib 30 mg + Topical Corticosteroids
Arm/Group Description:	Participants received placebo orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Participants received upadacitinib 15 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Participants received upadacitinib 30 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.
Overall Number of Participants Analyzed	304	300	297
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	6.9; (4.1 to 9.8)	31.0; (25.8 to 36.2)	44.1; (38.5 to 49.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Topical Corticosteroids, Upadacitinib 30 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the coprimary and all key secondary endpoints for upadacitinib 30 mg was controlled at the 0.05 level using a graphical multiple testing procedure following a pre-specified α transfer path which includes downstream transfer along the endpoints sequence within each dose as well as cross-dose transfer.
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for strata (Baseline vIGA-AD categories and age [adolescent vs. adult])
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	37.2
	Confidence Interval	(2-Sided) 95%; 31.0 to 43.3
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + Topical Corticosteroids, Upadacitinib 15 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the coprimary and all key secondary endpoints for upadacitinib 15 mg was controlled at the 0.05 level using a graphical multiple testing procedure following a pre-specified α transfer path which includes downstream transfer along the endpoints sequence within each dose as well as cross-dose transfer.
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for strata (Baseline vIGA-AD categories and age [adolescent vs. adult])
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	24.0
	Confidence Interval	(2-Sided) 95%; 18.1 to 29.9
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

8. Secondary Outcome

Title	Main Study: Percentage of Participants Achieving an EASI 90 Response at Week 4
Description	EASI is a tool used to measure the extent (area) and severity of atopic eczema based on assessments of the head/ neck, trunk, upper limbs and lower limbs. For each region the area score is recorded as the percentage of skin affected by eczema. For each region, the severity score is calculated as the sum of the intensity scores (scored as none [0], mild [1], moderate [2], or severe [3]) for redness (erythema, inflammation), thickness (induration, papulation, swelling - acute eczema), scratching (excoriation), and lichenification (lined skin, prurigo nodules - chronic eczema). The total EASI score for each region is calculated by multiplying the severity score by the area score, with adjustment for the proportion of the body region to the whole body. The final EASI score is the sum of the 4 region scores and ranges from 0 to 72 where higher scores represent worse disease.
Time Frame	Baseline and Week 4

Outcome Measure Data

Analysis Population Description

Intent-to-treat population for the main study; Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) was used.

Arm/Group Title	Placebo + Topical Corticosteroids	Upadacitinib 15 mg + Topical Corticosteroids	Upadacitinib 30 mg + Topical Corticosteroids
Arm/Group Description:	Participants received placebo orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Participants received upadacitinib 15 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Participants received upadacitinib 30 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.
Overall Number of Participants Analyzed	304	300	297
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	4.9; (2.5 to 7.4)	28.3; (23.2 to 33.4)	43.8; (38.1 to 49.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Topical Corticosteroids, Upadacitinib 30 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the coprimary and all key secondary endpoints for upadacitinib 30 mg was controlled at the 0.05 level using a graphical multiple testing procedure following a pre-specified α transfer path which includes downstream transfer along the endpoints sequence within each dose as well as cross-dose transfer.
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for strata (Baseline vIGA-AD categories and age [adolescent vs. adult])
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	38.8
	Confidence Interval	(2-Sided) 95%; 32.8 to 44.8
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + Topical Corticosteroids, Upadacitinib 15 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the coprimary and all key secondary endpoints for upadacitinib 15 mg was controlled at the 0.05 level using a graphical multiple testing procedure following a pre-specified α transfer path which includes downstream transfer along the endpoints sequence within each dose as well as cross-dose transfer.
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for strata (Baseline vIGA-AD categories and age [adolescent vs. adult])
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	23.3
	Confidence Interval	(2-Sided) 95%; 17.7 to 28.9
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

9. Secondary Outcome

Title	Main Study: Percentage of Participants Achieving a 100% Reduction From Baseline in EASI Score (EASI 100) at Week 16
Description	EASI is a tool used to measure the extent (area) and severity of atopic eczema based on assessments of the head/neck, trunk, upper limbs and lower limbs. For each region the area score is recorded as the percentage of skin affected by eczema. For each region, the severity score is calculated as the sum of the intensity scores (scored from 0 [none], to 3 [severe]) for redness, thickness, scratching, and lichenification. The total EASI score for each region is calculated by multiplying the severity score by the area score, with adjustment for the proportion of the body region to the whole body. The final EASI score is the sum of the 4 region scores and ranges from 0 to 72 where higher scores represent worse disease. The percentage of participants with an EASI 100 response at Week 16 was pre-specified as a ranked secondary endpoint for participants in the Upadacitinib 30 mg + Topical Corticosteroids group versus Placebo + Topical Corticosteroids group only.
Time Frame	Baseline and Week 16

Outcome Measure Data

Analysis Population Description

Intent-to-treat population for the main study; Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) was used.

Arm/Group Title	Placebo + Topical Corticosteroids	Upadacitinib 15 mg + Topical Corticosteroids	Upadacitinib 30 mg + Topical Corticosteroids
Arm/Group Description:	Participants received placebo orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Participants received upadacitinib 15 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Participants received upadacitinib 30 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.
Overall Number of Participants Analyzed	304	300	297
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	1.3; (0.0 to 2.6)	12.0; (8.3 to 15.7)	22.6; (17.8 to 27.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Topical Corticosteroids, Upadacitinib 30 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the coprimary and all key secondary endpoints for upadacitinib 30 mg was controlled at the 0.05 level using a graphical multiple testing procedure following a pre-specified α transfer path which includes downstream transfer along the endpoints sequence within each dose as well as cross-dose transfer.
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for strata (Baseline vIGA-AD categories and age [adolescent vs. adult])
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	21.2
	Confidence Interval	(2-Sided) 95%; 16.3 to 26.1
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

10. Secondary Outcome

Title	Main Study: Percentage of Participants Achieving a Reduction of ≥ 4 Points From Baseline in Worst Pruritus NRS at Week 1
Description	Participants were asked to rate itch (pruritus) intensity at its worst during the past 24 hours on a daily basis using an 11-point scale from 0 (no itch) to 10 (worst imaginable itch). Pruritus NRS was analyzed based on weekly rolling averages of daily scores.
Time Frame	Baseline (last available rolling average before the first dose of study drug) and Week 1

Outcome Measure Data

Analysis Population Description

Intent-to-treat population for the main study with Worst Pruritus NRS (weekly average) ≥ 4 at Baseline; Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) was used.

Arm/Group Title	Placebo + Topical Corticosteroids	Upadacitinib 15 mg + Topical Corticosteroids	Upadacitinib 30 mg + Topical Corticosteroids
Arm/Group Description:	Participants received placebo orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Participants received upadacitinib 15 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Participants received upadacitinib 30 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.
Overall Number of Participants Analyzed	294	288	291
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	3.1; (1.1 to 5.0)	12.2; (8.4 to 15.9)	19.2; (14.7 to 23.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Topical Corticosteroids, Upadacitinib 30 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the coprimary and all key secondary endpoints for upadacitinib 30 mg was controlled at the 0.05 level using a graphical multiple testing procedure following a pre-specified α transfer path which includes downstream transfer along the endpoints sequence within each dose as well as cross-dose transfer.
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for strata (Baseline vIGA-AD categories and age [adolescent vs. adult])
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	16.2
	Confidence Interval	(2-Sided) 95%; 11.3 to 21.1
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + Topical Corticosteroids, Upadacitinib 15 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the coprimary and all key secondary endpoints for upadacitinib 15 mg was controlled at the 0.05 level using a graphical multiple testing procedure following a pre-specified α transfer path which includes downstream transfer along the endpoints sequence within each dose as well as cross-dose transfer.
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for strata (Baseline vIGA-AD categories and age [adolescent vs. adult])
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	9.2
	Confidence Interval	(2-Sided) 95%; 4.9 to 13.4
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

11. Secondary Outcome

Title	Main Study: Percent Change From Baseline in Worst Pruritus NRS at Week 16
Description	Participants were asked to rate itch (pruritus) intensity at its worst during the past 24 hours on a daily basis using an 11-point scale from 0 (no itch) to 10 (worst imaginable itch). Pruritus NRS was analyzed based on weekly rolling averages of daily scores. A negative change from Baseline indicates improvement.
Time Frame	Baseline (last available rolling average before the first dose of study drug) and Week 16

Outcome Measure Data

Analysis Population Description

Intent-to-treat population for the main study with non-missing Baseline and Week 16 values; missing data were handled using a mixed-effect model with repeated measurements (MMRM) including observed measurements at all visits, except that measurements after any rescue medication were excluded.

Arm/Group Title	Placebo + Topical Corticosteroids	Upadacitinib 15 mg + Topical Corticosteroids	Upadacitinib 30 mg + Topical Corticosteroids
Arm/Group Description:	Participants received placebo orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Participants received upadacitinib 15 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Participants received upadacitinib 30 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.
Overall Number of Participants Analyzed	184	260	247
Least Squares Mean (95% Confidence Interval); Unit of Measure: percent change
	-25.07; (-31.64 to -18.49)	-58.14; (-64.24 to -52.05)	-66.85; (-72.99 to -60.72)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Topical Corticosteroids, Upadacitinib 30 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the coprimary and all key secondary endpoints for upadacitinib 30 mg was controlled at the 0.05 level using a graphical multiple testing procedure following a pre-specified α transfer path which includes downstream transfer along the endpoints sequence within each dose as well as cross-dose transfer. This endpoint was a multiplicity-controlled key secondary endpoint for European Union (EU)/European Medicines Agency (EMA) regulatory purposes only.
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Mixed Effect Model Repeated Measurement
	Comments	Mixed-effect model repeat measurement with Baseline, treatment, visit, treatment by visit interaction, Baseline vIGA-AD category and age in the model.
Method of Estimation	Estimation Parameter	Least Squares (LS) Mean Difference
	Estimated Value	-41.79
	Confidence Interval	(2-Sided) 95%; -50.46 to -33.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.417
	Estimation Comments	Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + Topical Corticosteroids, Upadacitinib 15 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the coprimary and all key secondary endpoints for upadacitinib 15 mg was controlled at the 0.05 level using a graphical multiple testing procedure following a pre-specified α transfer path which includes downstream transfer along the endpoints sequence within each dose as well as cross-dose transfer. This endpoint was a multiplicity-controlled key secondary endpoint for European Union (EU)/European Medicines Agency (EMA) regulatory purposes only.
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Mixed Effect Model Repeated Measurement
	Comments	Mixed-effect model repeat measurement with Baseline, treatment, visit, treatment by visit interaction, Baseline vIGA-AD category and age in the model.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-33.08
	Confidence Interval	(2-Sided) 95%; -41.72 to -24.44
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.403
	Estimation Comments	Difference = Upadacitinib - Placebo

12. Secondary Outcome

Title	Main Study: Percent Change From Baseline in EASI Score at Week 16
Description	EASI is a tool used to measure the extent (area) and severity of atopic eczema based on assessments of the head/neck, trunk, upper limbs and lower limbs. For each region the area score is recorded as the percentage of skin affected by eczema. For each region, the severity score is calculated as the sum of the intensity scores (scored as none [0], mild [1)] moderate [2], or severe [3]) for Redness (erythema, inflammation), Thickness (induration, papulation, swelling - acute eczema), Scratching (excoriation), and Lichenification (lined skin, prurigo nodules - chronic eczema). The total EASI score for each region is calculated by multiplying the severity score by the area score, with adjustment for the proportion of the body region to the whole body. The final EASI score is the sum of the 4 region scores and ranges from 0 to 72 where higher scores represent worse disease; a negative change from Baseline indicates improvement.
Time Frame	Baseline and Week 16

Outcome Measure Data

Analysis Population Description

Intent-to-treat population for the main study with non-missing Baseline and Week 16 values; missing data were handled using a mixed-effect model with repeated measurements (MMRM) including observed measurements at all visits, except that measurements after any rescue medication were excluded.

Arm/Group Title	Placebo + Topical Corticosteroids	Upadacitinib 15 mg + Topical Corticosteroids	Upadacitinib 30 mg + Topical Corticosteroids
Arm/Group Description:	Participants received placebo orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Participants received upadacitinib 15 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Participants received upadacitinib 30 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.
Overall Number of Participants Analyzed	206	275	276
Least Squares Mean (95% Confidence Interval); Unit of Measure: percent change
	-45.86; (-50.09 to -41.63)	-77.99; (-81.87 to -74.10)	-87.31; (-91.20 to -83.41)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Topical Corticosteroids, Upadacitinib 30 mg + Topical Corticosteroids
	Comments	The overall type I error rate of the coprimary and all key secondary endpoints for upadacitinib 30 mg was controlled at the 0.05 level using a graphical multiple testing procedure following a pre-specified α transfer path which includes downstream transfer along the endpoints sequence within each dose as well as cross-dose transfer. This endpoint was a multiplicity-controlled key secondary endpoint for EU/EMA regulatory purposes only.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Mixed Effect Model Repeated Measurement
	Comments	Mixed-effect model repeat measurement with Baseline, treatment, visit, treatment by visit interaction, Baseline vIGA-AD category and age in the model.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-41.45
	Confidence Interval	(2-Sided) 95%; -46.68 to -36.22
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.662
	Estimation Comments	Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + Topical Corticosteroids, Upadacitinib 15 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the coprimary and all key secondary endpoints for upadacitinib 15 mg was controlled at the 0.05 level using a graphical multiple testing procedure following a pre-specified α transfer path which includes downstream transfer along the endpoints sequence within each dose as well as cross-dose transfer. This endpoint was a multiplicity-controlled key secondary endpoint for EU/EMA regulatory purposes only.
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Mixed Effect Model Repeated Measurement
	Comments	Mixed-effect model repeat measurement with Baseline, treatment, visit, treatment by visit interaction, Baseline vIGA-AD category and age in the model.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-32.13
	Confidence Interval	(2-Sided) 95%; -37.35 to -26.91
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.659
	Estimation Comments	Difference = Upadacitinib - Placebo

13. Secondary Outcome

Title	Adolescents: Percentage of Participants Achieving an EASI 75 Response at Week 16
Description	EASI is a tool used to measure the extent (area) and severity of atopic eczema based on assessments of the head/neck, trunk, upper limbs and lower limbs. For each region the area score is recorded as the percentage of skin affected by eczema. For each region, the severity score is calculated as the sum of the intensity scores (scored as none [0], mild [1], moderate [2], or severe [3]) for redness (erythema, inflammation), thickness (induration, papulation, swelling - acute eczema), scratching (excoriation), and lichenification (lined skin, prurigo nodules - chronic eczema). The total EASI score for each region is calculated by multiplying the severity score by the area score, with adjustment for the proportion of the body region to the whole body. The final EASI score is the sum of the 4 region scores and ranges from 0 to 72 where higher scores represent worse disease. An EASI 75 response is defined as at least a 75% reduction (improvement) from Baseline in EASI score.
Time Frame	Baseline and Week 16

Outcome Measure Data

Analysis Population Description

The ITT population for adolescents (ITT_A) consists of all adolescent participants who were randomized in the main study or the adolescent sub-study. Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) was used.

Arm/Group Title	Adolescents: Placebo + Topical Corticosteroids	Adolescents: Upadacitinib 15 mg + Topical Corticosteroids	Adolescents: Upadacitinib 30 mg + Topical Corticosteroids
Arm/Group Description:	Adolescent participants received placebo orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Adolescent participants received upadacitinib 15 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Adolescent participants received upadacitinib 30 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.
Overall Number of Participants Analyzed	63	60	60
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	30.3; (18.9 to 41.6)	63.3; (51.1 to 75.5)	84.3; (74.9 to 93.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo + Topical Corticosteroids, Adolescents: Upadacitinib 30 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for stratum (Baseline vIGA-AD categories)
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	53.1
	Confidence Interval	(2-Sided) 95%; 38.8 to 67.4
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo + Topical Corticosteroids, Adolescents: Upadacitinib 15 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for stratum (Baseline vIGA-AD categories)
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	32.7
	Confidence Interval	(2-Sided) 95%; 16.3 to 49.0
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

14. Secondary Outcome

Title	Adolescents: Percentage of Participants Achieving a vIGA-AD of 0 or 1 With a Reduction From Baseline of ≥ 2 Points at Week 16
Description	The vIGA-AD is a validated assessment instrument to rate the severity of atopic dermatitis globally, based on the following scale: 0 - Clear: No signs of AD;; 1 - Almost clear: Barely perceptible erythema, induration/papulation and/or lichenification;; 2 - Mild: Slight but definite erythema, induration/papulation and/or minimal lichenification. No oozing or crusting;; 3 - Moderate: Clearly perceptible erythema, induration/papulation and/or lichenification, possible oozing or crusting;; 4 - Severe: Marked erythema, induration/papulation and/or lichenification; possible oozing or crusting.
Time Frame	Baseline and Week 16

Outcome Measure Data

Analysis Population Description

The ITT population for adolescents (ITT_A) consists of all adolescent participants who were randomized in the main study or the adolescent sub-study. Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) was used.

Arm/Group Title	Adolescents: Placebo + Topical Corticosteroids	Adolescents: Upadacitinib 15 mg + Topical Corticosteroids	Adolescents: Upadacitinib 30 mg + Topical Corticosteroids
Arm/Group Description:	Adolescent participants received placebo orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Adolescent participants received upadacitinib 15 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Adolescent participants received upadacitinib 30 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.
Overall Number of Participants Analyzed	63	60	60
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	11.2; (3.4 to 19.1)	38.3; (26.0 to 50.6)	67.4; (55.5 to 79.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo + Topical Corticosteroids, Adolescents: Upadacitinib 30 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for stratum (Baseline vIGA-AD categories)
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	55.4
	Confidence Interval	(2-Sided) 95%; 41.4 to 69.5
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo + Topical Corticosteroids, Adolescents: Upadacitinib 15 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for stratum (Baseline vIGA-AD categories)
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	26.3
	Confidence Interval	(2-Sided) 95%; 12.1 to 40.4
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

15. Secondary Outcome

Title	Adolescents: Percentage of Participants Achieving a Reduction of ≥ 4 Points From Baseline in Worst Pruritus NRS at Week 16
Description	Participants were asked to rate itch (pruritus) intensity at its worst during the past 24 hours on a daily basis using an 11-point scale from 0 (no itch) to 10 (worst imaginable itch). Worst pruritus NRS was analyzed based on weekly rolling averages of daily scores.
Time Frame	Baseline (last available rolling average before the first dose of study drug) and Week 16

Outcome Measure Data

Analysis Population Description

Intent-to-treat population for adolescents with Worst Pruritus NRS (weekly average) ≥ 4 at Baseline; Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) was used.

Arm/Group Title	Adolescents: Placebo + Topical Corticosteroids	Adolescents: Upadacitinib 15 mg + Topical Corticosteroids	Adolescents: Upadacitinib 30 mg + Topical Corticosteroids
Arm/Group Description:	Adolescent participants received placebo orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Adolescent participants received upadacitinib 15 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Adolescent participants received upadacitinib 30 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.
Overall Number of Participants Analyzed	61	57	56
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	21.3; (11.0 to 31.6)	45.6; (32.7 to 58.5)	51.8; (38.7 to 64.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo + Topical Corticosteroids, Adolescents: Upadacitinib 30 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for stratum (Baseline vIGA-AD categories)
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	30.5
	Confidence Interval	(2-Sided) 95%; 14.1 to 46.8
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo + Topical Corticosteroids, Adolescents: Upadacitinib 15 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.003
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for stratum (Baseline vIGA-AD categories)
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	24.5
	Confidence Interval	(2-Sided) 95%; 8.2 to 40.8
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

16. Secondary Outcome

Title	Adolescents: Percentage of Participants Achieving an EASI 90 Response at Week 16
Description	EASI is a tool used to measure the extent (area) and severity of atopic eczema based on assessments of the head/neck, trunk, upper limbs and lower limbs. For each region the area score is recorded as the percentage of skin affected by eczema. For each region, the severity score is calculated as the sum of the intensity scores (scored as none [0], mild [1], moderate [2], or severe [3]) for redness (erythema, inflammation), thickness (induration, papulation, swelling - acute eczema), scratching (excoriation), and lichenification (lined skin, prurigo nodules - chronic eczema). The total EASI score for each region is calculated by multiplying the severity score by the area score, with adjustment for the proportion of the body region to the whole body. The final EASI score is the sum of the 4 region scores and ranges from 0 to 72 where higher scores represent worse disease. An EASI 90 response is defined as at least a 90% reduction (improvement) from Baseline in EASI score.
Time Frame	Baseline and Week 16

Outcome Measure Data

Analysis Population Description

Intent-to-treat population for adolescents; Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) was used.

Arm/Group Title	Adolescents: Placebo + Topical Corticosteroids	Adolescents: Upadacitinib 15 mg + Topical Corticosteroids	Adolescents: Upadacitinib 30 mg + Topical Corticosteroids
Arm/Group Description:	Adolescent participants received placebo orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Adolescent participants received upadacitinib 15 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Adolescent participants received upadacitinib 30 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.
Overall Number of Participants Analyzed	63	60	60
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	20.7; (10.7 to 30.7)	48.3; (35.7 to 61.0)	73.6; (62.3 to 84.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo + Topical Corticosteroids, Adolescents: Upadacitinib 30 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for stratum (Baseline vIGA-AD categories)
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	52.0
	Confidence Interval	(2-Sided) 95%; 37.3 to 66.7
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo + Topical Corticosteroids, Adolescents: Upadacitinib 15 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for stratum (Baseline vIGA-AD categories)
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	27.1
	Confidence Interval	(2-Sided) 95%; 11.1 to 43.1
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

17. Secondary Outcome

Title	Adolescents: Percentage of Participants Achieving a Reduction of ≥ 4 Points From Baseline in Worst Pruritus NRS at Week 4
Description	Participants were asked to rate itch (pruritus) intensity at its worst during the past 24 hours on a daily basis using an 11-point scale from 0 (no itch) to 10 (worst imaginable itch). Worst pruritus NRS was analyzed based on weekly rolling averages of daily scores.
Time Frame	Baseline (last available rolling average before the first dose of study drug) and Week 4

Outcome Measure Data

Analysis Population Description

Intent-to-treat population for adolescents with Worst Pruritus NRS (weekly average) ≥ 4 at Baseline; Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) was used.

Arm/Group Title	Adolescents: Placebo + Topical Corticosteroids	Adolescents: Upadacitinib 15 mg + Topical Corticosteroids	Adolescents: Upadacitinib 30 mg + Topical Corticosteroids
Arm/Group Description:	Adolescent participants received placebo orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Adolescent participants received upadacitinib 15 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Adolescent participants received upadacitinib 30 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.
Overall Number of Participants Analyzed	61	57	56
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	23.0; (12.4 to 33.5)	45.6; (32.7 to 58.5)	46.4; (33.4 to 59.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo + Topical Corticosteroids, Adolescents: Upadacitinib 30 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.006
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for stratum (Baseline vIGA-AD categories)
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	23.5
	Confidence Interval	(2-Sided) 95%; 6.9 to 40.1
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo + Topical Corticosteroids, Adolescents: Upadacitinib 15 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.007
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for stratum (Baseline vIGA-AD categories)
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	22.7
	Confidence Interval	(2-Sided) 95%; 6.2 to 39.2
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

18. Secondary Outcome

Title	Adolescents: Percentage of Participants Achieving an EASI 75 Response at Week 4
Description	EASI is a tool used to measure the extent (area) and severity of atopic eczema based on assessments of the head/neck, trunk, upper limbs and lower limbs. For each region the area score is recorded as the percentage of skin affected by eczema. For each region, the severity score is calculated as the sum of the intensity scores (scored as none [0], mild [1], moderate [2], or severe [3]) for redness (erythema, inflammation), thickness (induration, papulation, swelling - acute eczema), scratching (excoriation), and lichenification (lined skin, prurigo nodules - chronic eczema). The total EASI score for each region is calculated by multiplying the severity score by the area score, with adjustment for the proportion of the body region to the whole body. The final EASI score is the sum of the 4 region scores and ranges from 0 to 72 where higher scores represent worse disease. An EASI 75 response is defined as at least a 75% reduction (improvement) from Baseline in EASI score.
Time Frame	Baseline and Week 4

Outcome Measure Data

Analysis Population Description

Intent-to-treat population for adolescents; Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) was used.

Arm/Group Title	Adolescents: Placebo + Topical Corticosteroids	Adolescents: Upadacitinib 15 mg + Topical Corticosteroids	Adolescents: Upadacitinib 30 mg + Topical Corticosteroids
Arm/Group Description:	Adolescent participants received placebo orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Adolescent participants received upadacitinib 15 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Adolescent participants received upadacitinib 30 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.
Overall Number of Participants Analyzed	63	60	60
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	28.6; (17.4 to 39.7)	54.9; (42.3 to 67.5)	78.3; (67.9 to 88.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo + Topical Corticosteroids, Adolescents: Upadacitinib 30 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for stratum (Baseline vIGA-AD categories)
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	49.3
	Confidence Interval	(2-Sided) 95%; 34.1 to 64.6
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo + Topical Corticosteroids, Adolescents: Upadacitinib 15 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.002
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for stratum (Baseline vIGA-AD categories)
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	26.2
	Confidence Interval	(2-Sided) 95%; 9.4 to 43.1
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

19. Secondary Outcome

Title	Adolescents: Percentage of Participants Achieving an EASI 75 Response at Week 2
Description	EASI is a tool used to measure the extent (area) and severity of atopic eczema based on assessments of the head/neck, trunk, upper limbs and lower limbs. For each region the area score is recorded as the percentage of skin affected by eczema. For each region, the severity score is calculated as the sum of the intensity scores (scored as none [0], mild [1], moderate [2], or severe [3]) for redness (erythema, inflammation), thickness (induration, papulation, swelling - acute eczema), scratching (excoriation), and lichenification (lined skin, prurigo nodules - chronic eczema). The total EASI score for each region is calculated by multiplying the severity score by the area score, with adjustment for the proportion of the body region to the whole body. The final EASI score is the sum of the 4 region scores and ranges from 0 to 72 where higher scores represent worse disease. An EASI 75 response is defined as at least a 75% reduction (improvement) from Baseline in EASI score.
Time Frame	Baseline and Week 2

Outcome Measure Data

Analysis Population Description

Intent-to-treat population for adolescents; Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) was used.

Arm/Group Title	Adolescents: Placebo + Topical Corticosteroids	Adolescents: Upadacitinib 15 mg + Topical Corticosteroids	Adolescents: Upadacitinib 30 mg + Topical Corticosteroids
Arm/Group Description:	Adolescent participants received placebo orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Adolescent participants received upadacitinib 15 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Adolescent participants received upadacitinib 30 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.
Overall Number of Participants Analyzed	63	60	60
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	9.5; (2.3 to 16.8)	33.7; (21.7 to 45.8)	51.7; (39.0 to 64.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo + Topical Corticosteroids, Adolescents: Upadacitinib 30 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for stratum (Baseline vIGA-AD categories)
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	41.5
	Confidence Interval	(2-Sided) 95%; 27.8 to 55.1
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo + Topical Corticosteroids, Adolescents: Upadacitinib 15 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for stratum (Baseline vIGA-AD categories)
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	24.4
	Confidence Interval	(2-Sided) 95%; 10.3 to 38.4
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

20. Secondary Outcome

Title	Adolescents: Percentage of Participants Achieving an EASI 90 Response at Week 4
Description	EASI is a tool used to measure the extent (area) and severity of atopic eczema based on assessments of the head/neck, trunk, upper limbs and lower limbs. For each region the area score is recorded as the percentage of skin affected by eczema. For each region, the severity score is calculated as the sum of the intensity scores (scored as none [0], mild [1], moderate [2], or severe [3]) for redness (erythema, inflammation), thickness (induration, papulation, swelling - acute eczema), scratching (excoriation), and lichenification (lined skin, prurigo nodules - chronic eczema). The total EASI score for each region is calculated by multiplying the severity score by the area score, with adjustment for the proportion of the body region to the whole body. The final EASI score is the sum of the 4 region scores and ranges from 0 to 72 where higher scores represent worse disease. An EASI 90 response is defined as at least a 90% reduction (improvement) from Baseline in EASI score.
Time Frame	Baseline and Week 4

Outcome Measure Data

Analysis Population Description

Intent-to-treat population for adolescents; Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) was used.

Arm/Group Title	Adolescents: Placebo + Topical Corticosteroids	Adolescents: Upadacitinib 15 mg + Topical Corticosteroids	Adolescents: Upadacitinib 30 mg + Topical Corticosteroids
Arm/Group Description:	Adolescent participants received placebo orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Adolescent participants received upadacitinib 15 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Adolescent participants received upadacitinib 30 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.
Overall Number of Participants Analyzed	63	60	60
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	9.5; (2.3 to 16.8)	34.2; (22.1 to 46.3)	45.0; (32.4 to 57.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo + Topical Corticosteroids, Adolescents: Upadacitinib 30 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for stratum (Baseline vIGA-AD categories)
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	34.9
	Confidence Interval	(2-Sided) 95%; 20.6 to 49.3
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo + Topical Corticosteroids, Adolescents: Upadacitinib 15 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for stratum (Baseline vIGA-AD categories)
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	24.5
	Confidence Interval	(2-Sided) 95%; 10.4 to 38.7
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

21. Secondary Outcome

Title	Adolescents: Percentage of Participants Achieving an EASI 100 Response at Week 16
Description	EASI is used to measure the extent and severity of atopic eczema based on assessments of the head/neck, trunk, upper limbs and lower limbs. For each region the area score is recorded as the percentage of skin affected by eczema. and the severity score is calculated as the sum of the intensity scores (scored from 0 [none], to 3 [severe]) for redness, thickness, scratching, and lichenification. The total EASI score for each region is calculated by multiplying the severity score by the area score, with adjustment for the proportion of the body region to the whole body. The final EASI score is the sum of the 4 region scores and ranges from 0 to 72 where higher scores represent worse disease. An EASI 100 response is defined as a 100% reduction (improvement) from Baseline in EASI score. The percentage of participants with an EASI 100 response at Week 16 was pre-specified as a secondary endpoint for participants in the Upadacitinib 30 mg + TCS group versus Placebo + TCS group only.
Time Frame	Baseline and Week 16

Outcome Measure Data

Analysis Population Description

Intent-to-treat population for adolescents; Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) was used.

Arm/Group Title	Adolescents: Placebo + Topical Corticosteroids	Adolescents: Upadacitinib 15 mg + Topical Corticosteroids	Adolescents: Upadacitinib 30 mg + Topical Corticosteroids
Arm/Group Description:	Adolescent participants received placebo orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Adolescent participants received upadacitinib 15 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Adolescent participants received upadacitinib 30 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.
Overall Number of Participants Analyzed	63	60	60
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	4.8; (0.0 to 10.0)	13.3; (4.7 to 21.9)	25.0; (14.0 to 36.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo + Topical Corticosteroids, Adolescents: Upadacitinib 30 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for stratum (Baseline vIGA-AD categories)
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	19.8
	Confidence Interval	(2-Sided) 95%; 7.8 to 31.8
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

22. Secondary Outcome

Title	Adolescents: Percentage of Participants Achieving a Reduction of ≥ 4 Points From Baseline in Worst Pruritus NRS at Week 1
Description	Participants were asked to rate itch (pruritus) intensity at its worst during the past 24 hours on a daily basis using an 11-point scale from 0 (no itch) to 10 (worst imaginable itch). Worst pruritus NRS was analyzed based on weekly rolling averages of daily scores.
Time Frame	Baseline (last available rolling average before the first dose of study drug) and Week 1

Outcome Measure Data

Analysis Population Description

Intent-to-treat population for adolescents with Worst Pruritus NRS (weekly average) ≥ 4 at Baseline; Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) was used.

Arm/Group Title	Adolescents: Placebo + Topical Corticosteroids	Adolescents: Upadacitinib 15 mg + Topical Corticosteroids	Adolescents: Upadacitinib 30 mg + Topical Corticosteroids
Arm/Group Description:	Adolescent participants received placebo orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Adolescent participants received upadacitinib 15 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Adolescent participants received upadacitinib 30 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.
Overall Number of Participants Analyzed	61	57	56
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	9.8; (2.4 to 17.3)	8.8; (1.4 to 16.1)	16.1; (6.5 to 25.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo + Topical Corticosteroids, Adolescents: Upadacitinib 30 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.306
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for stratum (Baseline vIGA-AD categories)
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	6.2
	Confidence Interval	(2-Sided) 95%; -5.7 to 18.2
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo + Topical Corticosteroids, Adolescents: Upadacitinib 15 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.855
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for stratum (Baseline vIGA-AD categories)
Method of Estimation	Estimation Parameter	Adjusted Response Rate Difference
	Estimated Value	-1.0
	Confidence Interval	(2-Sided) 95%; -11.2 to 9.3
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

23. Secondary Outcome

Title	Adolescents: Percent Change From Baseline in Worst Pruritus NRS at Week 16
Description	Participants were asked to rate itch (pruritus) intensity at its worst during the past 24 hours on a daily basis using an 11-point scale from 0 (no itch) to 10 (worst imaginable itch). Pruritus NRS was analyzed based on weekly rolling averages of daily scores. A negative change from Baseline indicates improvement.
Time Frame	Baseline (last available rolling average before the first dose of study drug) and Week 16

Outcome Measure Data

Analysis Population Description

Intent-to-treat population for adolescents with non-missing Baseline and Week 16 values; missing data were handled using a mixed-effect model with repeated measurements including observed measurements at all visits, except that measurements after any rescue medication were excluded.

Arm/Group Title	Adolescents: Placebo + Topical Corticosteroids	Adolescents: Upadacitinib 15 mg + Topical Corticosteroids	Adolescents: Upadacitinib 30 mg + Topical Corticosteroids
Arm/Group Description:	Adolescent participants received placebo orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Adolescent participants received upadacitinib 15 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Adolescent participants received upadacitinib 30 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.
Overall Number of Participants Analyzed	41	50	49
Least Squares Mean (95% Confidence Interval); Unit of Measure: percent change
	-32.96; (-49.87 to -16.05)	-59.34; (-75.78 to -42.90)	-49.02; (-65.35 to -32.69)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo + Topical Corticosteroids, Adolescents: Upadacitinib 30 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.180
	Comments	[Not Specified]
	Method	Mixed Effect Model Repeated Measurement
	Comments	Mixed-effect model repeat measurement with Baseline, treatment, visit, treatment by visit interaction, and Baseline vIGA-AD category in the model.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-16.05
	Confidence Interval	(2-Sided) 95%; -39.59 to 7.48
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 11.956
	Estimation Comments	Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo + Topical Corticosteroids, Adolescents: Upadacitinib 15 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.029
	Comments	[Not Specified]
	Method	Mixed Effect Model Repeated Measurement
	Comments	Mixed-effect model repeat measurement with Baseline, treatment, visit, treatment by visit interaction, and Baseline vIGA-AD category in the model.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-26.38
	Confidence Interval	(2-Sided) 95%; -49.97 to -2.79
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 11.986
	Estimation Comments	Difference = Upadacitinib - Placebo

24. Secondary Outcome

Title	Adolescents: Percent Change From Baseline in EASI Score at Week 16
Description	EASI is a tool used to measure the extent (area) and severity of atopic eczema based on assessments of the head/neck, trunk, upper limbs and lower limbs. For each region the area score is recorded as the percentage of skin affected by eczema. For each region, the severity score is calculated as the sum of the intensity scores (scored as none [0], mild [1)] moderate [2], or severe [3]) for Redness (erythema, inflammation), Thickness (induration, papulation, swelling - acute eczema), Scratching (excoriation), and Lichenification (lined skin, prurigo nodules - chronic eczema). The total EASI score for each region is calculated by multiplying the severity score by the area score, with adjustment for the proportion of the body region to the whole body. The final EASI score is the sum of the 4 region scores and ranges from 0 to 72 where higher scores represent worse disease; a negative change from Baseline indicates improvement.
Time Frame	Baseline and Week 16

Outcome Measure Data

Analysis Population Description

Intent-to-treat population for adolescents with non-missing Baseline and Week 16 values; missing data were handled using a mixed-effect model with repeated measurements including observed measurements at all visits, except that measurements after any rescue medication were excluded.

Arm/Group Title	Adolescents: Placebo + Topical Corticosteroids	Adolescents: Upadacitinib 15 mg + Topical Corticosteroids	Adolescents: Upadacitinib 30 mg + Topical Corticosteroids
Arm/Group Description:	Adolescent participants received placebo orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Adolescent participants received upadacitinib 15 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.	Adolescent participants received upadacitinib 30 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.
Overall Number of Participants Analyzed	48	55	58
Least Squares Mean (95% Confidence Interval); Unit of Measure: percent change
	-53.53; (-61.23 to -45.82)	-77.90; (-85.36 to -70.44)	-89.22; (-96.49 to -81.95)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo + Topical Corticosteroids, Adolescents: Upadacitinib 30 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Mixed Effect Model Repeated Measurement
	Comments	Mixed-Effect Model Repeat Measurement with Baseline, treatment, visit, treatment by visit interaction, and Baseline vIGA-AD category in the model.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-35.69
	Confidence Interval	(2-Sided) 95%; -46.28 to -25.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.354
	Estimation Comments	Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo + Topical Corticosteroids, Adolescents: Upadacitinib 15 mg + Topical Corticosteroids
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Mixed Effect Model Repeated Measurement
	Comments	Mixed-Effect Model Repeat Measurement with Baseline, treatment, visit, treatment by visit interaction, and Baseline vIGA-AD category in the model.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-24.37
	Confidence Interval	(2-Sided) 95%; -35.10 to -13.65
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.423
	Estimation Comments	Difference = Upadacitinib - Placebo

Adverse Events

Time Frame

From first dose of study drug up to Week 16, or 30 days after last dose for participants who did not enter the blinded extension period.

Adverse Event Reporting Description

[Not Specified]

Arm/Group Title

Adults: Placebo + Topical Corticosteroids

Adults: Upadacitinib 15 mg + Topical Corticosteroids

Adults: Upadacitinib 30 mg + Topical Corticosteroids

Adolescents: Placebo + Topical Corticosteroids

Adolescents: Upadacitinib 15 mg + Topical Corticosteroids

Adolescents: Upadacitinib 30 mg + Topical Corticosteroids

Arm/Group Description

Participants ≥ 18 years old received placebo orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.

Participants ≥ 18 years old received upadacitinib 15 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.

Participants ≥ 18 years old received upadacitinib 30 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.

Adolescent participants received placebo orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.

Adolescent participants received upadacitinib 15 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.

Adolescent participants received upadacitinib 30 mg orally once a day and topical corticosteroids following a step-down regimen for 16 weeks in the double-blind treatment period.

All-Cause Mortality

Adults: Placebo + Topical Corticosteroids

Adults: Upadacitinib 15 mg + Topical Corticosteroids

Adults: Upadacitinib 30 mg + Topical Corticosteroids

Adolescents: Placebo + Topical Corticosteroids

Adolescents: Upadacitinib 15 mg + Topical Corticosteroids

Adolescents: Upadacitinib 30 mg + Topical Corticosteroids

Affected / at Risk (%)

Affected / at Risk (%)

Affected / at Risk (%)

Affected / at Risk (%)

Affected / at Risk (%)

Affected / at Risk (%)

Total

0/264 (0.00%)

0/261 (0.00%)

0/260 (0.00%)

0/62 (0.00%)

0/60 (0.00%)

0/60 (0.00%)

Serious Adverse Events

Adults: Placebo + Topical Corticosteroids

Adults: Upadacitinib 15 mg + Topical Corticosteroids

Adults: Upadacitinib 30 mg + Topical Corticosteroids

Adolescents: Placebo + Topical Corticosteroids

Adolescents: Upadacitinib 15 mg + Topical Corticosteroids

Adolescents: Upadacitinib 30 mg + Topical Corticosteroids

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Total

9/264 (3.41%)

7/261 (2.68%)

4/260 (1.54%)

0/62 (0.00%)

1/60 (1.67%)

0/60 (0.00%)

Blood and lymphatic system disorders

PANCYTOPENIA † 1

0/264 (0.00%)

0

0/261 (0.00%)

0

1/260 (0.38%)

1

0/62 (0.00%)

0

0/60 (0.00%)

0

0/60 (0.00%)

0

Cardiac disorders

CARDIAC FAILURE CONGESTIVE † 1

0/264 (0.00%)

0

0/261 (0.00%)

0

1/260 (0.38%)

1

0/62 (0.00%)

0

0/60 (0.00%)

0

0/60 (0.00%)

0

Eye disorders

RETINAL DETACHMENT † 1

0/264 (0.00%)

0

1/261 (0.38%)

1

0/260 (0.00%)

0

0/62 (0.00%)

0

0/60 (0.00%)

0

0/60 (0.00%)

0

RHEGMATOGENOUS RETINAL DETACHMENT † 1

1/264 (0.38%)

1

0/261 (0.00%)

0

0/260 (0.00%)

0

0/62 (0.00%)

0

0/60 (0.00%)

0

0/60 (0.00%)

0

General disorders

VASCULAR STENT THROMBOSIS † 1

1/264 (0.38%)

1

0/261 (0.00%)

0

0/260 (0.00%)

0

0/62 (0.00%)

0

0/60 (0.00%)

0

0/60 (0.00%)

0

Immune system disorders

ANAPHYLACTIC REACTION † 1

1/264 (0.38%)

1

0/261 (0.00%)

0

1/260 (0.38%)

1

0/62 (0.00%)

0

0/60 (0.00%)

0

0/60 (0.00%)

0

Infections and infestations

ANAL ABSCESS † 1

1/264 (0.38%)

1

0/261 (0.00%)

0

0/260 (0.00%)

0

0/62 (0.00%)

0

0/60 (0.00%)

0

0/60 (0.00%)

0

APPENDICITIS † 1

0/264 (0.00%)

0

1/261 (0.38%)

1

0/260 (0.00%)

0

0/62 (0.00%)

0

0/60 (0.00%)

0

0/60 (0.00%)

0

PERITONSILLAR ABSCESS † 1

0/264 (0.00%)

0

1/261 (0.38%)

1

0/260 (0.00%)

0

0/62 (0.00%)

0

0/60 (0.00%)

0

0/60 (0.00%)

0

PHARYNGITIS STREPTOCOCCAL † 1

0/264 (0.00%)

0

1/261 (0.38%)

1

0/260 (0.00%)

0

0/62 (0.00%)

0

0/60 (0.00%)

0

0/60 (0.00%)

0

PNEUMONIA † 1

1/264 (0.38%)

1

0/261 (0.00%)

0

0/260 (0.00%)

0

0/62 (0.00%)

0

0/60 (0.00%)

0

0/60 (0.00%)

0

STAPHYLOCOCCAL SEPSIS † 1

1/264 (0.38%)

1

0/261 (0.00%)

0

0/260 (0.00%)

0

0/62 (0.00%)

0

0/60 (0.00%)

0

0/60 (0.00%)

0

URINARY TRACT INFECTION † 1

1/264 (0.38%)

1

0/261 (0.00%)

0

0/260 (0.00%)

0

0/62 (0.00%)

0

0/60 (0.00%)

0

0/60 (0.00%)

0

Injury, poisoning and procedural complications

LIGAMENT RUPTURE † 1

0/264 (0.00%)

0

0/261 (0.00%)

0

0/260 (0.00%)

0

0/62 (0.00%)

0

1/60 (1.67%)

1

0/60 (0.00%)

0

OVERDOSE † 1

0/264 (0.00%)

0

1/261 (0.38%)

1

0/260 (0.00%)

0

0/62 (0.00%)

0

0/60 (0.00%)

0

0/60 (0.00%)

0

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

ADENOCARCINOMA OF COLON † 1

0/264 (0.00%)

0

0/261 (0.00%)

0

1/260 (0.38%)

1

0/62 (0.00%)

0

0/60 (0.00%)

0

0/60 (0.00%)

0

Renal and urinary disorders

HYDRONEPHROSIS † 1

0/264 (0.00%)

0

1/261 (0.38%)

1

0/260 (0.00%)

0

0/62 (0.00%)

0

0/60 (0.00%)

0

0/60 (0.00%)

0

NEPHROLITHIASIS † 1

0/264 (0.00%)

0

1/261 (0.38%)

1

0/260 (0.00%)

0

0/62 (0.00%)

0

0/60 (0.00%)

0

0/60 (0.00%)

0

Respiratory, thoracic and mediastinal disorders

ACUTE RESPIRATORY FAILURE † 1

1/264 (0.38%)

1

0/261 (0.00%)

0

0/260 (0.00%)

0

0/62 (0.00%)

0

0/60 (0.00%)

0

0/60 (0.00%)

0

ASTHMA † 1

0/264 (0.00%)

0

1/261 (0.38%)

1

0/260 (0.00%)

0

0/62 (0.00%)

0

0/60 (0.00%)

0

0/60 (0.00%)

0

OROPHARYNGEAL PAIN † 1

0/264 (0.00%)

0

1/261 (0.38%)

1

0/260 (0.00%)

0

0/62 (0.00%)

0

0/60 (0.00%)

0

0/60 (0.00%)

0

PLEURAL EFFUSION † 1

0/264 (0.00%)

0

1/261 (0.38%)

1

0/260 (0.00%)

0

0/62 (0.00%)

0

0/60 (0.00%)

0

0/60 (0.00%)

0

STATUS ASTHMATICUS † 1

0/264 (0.00%)

0

1/261 (0.38%)

1

0/260 (0.00%)

0

0/62 (0.00%)

0

0/60 (0.00%)

0

0/60 (0.00%)

0

Skin and subcutaneous tissue disorders

DERMATITIS EXFOLIATIVE GENERALISED † 1

1/264 (0.38%)

1

0/261 (0.00%)

0

0/260 (0.00%)

0

0/62 (0.00%)

0

0/60 (0.00%)

0

0/60 (0.00%)

0

ECZEMA † 1

1/264 (0.38%)

1

0/261 (0.00%)

0

0/260 (0.00%)

0

0/62 (0.00%)

0

0/60 (0.00%)

0

0/60 (0.00%)

0

ERYTHRODERMIC ATOPIC DERMATITIS † 1

1/264 (0.38%)

1

0/261 (0.00%)

0

0/260 (0.00%)

0

0/62 (0.00%)

0

0/60 (0.00%)

0

0/60 (0.00%)

0

Vascular disorders

HAEMATOMA † 1

1/264 (0.38%)

1

0/261 (0.00%)

0

0/260 (0.00%)

0

0/62 (0.00%)

0

0/60 (0.00%)

0

0/60 (0.00%)

0

1 Term from vocabulary, MedDRA (22.1); † Indicates events were collected by systematic assessment

Other (Not Including Serious) Adverse Events

Frequency Threshold for Reporting Other Adverse Events

5%

Adults: Placebo + Topical Corticosteroids

Adults: Upadacitinib 15 mg + Topical Corticosteroids

Adults: Upadacitinib 30 mg + Topical Corticosteroids

Adolescents: Placebo + Topical Corticosteroids

Adolescents: Upadacitinib 15 mg + Topical Corticosteroids

Adolescents: Upadacitinib 30 mg + Topical Corticosteroids

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Total

99/264 (37.50%)

111/261 (42.53%)

123/260 (47.31%)

21/62 (33.87%)

24/60 (40.00%)

32/60 (53.33%)

Gastrointestinal disorders

ABDOMINAL PAIN † 1

0/264 (0.00%)

0

6/261 (2.30%)

7

2/260 (0.77%)

3

1/62 (1.61%)

1

0/60 (0.00%)

0

3/60 (5.00%)

3

DIARRHOEA † 1

4/264 (1.52%)

4

10/261 (3.83%)

10

9/260 (3.46%)

10

4/62 (6.45%)

4

1/60 (1.67%)

2

3/60 (5.00%)

3

VOMITING † 1

2/264 (0.76%)

2

1/261 (0.38%)

1

0/260 (0.00%)

0

1/62 (1.61%)

1

1/60 (1.67%)

1

4/60 (6.67%)

4

General disorders

PYREXIA † 1

3/264 (1.14%)

3

5/261 (1.92%)

5

3/260 (1.15%)

3

0/62 (0.00%)

0

0/60 (0.00%)

0

4/60 (6.67%)

5

Infections and infestations

NASOPHARYNGITIS † 1

31/264 (11.74%)

38

31/261 (11.88%)

38

37/260 (14.23%)

42

3/62 (4.84%)

3

6/60 (10.00%)

8

3/60 (5.00%)

3

ORAL HERPES † 1

5/264 (1.89%)

7

9/261 (3.45%)

13

22/260 (8.46%)

26

1/62 (1.61%)

1

2/60 (3.33%)

2

1/60 (1.67%)

1

STAPHYLOCOCCAL SKIN INFECTION † 1

1/264 (0.38%)

2

1/261 (0.38%)

1

1/260 (0.38%)

1

4/62 (6.45%)

5

0/60 (0.00%)

0

1/60 (1.67%)

2

UPPER RESPIRATORY TRACT INFECTION † 1

21/264 (7.95%)

24

20/261 (7.66%)

21

19/260 (7.31%)

21

1/62 (1.61%)

1

1/60 (1.67%)

1

4/60 (6.67%)

7

VIRAL UPPER RESPIRATORY TRACT INFECTION † 1

3/264 (1.14%)

3

5/261 (1.92%)

6

3/260 (1.15%)

3

1/62 (1.61%)

1

0/60 (0.00%)

0

3/60 (5.00%)

4

Investigations

BLOOD CREATINE PHOSPHOKINASE INCREASED † 1

7/264 (2.65%)

7

12/261 (4.60%)

12

16/260 (6.15%)

16

1/62 (1.61%)

1

1/60 (1.67%)

1

3/60 (5.00%)

3

Nervous system disorders

HEADACHE † 1

12/264 (4.55%)

13

11/261 (4.21%)

13

11/260 (4.23%)

15

4/62 (6.45%)

5

5/60 (8.33%)

5

4/60 (6.67%)

4

Respiratory, thoracic and mediastinal disorders

CATARRH † 1

0/264 (0.00%)

0

2/261 (0.77%)

2

0/260 (0.00%)

0

1/62 (1.61%)

1

2/60 (3.33%)

2

3/60 (5.00%)

3

COUGH † 1

4/264 (1.52%)

5

10/261 (3.83%)

11

10/260 (3.85%)

10

0/62 (0.00%)

0

3/60 (5.00%)

3

1/60 (1.67%)

1

Skin and subcutaneous tissue disorders

ACNE † 1

6/264 (2.27%)

6

25/261 (9.58%)

27

36/260 (13.85%)

39

1/62 (1.61%)

1

8/60 (13.33%)

9

9/60 (15.00%)

9

DERMATITIS ATOPIC † 1

18/264 (6.82%)

19

8/261 (3.07%)

8

2/260 (0.77%)

2

4/62 (6.45%)

5

3/60 (5.00%)

3

0/60 (0.00%)

0

1 Term from vocabulary, MedDRA (22.1); † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

AbbVie requests that any investigator or institution that plans on presenting/publishing results disclosure, provide written notification of their request 60 days prior to their presentation/publication. AbbVie requests that no presentation/publication will be instituted until 12 months after a study is completed, or after the first presentation/publication whichever occurs first. A delay may be proposed of a presentation/publication if AbbVie needs to secure patent or proprietary protection.

Results Point of Contact

• Name/Title: Global Medical Services
• Organization: AbbVie
• Phone: 800-633-9110
• EMail: abbvieclinicaltrials@abbvie.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Silverberg JI, Simpson EL, Calimlim BM, Litcher-Kelly L, Li X, Sun X, Leshem YA. Determining Severity Strata for Three Atopic Dermatitis Patient-Reported Outcome Questionnaires: Defining Severity Score Ranges for the Worst Pruritus Numerical Rating Scale and the Atopic Dermatitis Symptom and Impact Scales (ADerm-SS and ADerm-IS). Dermatol Ther (Heidelb). 2022 Dec;12(12):2817-2827. doi: 10.1007/s13555-022-00836-5. Epub 2022 Nov 4.

Mendes-Bastos P, Ladizinski B, Guttman-Yassky E, Jiang P, Liu J, Prajapati VH, Simpson EL, Vigna N, Teixeira HD, Barbarot S. Characterization of acne associated with upadacitinib treatment in patients with moderate-to-severe atopic dermatitis: A post hoc integrated analysis of 3 phase 3 randomized, double-blind, placebo-controlled trials. J Am Acad Dermatol. 2022 Oct;87(4):784-791. doi: 10.1016/j.jaad.2022.06.012. Epub 2022 Jun 15.

Reich K, Teixeira HD, de Bruin-Weller M, Bieber T, Soong W, Kabashima K, Werfel T, Zeng J, Huang X, Hu X, Hendrickson BA, Ladizinski B, Chu AD, Silverberg JI. Safety and efficacy of upadacitinib in combination with topical corticosteroids in adolescents and adults with moderate-to-severe atopic dermatitis (AD Up): results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2021 Jun 5;397(10290):2169-2181. doi: 10.1016/S0140-6736(21)00589-4. Epub 2021 May 21. Erratum In: Lancet. 2021 Jun 19;397(10292):2336. Lancet. 2021 Aug 28;398(10302):746.

• Responsible Party: AbbVie
• ClinicalTrials.gov Identifier: NCT03568318
• Other Study ID Numbers: M16-047; 2017-005126-37 ( EudraCT Number )
• First Submitted: June 14, 2018
• First Posted: June 26, 2018
• Results First Submitted: February 7, 2022
• Results First Posted: March 31, 2022
• Last Update Posted: March 31, 2022