Evaluation of Upadacitinib in Adolescent and Adult Patients With Moderate to Severe Atopic Dermatitis (Eczema) (Measure Up 1)

• ClinicalTrials.gov Identifier: NCT03569293
• Recruitment Status: Active, not recruiting
• First Posted: June 26, 2018
• Results First Posted: February 3, 2022
• Last Update Posted: February 3, 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 for Upadacitinib; Drug: Upadacitinib
• Enrollment: 912

Participant Flow

Recruitment Details

Participants were enrolled at 151 study sites in 24 countries across Europe, North and South America, Oceania, and the Asia-Pacific region. The study included a 16-week double-blind treatment period followed by an ongoing blinded extension period. 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	Adults: Upadacitinib 15 mg QD	Adults: Upadacitinib 30 mg QD	Adolescents: Placebo	Adolescents: Upadacitinib 15 mg QD	Adolescents: Upadacitinib 30 mg QD
Arm/Group Description	Participants ≥ 18 years old received placebo orally once a day (QD) for 16 weeks.	Participants ≥ 18 years old received upadacitinib 15 mg orally once a day for 16 weeks.	Participants ≥ 18 years old received upadacitinib 30 mg orally once a day for 16 weeks.	Adolescent participants (12 - 17 years old) received placebo orally once a day for 16 weeks.	Adolescent participants received upadacitinib 15 mg orally once a day for 16 weeks.	Adolescent participants received upadacitinib 30 mg orally once a day for 16 weeks.
Period Title: Overall Study
Started [1]	241	239	243	61	64	64
Received Study Drug	241	239	243	61	64	64
Completed [2]	204	230	229	57	64	64
Not Completed	37	9	14	4	0	0
Reason Not Completed
Adverse Event	4	1	5	1	0	0
Withdrawal by Subject	16	2	4	1	0	0
Lost to Follow-up	1	3	1	1	0	0
Other	8	2	1	1	0	0
Ongoing at Time of Analysis	8	1	3	0	0	0
[1] Randomized into study; [2] Completed Week 16

Baseline Characteristics

Arm/Group Title		Adults: Placebo	Adults: Upadacitinib 15 mg QD	Adults: Upadacitinib 30 mg QD	Adolescents: Placebo	Adolescents: Upadacitinib 15 mg QD	Adolescents: Upadacitinib 30 mg QD	Total
Arm/Group Description		Participants ≥ 18 years old received placebo orally once a day for 16 weeks.	Participants ≥ 18 years old received upadacitinib 15 mg orally once a day for 16 weeks.	Participants ≥ 18 years old received upadacitinib 30 mg orally once a day for 16 weeks.	Adolescent participants (12 - 17 years old) received placebo orally once a day for 16 weeks.	Adolescent participants received upadacitinib 15 mg orally once a day for 16 weeks.	Adolescent participants received upadacitinib 30 mg orally once a day for 16 weeks.	Total of all reporting groups
Overall Number of Baseline Participants		241	239	243	61	64	64	912
Baseline Analysis Population Description		All randomized participants
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	241 participants	239 participants	243 participants	61 participants	64 participants	64 participants	912 participants
		37.6 (14.44)	37.3 (14.80)	36.7 (15.12)	15.1 (1.70)	15.5 (1.99)	15.7 (1.63)	32.7 (15.87)
Age, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	241 participants	239 participants	243 participants	61 participants	64 participants	64 participants	912 participants
	12 - 14 years	0 0.0%	0 0.0%	0 0.0%	23 37.7%	22 34.4%	15 23.4%	60 6.6%
	15 - 17 years	0 0.0%	0 0.0%	0 0.0%	38 62.3%	42 65.6%	49 76.6%	129 14.1%
	18 - < 40 years	145 60.2%	143 59.8%	154 63.4%	0 0.0%	0 0.0%	0 0.0%	442 48.5%
	40 - < 65 years	85 35.3%	83 34.7%	74 30.5%	0 0.0%	0 0.0%	0 0.0%	242 26.5%
	≥ 65 years	11 4.6%	13 5.4%	15 6.2%	0 0.0%	0 0.0%	0 0.0%	39 4.3%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	241 participants	239 participants	243 participants	61 participants	64 participants	64 participants	912 participants
	Female	114 47.3%	103 43.1%	110 45.3%	33 54.1%	34 53.1%	36 56.3%	430 47.1%
	Male	127 52.7%	136 56.9%	133 54.7%	28 45.9%	30 46.9%	28 43.8%	482 52.9%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	241 participants	239 participants	243 participants	61 participants	64 participants	64 participants	912 participants
	Hispanic or Latino	30 12.4%	27 11.3%	34 14.0%	10 16.4%	13 20.3%	19 29.7%	133 14.6%
	Not Hispanic or Latino	211 87.6%	212 88.7%	209 86.0%	51 83.6%	51 79.7%	45 70.3%	779 85.4%
	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	241 participants	239 participants	243 participants	61 participants	64 participants	64 participants	912 participants
	American Indian or Alaska Native	1 0.4%	0 0.0%	0 0.0%	2 3.3%	0 0.0%	0 0.0%	3 0.3%
	Asian	62 25.7%	57 23.8%	61 25.1%	10 16.4%	12 18.8%	10 15.6%	212 23.2%
	Native Hawaiian or Other Pacific Islander	1 0.4%	1 0.4%	1 0.4%	0 0.0%	0 0.0%	0 0.0%	3 0.3%
	Black or African American	16 6.6%	20 8.4%	7 2.9%	6 9.8%	6 9.4%	0 0.0%	55 6.0%
	White	157 65.1%	153 64.0%	163 67.1%	41 67.2%	45 70.3%	50 78.1%	609 66.8%
	More than one race	4 1.7%	8 3.3%	11 4.5%	2 3.3%	1 1.6%	4 6.3%	30 3.3%
	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	241 participants	239 participants	243 participants	61 participants	64 participants	64 participants	912 participants
	Main Study	241 100.0%	239 100.0%	243 100.0%	40 65.6%	42 65.6%	42 65.6%	847 92.9%
	Adolescent Substudy	0 0.0%	0 0.0%	0 0.0%	21 34.4%	22 34.4%	22 34.4%	65 7.1%
Geographic Region; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	241 participants	239 participants	243 participants	61 participants	64 participants	64 participants	912 participants
	US/Puerto Rico/Canada	108 44.8%	107 44.8%	108 44.4%	31 50.8%	33 51.6%	33 51.6%	420 46.1%
	Japan	13 5.4%	14 5.9%	14 5.8%	1 1.6%	1 1.6%	2 3.1%	45 4.9%
	China	13 5.4%	13 5.4%	15 6.2%	1 1.6%	1 1.6%	2 3.1%	45 4.9%
	Other	107 44.4%	105 43.9%	106 43.6%	28 45.9%	29 45.3%	27 42.2%	402 44.1%
vIGA-AD [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	241 participants	239 participants	243 participants	61 participants	64 participants	64 participants	912 participants
	3 (Moderate)	132 54.8%	130 54.4%	129 53.1%	35 57.4%	35 54.7%	37 57.8%	498 54.6%
	4 (Severe)	109 45.2%	109 45.6%	114 46.9%	26 42.6%	29 45.3%	27 42.2%	414 45.4%
		[1] Measure Description: The vIGA-AD was used to assess the severity of AD 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	241 participants	239 participants	243 participants	61 participants	64 participants	64 participants	912 participants
		28.39 (12.082)	30.34 (12.651)	29.06 (11.270)	29.65 (14.054)	30.70 (12.816)	27.77 (10.625)	29.28 (12.125)
		[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; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	241 participants	239 participants	243 participants	61 participants	64 participants	64 participants	912 participants
		22.704 (15.9393)	22.010 (16.6733)	21.655 (15.0471)	11.391 (5.0989)	12.027 (4.5017)	12.443 (4.4464)	20.017 (14.8779)

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	Upadacitinib 15 mg QD	Upadacitinib 30 mg QD
Arm/Group Description:	Participants received placebo orally once a day for 16 weeks.	Participants received upadacitinib 15 mg orally once daily for 16 weeks.	Participants received upadacitinib 30 mg orally once daily for 16 weeks.
Overall Number of Participants Analyzed	281	281	285
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	16.3; (12.0 to 20.7)	69.6; (64.2 to 75.0)	79.7; (75.0 to 84.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 30 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 30 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	63.4
	Confidence Interval	(2-Sided) 95%; 57.1 to 69.8
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 15 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	53.3
	Confidence Interval	(2-Sided) 95%; 46.4 to 60.2
	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	Upadacitinib 15 mg QD	Upadacitinib 30 mg QD
Arm/Group Description:	Participants received placebo orally once a day for 16 weeks.	Participants received upadacitinib 15 mg orally once daily for 16 weeks.	Participants received upadacitinib 30 mg orally once daily for 16 weeks.
Overall Number of Participants Analyzed	281	281	285
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	8.4; (5.2 to 11.7)	48.1; (42.3 to 54.0)	62.0; (56.4 to 67.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 30 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 30 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	53.6
	Confidence Interval	(2-Sided) 95%; 47.2 to 60.0
	Estimation Comments	Response rate difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 15 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	39.8
	Confidence Interval	(2-Sided) 95%; 33.2 to 46.4
	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	Upadacitinib 15 mg QD	Upadacitinib 30 mg QD
Arm/Group Description:	Participants received placebo orally once a day for 16 weeks.	Participants received upadacitinib 15 mg orally once daily for 16 weeks.	Participants received upadacitinib 30 mg orally once daily for 16 weeks.
Overall Number of Participants Analyzed	272	274	280
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	11.8; (7.9 to 15.6)	52.2; (46.3 to 58.1)	60.0; (54.3 to 65.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 30 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 30 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	48.2
	Confidence Interval	(2-Sided) 95%; 41.3 to 55.0
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 15 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	40.5
	Confidence Interval	(2-Sided) 95%; 33.5 to 47.5
	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	Upadacitinib 15 mg QD	Upadacitinib 30 mg QD
Arm/Group Description:	Participants received placebo orally once a day for 16 weeks.	Participants received upadacitinib 15 mg orally once daily for 16 weeks.	Participants received upadacitinib 30 mg orally once daily for 16 weeks.
Overall Number of Participants Analyzed	281	281	285
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	8.1; (4.9 to 11.3)	53.1; (47.2 to 58.9)	65.8; (60.2 to 71.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 30 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 30 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	57.8
	Confidence Interval	(2-Sided) 95%; 51.5 to 64.1
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 15 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	45.1
	Confidence Interval	(2-Sided) 95%; 38.6 to 51.7
	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	Upadacitinib 15 mg QD	Upadacitinib 30 mg QD
Arm/Group Description:	Participants received placebo orally once a day for 16 weeks.	Participants received upadacitinib 15 mg orally once daily for 16 weeks.	Participants received upadacitinib 30 mg orally once daily for 16 weeks.
Overall Number of Participants Analyzed	272	274	280
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	4.4; (2.0 to 6.9)	51.5; (45.5 to 57.4)	66.8; (61.3 to 72.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 30 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 30 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	62.3
	Confidence Interval	(2-Sided) 95%; 56.3 to 68.3
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 15 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	47.1
	Confidence Interval	(2-Sided) 95%; 40.7 to 53.4
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

6. 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	Upadacitinib 15 mg QD	Upadacitinib 30 mg QD
Arm/Group Description:	Participants received placebo orally once a day for 16 weeks.	Participants received upadacitinib 15 mg orally once daily for 16 weeks.	Participants received upadacitinib 30 mg orally once daily for 16 weeks.
Overall Number of Participants Analyzed	281	281	285
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	3.6; (1.4 to 5.7)	38.1; (32.4 to 43.8)	47.4; (41.6 to 53.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 30 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 30 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	43.9
	Confidence Interval	(2-Sided) 95%; 37.7 to 50.0
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 15 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	34.5
	Confidence Interval	(2-Sided) 95%; 28.6 to 40.5
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

7. 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	Upadacitinib 15 mg QD	Upadacitinib 30 mg QD
Arm/Group Description:	Participants received placebo orally once a day for 16 weeks.	Participants received upadacitinib 15 mg orally once daily for 16 weeks.	Participants received upadacitinib 30 mg orally once daily for 16 weeks.
Overall Number of Participants Analyzed	272	274	280
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	0.4; (0.0 to 1.1)	15.0; (10.7 to 19.2)	19.6; (15.0 to 24.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 30 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 30 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	19.2
	Confidence Interval	(2-Sided) 95%; 14.6 to 23.9
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 15 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	14.6
	Confidence Interval	(2-Sided) 95%; 10.3 to 18.8
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

8. Secondary Outcome

Title	Main Study: Percentage of Participants Achieving a Reduction of ≥ 4 Points From Baseline in Worst Pruritus NRS at Day 2
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). The percentage of participants who had a 4-point or greater improvement from Baseline in Worst Pruritus NRS score at Day 2 was pre-specified as a ranked secondary endpoint for participants in the upadacitinib 30 mg group versus placebo group only.
Time Frame	Baseline and Day 2

Outcome Measure Data

Analysis Population Description

Intent-to-treat population for the main study with Worst Pruritus NRS (daily score) ≥ 4 at Baseline; Non-responder imputation with no special data handling for missing data due to COVID-19 (NRI-NC) was used.

Arm/Group Title	Placebo	Upadacitinib 15 mg QD	Upadacitinib 30 mg QD
Arm/Group Description:	Participants received placebo orally once a day for 16 weeks.	Participants received upadacitinib 15 mg orally once daily for 16 weeks.	Participants received upadacitinib 30 mg orally once daily for 16 weeks.
Overall Number of Participants Analyzed	270	275	279
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	3.7; (1.5 to 6.0)	10.5; (6.9 to 14.2)	11.8; (8.0 to 15.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 30 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 30 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	8.1
	Confidence Interval	(2-Sided) 95%; 3.8 to 12.5
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

9. Secondary Outcome

Title	Main Study: Percentage of Participants Achieving a Reduction of ≥ 4 Points From Baseline in Worst Pruritus NRS at Day 3
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). The percentage of participants who had a 4-point or greater improvement in Worst Pruritus NRS score from Baseline at Day 3 was pre-specified as a ranked secondary endpoint for participants in the upadacitinib 15 mg group versus placebo group only.
Time Frame	Baseline and Day 3

Outcome Measure Data

Analysis Population Description

Intent-to-treat population for the main study with Worst Pruritus NRS (daily score) ≥ 4 at Baseline; Non-responder imputation with no special data handling for missing data due to COVID-19 (NRI-NC) was used.

Arm/Group Title	Placebo	Upadacitinib 15 mg QD	Upadacitinib 30 mg QD
Arm/Group Description:	Participants received placebo orally once a day for 16 weeks.	Participants received upadacitinib 15 mg orally once daily for 16 weeks.	Participants received upadacitinib 30 mg orally once daily for 16 weeks.
Overall Number of Participants Analyzed	270	275	279
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	3.3; (1.2 to 5.5)	16.4; (12.0 to 20.7)	21.1; (16.4 to 25.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 15 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	13.0
	Confidence Interval	(2-Sided) 95%; 8.1 to 17.8
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

10. Secondary Outcome

Title	Main Study: Percentage of Participants Experiencing a Flare During the Double-blind Treatment Period
Description	A flare, characterized as a clinically meaningful worsening in EASI, is defined as an increase in EASI score of ≥ 6.6 points from Baseline during the double-blind treatment period and prior to use of any rescue medication. Flare was assessed in participants with an EASI score of 65.4 or less at Baseline.
Time Frame	From first dose of study drug to Week 16

Outcome Measure Data

Analysis Population Description

Intent-to-treat population for the main study with an EASI score ≤ 65.4 at Baseline and at least one EASI post-baseline assessment prior to use of rescue medication.

Arm/Group Title	Placebo	Upadacitinib 15 mg QD	Upadacitinib 30 mg QD
Arm/Group Description:	Participants received placebo orally once a day for 16 weeks.	Participants received upadacitinib 15 mg orally once daily for 16 weeks.	Participants received upadacitinib 30 mg orally once daily for 16 weeks.
Overall Number of Participants Analyzed	274	279	285
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	25.2; (20.0 to 30.3)	1.1; (0.0 to 2.3)	0.0 [1]; (NA to NA)

[1]

Could not be calculated using the normal approximation to the binomial distribution

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 30 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 30 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	-25.2
	Confidence Interval	(2-Sided) 95%; -30.3 to -20.1
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 15 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	-24.1
	Confidence Interval	(2-Sided) 95%; -29.3 to -18.9
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

11. Secondary Outcome

Title	Main Study: Percentage of Participants Achieving a Reduction of ≥ 12 Points From Baseline in Atopic Dermatitis Impact Scale (ADerm-IS) Sleep Domain Score at Week 16
Description	The ADerm-IS is a 10-item patient reported outcome (PRO) questionnaire designed to assess a variety of impacts that participants experience from their AD. The ADerm-IS sleep domain consists of 3 questions designed to assess the impact of AD on sleep on a daily basis over a 24-hour recall period. The items include difficulty falling asleep, impact on sleep, and waking at night. Each question is scored on an 11-point NRS from 0 (no impact) to 10 (extreme impact). The ADerm-IS sleep domain score is the sum of the 3 item scores and ranges from 0 (no impact) to 30 (worst impact). The ADerm-IS sleep domain was analyzed based on weekly rolling averages of daily scores. The minimal clinically important difference for ADerm-IS sleep domain score is 12.
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 ADerm-IS Sleep Domain score ≥ 12 at Baseline; Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) was used.

Arm/Group Title	Placebo	Upadacitinib 15 mg QD	Upadacitinib 30 mg QD
Arm/Group Description:	Participants received placebo orally once a day for 16 weeks.	Participants received upadacitinib 15 mg orally once daily for 16 weeks.	Participants received upadacitinib 30 mg orally once daily for 16 weeks.
Overall Number of Participants Analyzed	220	218	218
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	13.2; (8.7 to 17.7)	55.0; (48.4 to 61.6)	66.1; (59.8 to 72.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 30 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 30 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	52.9
	Confidence Interval	(2-Sided) 95%; 45.2 to 60.6
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 15 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	41.8
	Confidence Interval	(2-Sided) 95%; 33.9 to 49.7
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

12. Secondary Outcome

Title	Main Study: Percentage of Participants Achieving a Reduction of ≥ 4 Points From Baseline in Atopic Dermatitis Symptom Scale (ADerm-SS) Skin Pain Score at Week 16
Description	The ADerm-SS is an 11-item PRO questionnaire designed to assess signs and symptoms that patients may experience due to AD using a 24-hour recall period. For the skin pain item participants were asked on a daily basis to indicate how bad their worst skin pain due to AD was in the past 24 hours on an NRS from 0 (no pain) to 10 (worst imaginable pain). The ADerm-SS skin pain score was analyzed using weekly rolling averages of daily scores. The minimal clinically important difference for ADerm-SS skin pain score is 4.
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 ADerm-SS Skin Pain Score ≥ 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	Upadacitinib 15 mg QD	Upadacitinib 30 mg QD
Arm/Group Description:	Participants received placebo orally once a day for 16 weeks.	Participants received upadacitinib 15 mg orally once daily for 16 weeks.	Participants received upadacitinib 30 mg orally once daily for 16 weeks.
Overall Number of Participants Analyzed	233	237	249
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	15.0; (10.4 to 19.6)	53.6; (47.2 to 59.9)	63.5; (57.5 to 69.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 30 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 30 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	48.6
	Confidence Interval	(2-Sided) 95%; 41.0 to 56.1
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 15 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	38.7
	Confidence Interval	(2-Sided) 95%; 30.9 to 46.5
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

13. Secondary Outcome

Title	Main Study: Percentage of Participants Achieving a Reduction of ≥ 28 Points From Baseline in ADerm-SS 7-Item Total Symptom Score (TSS-7) at Week 16
Description	The ADerm-SS is an 11-item questionnaire designed to assess signs and symptoms that participants may experience due to AD using a 24-hour recall period. The 7-item total symptom score includes 7 symptoms (items 1-7 of the ADerm-SS), each assessed on a NRS from 0 (no symptom) to 10 (worst imaginable). The 7 symptoms included in the score are itch while asleep, itch while awake, skin pain (each assessed daily), skin cracking, skin cracking pain, dry skin, and skin flaking (assessed weekly). The TSS-7 score ranges from 0 to 70, with higher scores indicating worsening symptoms. The minimal clinically important difference for ADerm-SS TSS-7 is 28.
Time Frame	Baseline and Week 16

Outcome Measure Data

Analysis Population Description

Intent-to-treat population for the main study with ADerm-SS TSS-7 ≥ 28 at Baseline; Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) was used.

Arm/Group Title	Placebo	Upadacitinib 15 mg QD	Upadacitinib 30 mg QD
Arm/Group Description:	Participants received placebo orally once a day for 16 weeks.	Participants received upadacitinib 15 mg orally once daily for 16 weeks.	Participants received upadacitinib 30 mg orally once daily for 16 weeks.
Overall Number of Participants Analyzed	226	233	246
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	15.0; (10.4 to 19.7)	53.6; (47.2 to 60.1)	67.9; (62.1 to 73.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 30 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 30 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	52.9
	Confidence Interval	(2-Sided) 95%; 45.4 to 60.3
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 15 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	38.3
	Confidence Interval	(2-Sided) 95%; 30.4 to 46.2
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

14. Secondary Outcome

Title	Main Study: Percentage of Participants Achieving a Reduction of ≥ 11 Points From Baseline in ADerm-IS Emotional State Domain Score at Week 16
Description	The ADerm-IS is a 10-item PRO questionnaire designed to assess a variety of impacts that participants experience from their AD. ADerm-IS emotional state sums three items [Items 8-10] measuring self-consciousness, embarrassment, and sadness with a 7-day recall. Each question is scored on an 11-point NRS from 0 (no impact) to 10 (extreme impact). The emotional state domain score ranges from 0 to 30, where higher scores represent worst impact. The minimal clinically important difference for ADerm-IS emotional state domain score is 11.
Time Frame	Baseline and Week 16

Outcome Measure Data

Analysis Population Description

Intent-to-treat population for the main study with ADerm-IS Emotional State domain score ≥ 11 at Baseline; Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) was used.

Arm/Group Title	Placebo	Upadacitinib 15 mg QD	Upadacitinib 30 mg QD
Arm/Group Description:	Participants received placebo orally once a day for 16 weeks.	Participants received upadacitinib 15 mg orally once daily for 16 weeks.	Participants received upadacitinib 30 mg orally once daily for 16 weeks.
Overall Number of Participants Analyzed	212	227	226
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	19.8; (14.4 to 25.2)	62.6; (56.3 to 68.9)	72.6; (66.7 to 78.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 30 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 30 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	52.5
	Confidence Interval	(2-Sided) 95%; 44.7 to 60.4
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 15 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	42.7
	Confidence Interval	(2-Sided) 95%; 34.4 to 50.9
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

15. Secondary Outcome

Title	Main Study: Percentage of Participants Achieving a Reduction of ≥ 14 Points From Baseline in in ADerm-IS Daily Activities Domain Score at Week 16
Description	The ADerm-IS is a 10-item PRO questionnaire designed to assess a variety of impacts that participants experience from their AD. ADerm-IS daily activities sums four items measuring limitations of household, physical, and social activities, and difficulty concentrating with a 7-day recall. Each question is scored on an 11-point NRS from 0 (no impact) to 10 (extreme impact). The daily activities domain score ranges from 0 to 40, where higher scores represent worst impact. The minimal clinically important difference for the ADerm-IS daily activities domain score is 14.
Time Frame	Baseline and Week 16

Outcome Measure Data

Analysis Population Description

Intent-to-treat population for the main study with ADerm-IS Daily Activities Domain Score ≥ 14 at Baseline; Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) was used.

Arm/Group Title	Placebo	Upadacitinib 15 mg QD	Upadacitinib 30 mg QD
Arm/Group Description:	Participants received placebo orally once a day for 16 weeks.	Participants received upadacitinib 15 mg orally once daily for 16 weeks.	Participants received upadacitinib 30 mg orally once daily for 16 weeks.
Overall Number of Participants Analyzed	197	203	205
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	20.3; (14.7 to 25.9)	65.0; (58.5 to 71.6)	73.2; (67.1 to 79.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 30 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 30 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	53.1
	Confidence Interval	(2-Sided) 95%; 44.9 to 61.3
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 15 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	44.7
	Confidence Interval	(2-Sided) 95%; 36.2 to 53.2
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

16. 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 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	Upadacitinib 15 mg QD	Upadacitinib 30 mg QD
Arm/Group Description:	Participants received placebo orally once a day for 16 weeks.	Participants received upadacitinib 15 mg orally once daily for 16 weeks.	Participants received upadacitinib 30 mg orally once daily for 16 weeks.
Overall Number of Participants Analyzed	281	281	285
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	1.8; (0.2 to 3.3)	16.7; (12.4 to 21.1)	27.0; (21.9 to 32.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 30 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 30 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	25.3
	Confidence Interval	(2-Sided) 95%; 20.0 to 30.6
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 15 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	15.0
	Confidence Interval	(2-Sided) 95%; 10.4 to 19.6
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

17. 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	Upadacitinib 15 mg QD	Upadacitinib 30 mg QD
Arm/Group Description:	Participants received placebo orally once a day for 16 weeks.	Participants received upadacitinib 15 mg orally once daily for 16 weeks.	Participants received upadacitinib 30 mg orally once daily for 16 weeks.
Overall Number of Participants Analyzed	123	225	236
Least Squares Mean (95% Confidence Interval); Unit of Measure: percent change
	-26.06; (-36.66 to -15.46)	-62.79; (-71.60 to -53.99)	-72.04; (-80.69 to -63.39)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 30 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 30 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	-45.98
	Confidence Interval	(2-Sided) 95%; -58.82 to -33.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 6.549
	Estimation Comments	Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 15 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	-36.74
	Confidence Interval	(2-Sided) 95%; -49.66 to -23.81
	Estimation Comments	Difference = Upadacitinib - Placebo

18. 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	Upadacitinib 15 mg QD	Upadacitinib 30 mg QD
Arm/Group Description:	Participants received placebo orally once a day for 16 weeks.	Participants received upadacitinib 15 mg orally once daily for 16 weeks.	Participants received upadacitinib 30 mg orally once daily for 16 weeks.
Overall Number of Participants Analyzed	128	244	259
Least Squares Mean (95% Confidence Interval); Unit of Measure: percent change
	-40.71; (-45.18 to -36.23)	-80.24; (-83.99 to -76.49)	-87.74; (-91.42 to -84.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 30 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 30 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	-47.03
	Confidence Interval	(2-Sided) 95%; -52.37 to -41.70
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.716
	Estimation Comments	Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 15 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	-39.53
	Confidence Interval	(2-Sided) 95%; -44.91 to -34.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.738
	Estimation Comments	Difference = Upadacitinib - Placebo

19. Secondary Outcome

Title	Main Study: Percentage of Participants Achieving a Reduction of ≥ 4 Points From Baseline in Patient Oriented Eczema Measure (POEM) Total Score at Week 16
Description	The POEM is a 7-item, validated questionnaire used to assess disease symptoms in both children and adults. Participants respond to 7 questions, including dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping, each scored on a 5-point scale based on frequency of occurrence during the previous week: 0 = no days, 1 = 1 to 2 days, 2 = 3 to 4 days, 3 = 5 to 6 days, and 4 = all days. Item scores are added to provide a total score ranging from 0 (clear) to 28 (very severe atopic eczema). A change in POEM score of 3.4 points is considered the minimal clinically important difference.
Time Frame	Baseline and Week 16

Outcome Measure Data

Analysis Population Description

Intent-to-treat population for the main study with POEM score ≥ 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	Upadacitinib 15 mg QD	Upadacitinib 30 mg QD
Arm/Group Description:	Participants received placebo orally once a day for 16 weeks.	Participants received upadacitinib 15 mg orally once daily for 16 weeks.	Participants received upadacitinib 30 mg orally once daily for 16 weeks.
Overall Number of Participants Analyzed	276	278	280
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	22.8; (17.8 to 27.8)	75.0; (69.9 to 80.1)	81.4; (76.9 to 86.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 30 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 30 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	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	58.6
	Confidence Interval	(2-Sided) 95%; 51.9 to 65.3
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 15 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	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	52.3
	Confidence Interval	(2-Sided) 95%; 45.2 to 59.4
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

20. Secondary Outcome

Title	Main Study: Percentage of Participants Achieving a Reduction of ≥ 4 Points From Baseline in Dermatology Life Quality Index (DLQI) at Week 16
Description	The DLQI is a 10-item validated questionnaire used to assess the impact of AD disease symptoms and treatment on quality of life (QoL). It consists of 10 questions evaluating impact of skin diseases on different aspects of a participant's QoL over the prior week, including symptoms and feelings, daily activities, leisure, work or school, personal relationships, and the side effects of treatment. Each item is scored on a 4-point scale (0 = not at all/not relevant; 1 = a little; 2 = a lot; and 3 = very much). Item scores are added to provide a total score, ranging from 0 to 30, with higher scores indicating greater impairment of QoL. the DLQI was administered to participants who were ≥ 16 (16 to 75) years old at the time of the Screening visit.
Time Frame	Baseline and Week 16

Outcome Measure Data

Analysis Population Description

Intent-to-treat population for the main study who were ≥ 16 years old at Screening with DLQI score ≥ 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	Upadacitinib 15 mg QD	Upadacitinib 30 mg QD
Arm/Group Description:	Participants received placebo orally once a day for 16 weeks.	Participants received upadacitinib 15 mg orally once daily for 16 weeks.	Participants received upadacitinib 30 mg orally once daily for 16 weeks.
Overall Number of Participants Analyzed	250	254	256
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	29.0; (23.3 to 34.7)	75.4; (70.1 to 80.8)	82.0; (77.3 to 86.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 30 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 30 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	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	53.2
	Confidence Interval	(2-Sided) 95%; 45.9 to 60.5
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 15 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	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	46.7
	Confidence Interval	(2-Sided) 95%; 39.0 to 54.4
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

21. Secondary Outcome

Title	Main Study: Percent Change From Baseline in Scoring Atopic Dermatitis (SCORAD) Score at Week 16
Description	SCORAD is a clinical tool used to assess the extent and severity of eczema (SCORing Atopic Dermatitis). The extent is assessed using the rule of 9 to calculate the affected area (A) as a percentage of the whole body (0-100%). The intensity part of the SCORAD (B) consists of 6 items: erythema, oedema/papulation, excoriations, lichenification, oozing/crusts and dryness, each graded on a scale from 0 (none) to 3 (severe), for a total score of 0 to 18. Subjective items (C) include daily pruritus and sleeplessness, each scored on a visual analogue scale (VAS) from 0 to 10 (total score 0-20). SCORAD is calculated as A/5 + 7B/2 + C, and ranges from 0 to 103 (worst). 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	Upadacitinib 15 mg QD	Upadacitinib 30 mg QD
Arm/Group Description:	Participants received placebo orally once a day for 16 weeks.	Participants received upadacitinib 15 mg orally once daily for 16 weeks.	Participants received upadacitinib 30 mg orally once daily for 16 weeks.
Overall Number of Participants Analyzed	125	239	253
Least Squares Mean (95% Confidence Interval); Unit of Measure: percent change
	-32.68; (-37.26 to -28.11)	-65.71; (-69.20 to -62.23)	-73.07; (-76.47 to -69.68)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 30 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 30 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	-40.39
	Confidence Interval	(2-Sided) 95%; -45.75 to -35.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.732
	Estimation Comments	Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 15 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	-33.03
	Confidence Interval	(2-Sided) 95%; -38.44 to -27.61
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.758
	Estimation Comments	Difference = Upadacitinib - Placebo

22. Secondary Outcome

Title	Main Study: Percentage of Participants Achieving a Hospital Anxiety and Depression Scale-Anxiety (HADS-A) Score and Hospital Anxiety and Depression Scale-Depression (HADS-D) Score of < 8 at Week 16
Description	The HADS is a 14-item questionnaire, with seven items related to anxiety (HADS-A) and seven items related to depression (HADS-D). Each item is scored from 0 to 3; scores for each subscale range from 0 to 21, with higher scores indicating more distress. For each domain, scores 7 or lower are considered normal, 8 to 10 are borderline, and 11 or higher indicate clinical anxiety or depression.
Time Frame	Baseline and Week 16

Outcome Measure Data

Analysis Population Description

Intent-to-treat population for the main study with HADS-A ≥ 8 or HADS-D ≥ 8 at Baseline; Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) was used.

Arm/Group Title	Placebo	Upadacitinib 15 mg QD	Upadacitinib 30 mg QD
Arm/Group Description:	Participants received placebo orally once a day for 16 weeks.	Participants received upadacitinib 15 mg orally once daily for 16 weeks.	Participants received upadacitinib 30 mg orally once daily for 16 weeks.
Overall Number of Participants Analyzed	126	145	144
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	14.3; (8.2 to 20.4)	45.5; (37.4 to 53.6)	49.2; (41.0 to 57.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 30 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 30 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	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	34.9
	Confidence Interval	(2-Sided) 95%; 24.8 to 45.1
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 15 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	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	31.5
	Confidence Interval	(2-Sided) 95%; 21.4 to 41.6
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

23. Secondary Outcome

Title	Main Study: Percentage of Participants Achieving a DLQI Score of 0 or 1 at Week 16
Description	The DLQI is a 10-item validated questionnaire used to assess the impact of AD disease symptoms and treatment on quality of life (QoL). It consists of 10 questions evaluating impact of skin diseases on different aspects of a participant's QoL over the prior week, including symptoms and feelings, daily activities, leisure, work or school, personal relationships, and the side effects of treatment. Each item is scored on a 4-point scale (0 = not at all/not relevant; 1 = a little; 2 = a lot; and 3 = very much). Item scores are added to provide a total score, ranging from 0 to 30, with higher scores indicating greater impairment of QoL. A score of 0 or 1 means that the disease has no effect at all. the DLQI was administered to participants who were ≥ 16 (16 to 75) years old at the time of the Screening visit.
Time Frame	Week 16

Outcome Measure Data

Analysis Population Description

Intent-to-treat population for the main study who were ≥ 16 years old at Screening with DLQI score ≥ 1 at Baseline; Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) was used.

Arm/Group Title	Placebo	Upadacitinib 15 mg QD	Upadacitinib 30 mg QD
Arm/Group Description:	Participants received placebo orally once a day for 16 weeks.	Participants received upadacitinib 15 mg orally once daily for 16 weeks.	Participants received upadacitinib 30 mg orally once daily for 16 weeks.
Overall Number of Participants Analyzed	252	258	261
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	4.4; (1.9 to 7.0)	30.3; (24.7 to 35.9)	41.5; (35.5 to 47.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 30 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 30 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	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	37.3
	Confidence Interval	(2-Sided) 95%; 30.8 to 43.8
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and secondary endpoints for upadacitinib 15 mg was strongly controlled using a graphical multiple testing procedure at the two-sided 0.05 level 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	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	25.9
	Confidence Interval	(2-Sided) 95%; 19.7 to 32.1
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

24. 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 are 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	Adolescents: Upadacitinib 15 mg QD	Adolescents: Upadacitinib 30 mg QD
Arm/Group Description:	Adolescent participants received placebo orally once a day for 16 weeks.	Adolescent participants received upadacitinib 15 mg orally once daily for 16 weeks.	Adolescent participants received upadacitinib 30 mg orally once daily for 16 weeks.
Overall Number of Participants Analyzed	61	64	64
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	11.5; (3.5 to 19.5)	73.4; (62.6 to 84.3)	78.1; (68.0 to 88.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo, Adolescents: Upadacitinib 30 mg QD
	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	66.6
	Confidence Interval	(2-Sided) 95%; 53.8 to 79.4
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo, Adolescents: Upadacitinib 15 mg QD
	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	62.0
	Confidence Interval	(2-Sided) 95%; 48.6 to 75.4
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

25. 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; Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) was used.

Arm/Group Title	Adolescents: Placebo	Adolescents: Upadacitinib 15 mg QD	Adolescents: Upadacitinib 30 mg QD
Arm/Group Description:	Adolescent participants received placebo orally once a day for 16 weeks.	Adolescent participants received upadacitinib 15 mg orally once daily for 16 weeks.	Adolescent participants received upadacitinib 30 mg orally once daily for 16 weeks.
Overall Number of Participants Analyzed	61	64	64
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	6.6; (0.3 to 12.8)	45.3; (33.1 to 57.5)	64.1; (52.3 to 75.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo, Adolescents: Upadacitinib 30 mg QD
	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	57.4
	Confidence Interval	(2-Sided) 95%; 44.6 to 70.2
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo, Adolescents: Upadacitinib 15 mg QD
	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	39.1
	Confidence Interval	(2-Sided) 95%; 25.6 to 52.6
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

26. 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	Adolescents: Upadacitinib 15 mg QD	Adolescents: Upadacitinib 30 mg QD
Arm/Group Description:	Adolescent participants received placebo orally once a day for 16 weeks.	Adolescent participants received upadacitinib 15 mg orally once daily for 16 weeks.	Adolescent participants received upadacitinib 30 mg orally once daily for 16 weeks.
Overall Number of Participants Analyzed	60	62	62
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	10.0; (2.4 to 17.6)	48.4; (35.9 to 60.8)	56.5; (44.1 to 68.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo, Adolescents: Upadacitinib 30 mg QD
	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	46.6
	Confidence Interval	(2-Sided) 95%; 32.6 to 60.6
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo, Adolescents: Upadacitinib 15 mg QD
	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	38.7
	Confidence Interval	(2-Sided) 95%; 24.3 to 53.1
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

27. 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	Adolescents: Upadacitinib 15 mg QD	Adolescents: Upadacitinib 30 mg QD
Arm/Group Description:	Adolescent participants received placebo orally once a day for 16 weeks.	Adolescent participants received upadacitinib 15 mg orally once daily for 16 weeks.	Adolescent participants received upadacitinib 30 mg orally once daily for 16 weeks.
Overall Number of Participants Analyzed	61	64	64
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	3.3; (0.0 to 7.7)	46.9; (34.6 to 59.1)	67.2; (55.7 to 78.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo, Adolescents: Upadacitinib 30 mg QD
	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	63.9
	Confidence Interval	(2-Sided) 95%; 51.8 to 75.9
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo, Adolescents: Upadacitinib 15 mg QD
	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	43.8
	Confidence Interval	(2-Sided) 95%; 30.9 to 56.7
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

28. 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	Adolescents: Upadacitinib 15 mg QD	Adolescents: Upadacitinib 30 mg QD
Arm/Group Description:	Adolescent participants received placebo orally once a day for 16 weeks.	Adolescent participants received upadacitinib 15 mg orally once daily for 16 weeks.	Adolescent participants received upadacitinib 30 mg orally once daily for 16 weeks.
Overall Number of Participants Analyzed	60	62	62
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	3.3; (0.0 to 7.9)	48.4; (35.9 to 60.8)	58.1; (45.8 to 70.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo, Adolescents: Upadacitinib 30 mg QD
	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	54.7
	Confidence Interval	(2-Sided) 95%; 41.7 to 67.8
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo, Adolescents: Upadacitinib 15 mg QD
	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	45.2
	Confidence Interval	(2-Sided) 95%; 32.0 to 58.3
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

29. 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	Adolescents: Upadacitinib 15 mg QD	Adolescents: Upadacitinib 30 mg QD
Arm/Group Description:	Adolescent participants received placebo orally once a day for 16 weeks.	Adolescent participants received upadacitinib 15 mg orally once daily for 16 weeks.	Adolescent participants received upadacitinib 30 mg orally once daily for 16 weeks.
Overall Number of Participants Analyzed	61	64	64
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	3.3; (0.0 to 7.7)	39.1; (27.1 to 51.0)	50.4; (38.0 to 62.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo, Adolescents: Upadacitinib 30 mg QD
	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	47.1
	Confidence Interval	(2-Sided) 95%; 34.0 to 60.2
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo, Adolescents: Upadacitinib 15 mg QD
	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	35.9
	Confidence Interval	(2-Sided) 95%; 23.2 to 48.6
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

30. 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	Adolescents: Upadacitinib 15 mg QD	Adolescents: Upadacitinib 30 mg QD
Arm/Group Description:	Adolescent participants received placebo orally once a day for 16 weeks.	Adolescent participants received upadacitinib 15 mg orally once daily for 16 weeks.	Adolescent participants received upadacitinib 30 mg orally once daily for 16 weeks.
Overall Number of Participants Analyzed	60	62	62
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	0.0 [1]; (NA to NA)	9.7; (2.3 to 17.0)	21.0; (10.8 to 31.1)

[1]

Could not be calculated using the normal approximation to the binomial distribution

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo, Adolescents: Upadacitinib 30 mg QD
	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	21.0
	Confidence Interval	(2-Sided) 95%; 11.0 to 31.1
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo, Adolescents: Upadacitinib 15 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.008
	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	9.4
	Confidence Interval	(2-Sided) 95%; 2.5 to 16.4
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

31. Secondary Outcome

Title	Adolescents: Percentage of Participants Achieving a Reduction of ≥ 4 Points From Baseline in Worst Pruritus NRS at Day 2
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).
Time Frame	Baseline and Day 2

Outcome Measure Data

Analysis Population Description

Intent-to-treat population for adolescents with Worst Pruritus NRS (daily score) ≥ 4 at Baseline; Non-responder imputation with no special data handling for missing data due to COVID-19 was used.

Arm/Group Title	Adolescents: Placebo	Adolescents: Upadacitinib 15 mg QD	Adolescents: Upadacitinib 30 mg QD
Arm/Group Description:	Adolescent participants received placebo orally once a day for 16 weeks.	Adolescent participants received upadacitinib 15 mg orally once daily for 16 weeks.	Adolescent participants received upadacitinib 30 mg orally once daily for 16 weeks.
Overall Number of Participants Analyzed	59	60	63
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	1.7; (0.0 to 5.0)	8.3; (1.3 to 15.3)	12.7; (4.5 to 20.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo, Adolescents: Upadacitinib 30 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.015
	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	11.0
	Confidence Interval	(2-Sided) 95%; 2.1 to 19.9
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo, Adolescents: Upadacitinib 15 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.086
	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	6.5
	Confidence Interval	(2-Sided) 95%; -0.9 to 13.9
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

32. Secondary Outcome

Title	Adolescents: Percentage of Participants Achieving a Reduction of ≥ 4 Points From Baseline in Worst Pruritus NRS at Day 3
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).
Time Frame	Baseline and Day 3

Outcome Measure Data

Analysis Population Description

Intent-to-treat population for adolescents with Worst Pruritus NRS (daily score) ≥ 4 at Baseline; Non-responder imputation with no special data handling for missing data due to COVID-19 was used.

Arm/Group Title	Adolescents: Placebo	Adolescents: Upadacitinib 15 mg QD	Adolescents: Upadacitinib 30 mg QD
Arm/Group Description:	Adolescent participants received placebo orally once a day for 16 weeks.	Adolescent participants received upadacitinib 15 mg orally once daily for 16 weeks.	Adolescent participants received upadacitinib 30 mg orally once daily for 16 weeks.
Overall Number of Participants Analyzed	59	60	63
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	5.1; (0.0 to 10.7)	16.7; (7.2 to 26.1)	15.9; (6.8 to 24.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo, Adolescents: Upadacitinib 30 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.045
	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	10.8
	Confidence Interval	(2-Sided) 95%; 0.2 to 21.4
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo, Adolescents: Upadacitinib 15 mg QD
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.040
	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	11.0
	Confidence Interval	(2-Sided) 95%; 0.5 to 21.5
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

33. Secondary Outcome

Title	Adolescents: Percentage of Participants Experiencing a Flare During the Double-blind Treatment Period
Description	A flare, characterized as a clinically meaningful worsening in EASI, is defined as an increase in EASI score of ≥ 6.6 points from Baseline during the double-blind treatment period and prior to use of any rescue medication. Flares were assessed in participants with an EASI score of 65.4 or less at Baseline.
Time Frame	From first dose of study drug to Week 16

Outcome Measure Data

Analysis Population Description

Intent-to-treat population for adolescents with an EASI score ≤ 65.4 at Baseline and at least one EASI post-baseline assessment prior to use of rescue medication.

Arm/Group Title	Adolescents: Placebo	Adolescents: Upadacitinib 15 mg QD	Adolescents: Upadacitinib 30 mg QD
Arm/Group Description:	Adolescent participants received placebo orally once a day for 16 weeks.	Adolescent participants received upadacitinib 15 mg orally once daily for 16 weeks.	Adolescent participants received upadacitinib 30 mg orally once daily for 16 weeks.
Overall Number of Participants Analyzed	59	63	64
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	22.0; (11.5 to 32.6)	0.0 [1]; (NA to NA)	0.0 [1]; (NA to NA)

[1]

Could not be calculated using the normal approximation to the binomial distribution

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo, Adolescents: Upadacitinib 30 mg QD
	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	-22.1
	Confidence Interval	(2-Sided) 95%; -32.6 to -11.5
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo, Adolescents: Upadacitinib 15 mg QD
	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	-22.1
	Confidence Interval	(2-Sided) 95%; -32.7 to -11.5
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

34. Secondary Outcome

Title	Adolescents: Percentage of Participants Achieving a Reduction of ≥ 12 Points From Baseline in ADerm-IS Sleep Domain Score at Week 16
Description	The ADerm-IS is a 10-item patient reported outcome questionnaire designed to assess a variety of impacts that participants experience from their AD. The ADerm-IS sleep domain consists of 3 questions designed to assess the impact of AD on sleep on a daily basis over a 24-hour recall period. The items include difficulty falling asleep, impact on sleep, and waking at night. Each question is scored on an 11-point NRS from 0 (no impact) to 10 (extreme impact). The ADerm-IS sleep domain score is the sum of the 3 item scores and ranges from 0 (no impact) to 30 (worst impact). The ADerm-IS sleep domain was analyzed based on weekly rolling averages of daily scores. The minimal clinically important difference for ADerm-IS sleep domain score is 12.
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 ADerm-IS Sleep Domain score ≥ 12 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	Adolescents: Upadacitinib 15 mg QD	Adolescents: Upadacitinib 30 mg QD
Arm/Group Description:	Adolescent participants received placebo orally once a day for 16 weeks.	Adolescent participants received upadacitinib 15 mg orally once daily for 16 weeks.	Adolescent participants received upadacitinib 30 mg orally once daily for 16 weeks.
Overall Number of Participants Analyzed	48	49	47
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	12.5; (3.1 to 21.9)	46.9; (33.0 to 60.9)	66.0; (52.4 to 79.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo, Adolescents: Upadacitinib 30 mg QD
	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	53.6
	Confidence Interval	(2-Sided) 95%; 37.7 to 69.4
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo, Adolescents: Upadacitinib 15 mg QD
	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	34.8
	Confidence Interval	(2-Sided) 95%; 18.1 to 51.4
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

35. Secondary Outcome

Title	Adolescents: Percentage of Participants Achieving a Reduction of ≥ 4 Points From Baseline in ADerm-SS Skin Pain Score at Week 16
Description	The ADerm-SS is an 11-item PRO questionnaire designed to assess signs and symptoms that patients may experience due to AD using a 24-hour recall period. For the skin pain item participants were asked to indicate on a daily basis how bad their worst skin pain due to AD was in the past 24 hours on an NRS from 0 (no pain) to 10 (worst imaginable pain). The minimal clinically important difference for ADerm-SS skin pain score is 4. The ADerm-SS skin pain score 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 ADerm-SS Skin Pain score ≥ 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	Adolescents: Upadacitinib 15 mg QD	Adolescents: Upadacitinib 30 mg QD
Arm/Group Description:	Adolescent participants received placebo orally once a day for 16 weeks.	Adolescent participants received upadacitinib 15 mg orally once daily for 16 weeks.	Adolescent participants received upadacitinib 30 mg orally once daily for 16 weeks.
Overall Number of Participants Analyzed	44	54	59
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	9.1; (0.6 to 17.6)	42.6; (29.4 to 55.8)	64.4; (52.2 to 76.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo, Adolescents: Upadacitinib 30 mg QD
	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	56.6
	Confidence Interval	(2-Sided) 95%; 42.0 to 71.1
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Adolescents: Placebo, Adolescents: Upadacitinib 15 mg QD
	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	32.5
	Confidence Interval	(2-Sided) 95%; 16.9 to 48.1
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

36. Secondary Outcome

Title	Adolescents: Percentage of Participants Achieving a Reduction of ≥ 28 Points From Baseline in ADerm-SS TSS-7 at Week 16
Description	The ADerm-SS is an 11-item questionnaire designed to assess signs and symptoms that participants may experience due to AD using a 24-hour recall period. The 7-item total symptom score includes 7 symptoms (items 1-7 of the ADerm-SS), each assessed on a NRS from 0 (no symptom) to 10 (worst imaginable). The 7 symptoms included in the score are itch while asleep, itch while awake, skin pain (each assessed daily), skin cracking, skin cracking pain, dry skin, and skin flaking (assessed weekly). The TSS-7 score ranges from 0 to 70, with higher scores indicating worsening symptoms. The minimal clinically important difference for ADerm-SS TSS-7 is 28.
Time Frame	Baseline and Week 16

Outcome Measure Data

Analysis Population Description

Intent-to-treat population for adolescents with ADerm-SS TSS-7 ≥ 28 at Baseline; Non-responder imputation incorporating mult