Atopic Dermatitis
Conditions
Keywords
Upadacitinib, ABT-494, Dupilumab, Atopic Dermatitis
Brief summary
This study will evaluate upadacitinib compared to dupilumab (Dupixent®) in adults with moderate to severe atopic dermatitis (AD) who are candidates for systemic therapy.
Detailed description
The study is comprised of a 35-day screening period, a 24-week double-blinded treatment period, and a follow-up visit 12 weeks after the last dose. Participants who complete Week 24 have the option to enroll into an open-label study (Study M19-850; NCT04195698) of upadacitinib 30 mg once daily and receive treatment with upadacitinib for an additional 52 weeks. Participants who meet eligibility criteria will be randomized in a 1:1 ratio to receive either upadacitinib or dupilumab. Randomization will be stratified by Baseline disease severity (Validated Investigator Global Assessment scale for Atopic Dermatitis \[vIGA-AD\] score of moderate \[3\] versus severe \[4\]) and age (\<40, ≥ 40 to \< 65, ≥ 65 years).
Interventions
BIOLOGICALUpadacitinib
Extended release tablet
BIOLOGICALDupilumab
Dupilumab is administered as a subcutaneous (SC) injection
DRUGPlacebo to dupilumab
Placebo administered as a subcutaneous injection
Tablet
Sponsors
AbbVie
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 76 Years
Healthy volunteers
No
Inclusion criteria
* Participant has active moderate to severe atopic dermatitis (AD) defined by Eczema Area and Severity Index (EASI) ≥ 16, Investigator's Global Assessment (IGA) ≥ 3, ≥ 10% body surface area (BSA) of AD involvement at the Screening and Baseline Visits, and Baseline weekly average of daily Worst Pruritus NRS ≥ 4. * Participant is a candidate for systemic therapy or have recently required systemic therapy for AD.
Exclusion criteria
* Participant has prior exposure to Janus Kinase (JAK) inhibitor. * Participant has prior exposure to dupilumab. * Participant is unable or unwilling to discontinue current AD treatments prior to the study. * Participant has requirement of prohibited medications during the study. * Participant has other active skin diseases or skin infections requiring systemic treatment or would interfere with appropriate assessment of AD lesions. * Female participant who is pregnant, breastfeeding, or considering pregnancy during the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving a 75% Reduction From Baseline in Eczema Area and Severity Index Score (EASI 75) at Week 16 | Baseline and Week 16 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving a 100% Reduction From Baseline in EASI Score (EASI 100) at Week 16 | Baseline and Week 16 | 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. |
| Percentage of Participants Achieving a 90% Reduction From Baseline in EASI Score (EASI 90) at Week 16 | Baseline and Week 16 | 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. |
| Percent Change From Baseline in Worst Pruritus Numerical Rating Scale (NRS) Score at Week 4 | Baseline (Week 0) to Week 4 | The Worst Pruritus NRS is an assessment tool that participants used to report the intensity of their pruritus during a 24-hour recall period using an electronic hand-held device. Participants were asked to rate itch (pruritus) intensity at its worst during the past 24 hours on an 11-point scale from 0 (no itch) to 10 (worst imaginable itch). The percent change from Baseline was calculated from a rolling weekly average; a negative change from Baseline indicates improvement. |
| Percent Change From Baseline in Worst Pruritus Numerical Rating Scale (NRS) Score at Week 16 | Baseline (Week 0) to Week 16 | The Worst Pruritus NRS is an assessment tool that participants used to report the intensity of their pruritus during a 24-hour recall period using an electronic hand-held device. Participants were asked to rate itch (pruritus) intensity at its worst during the past 24 hours on an 11-point scale from 0 (no itch) to 10 (worst imaginable itch). The percent change from Baseline was calculated from a rolling weekly average; a negative change from Baseline indicates improvement. |
| Percent Change From Baseline in Worst Pruritus Numerical Rating Scale (NRS) Score at Week 1 | Baseline (Week 0) to Week 1 | The Worst Pruritus NRS is an assessment tool that participants used to report the intensity of their pruritus during a 24-hour recall period using an electronic hand-held device. Participants were asked to rate itch (pruritus) intensity at its worst during the past 24 hours on an 11-point scale from 0 (no itch) to 10 (worst imaginable itch). The percent change from Baseline was calculated from a rolling weekly average; a negative change from Baseline indicates improvement. |
| Percentage of Participants Achieving a Reduction of ≥ 4 Points From Baseline in Worst Pruritus NRS at Week 16 | Baseline and Week 16 | The Worst Pruritus NRS is an assessment tool that participants used to report the intensity of their pruritus during a 24-hour recall period using an electronic hand-held device. Participants were asked to rate itch (pruritus) intensity at its worst during the past 24 hours on an 11-point scale from 0 (no itch) to 10 (worst imaginable itch). |
| Percentage of Participants Achieving a 75% Reduction From Baseline in EASI Score at Week 2 | Baseline and Week 2 | 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. |
Countries
Australia, Canada, Croatia, Czechia, Finland, France, Germany, Hungary, Ireland, Israel, Italy, Malaysia, Netherlands, New Zealand, Norway, Poland, Singapore, Spain, Sweden, Taiwan, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
Participants were randomized at 128 sites located in 22 countries (Australia, Canada, Croatia, Czechia, Finland, France, Germany, Hungary, Ireland, Israel, Italy, Malaysia, Netherlands, New Zealand, Norway, Poland, Singapore, Spain, Taiwan, Ukraine, United Kingdom, and the United States).
Pre-assignment details
Participants were randomly assigned in a 1:1 ratio to receive upadacitinib or dupilumab. Randomization was stratified by disease severity (Validated Investigator Global Assessment Scale for Atopic Dermatitis \[vIGA-AD\] moderate \[3\] vs severe \[4\]) and age (\<40, ≥ 40 to \< 65, ≥ 65 years).
Participants by arm
| Arm | Count |
|---|---|
| Dupilumab 300 mg EOW Participants received a loading dose of 600 mg dupilumab by SC injection on Day 1 followed by 300 mg dupilumab SC EOW until Week 22 and placebo to upadacitinib orally QD up to Week 24. | 331 |
| Upadacitinib 30 mg QD Participants received 30 mg upadacitinib orally once a day up to Week 24 and placebo to dupilumab SC EOW up to Week 22. | 342 |
| Total | 673 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 7 |
| Overall Study | COVID-19 Logistical Restrictions | 1 | 1 |
| Overall Study | Lost to Follow-up | 7 | 5 |
| Overall Study | Other | 4 | 6 |
| Overall Study | Withdrawal by Subject | 8 | 11 |
Baseline characteristics
| Characteristic | Dupilumab 300 mg EOW | Upadacitinib 30 mg QD | Total |
|---|---|---|---|
| Age, Continuous | 36.3 years STANDARD_DEVIATION 13.81 | 36.2 years STANDARD_DEVIATION 14.42 | 36.3 years STANDARD_DEVIATION 14.11 |
| Age, Customized ≥ 40 to < 65 years | 94 Participants | 98 Participants | 192 Participants |
| Age, Customized < 40 years | 223 Participants | 228 Participants | 451 Participants |
| Age, Customized ≥ 65 years | 14 Participants | 16 Participants | 30 Participants |
| Disease Severity 3 (Moderate) | 159 Participants | 169 Participants | 328 Participants |
| Disease Severity 4 (Severe) | 172 Participants | 173 Participants | 345 Participants |
| Duration Since AD Diagnosis | 25.474 years STANDARD_DEVIATION 14.8251 | 23.608 years STANDARD_DEVIATION 14.7697 | 24.526 years STANDARD_DEVIATION 14.8154 |
| Eczema Area and Severity Index (EASI) Score | 29.21 score on a scale STANDARD_DEVIATION 11.551 | 30.96 score on a scale STANDARD_DEVIATION 12.55 | 30.10 score on a scale STANDARD_DEVIATION 12.092 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 31 Participants | 25 Participants | 56 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 300 Participants | 317 Participants | 617 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian/Alaska Native | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Asian | 78 Participants | 77 Participants | 155 Participants |
| Race/Ethnicity, Customized Black or African American | 15 Participants | 25 Participants | 40 Participants |
| Race/Ethnicity, Customized Multiple | 5 Participants | 6 Participants | 11 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 3 Participants | 4 Participants |
| Race/Ethnicity, Customized White | 231 Participants | 229 Participants | 460 Participants |
| Sex: Female, Male Female | 139 Participants | 159 Participants | 298 Participants |
| Sex: Female, Male Male | 192 Participants | 183 Participants | 375 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 331 | 1 / 342 |
| other Total, other adverse events | 134 / 331 | 167 / 342 |
| serious Total, serious adverse events | 7 / 331 | 14 / 342 |
Outcome results
Primary
Percentage of Participants Achieving a 75% Reduction From Baseline in Eczema Area and Severity Index Score (EASI 75) at Week 16
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
Population: Intent-to-treat population; non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dupilumab 300 mg EOW | Percentage of Participants Achieving a 75% Reduction From Baseline in Eczema Area and Severity Index Score (EASI 75) at Week 16 | 62.6 percentage of participants |
| Upadacitinib 30 mg QD | Percentage of Participants Achieving a 75% Reduction From Baseline in Eczema Area and Severity Index Score (EASI 75) at Week 16 | 72.4 percentage of participants |
p-value: 0.00795% CI: [2.6, 16.7]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Achieving a 100% Reduction From Baseline in EASI Score (EASI 100) at Week 16
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
Population: Intent-to-treat population; non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dupilumab 300 mg EOW | Percentage of Participants Achieving a 100% Reduction From Baseline in EASI Score (EASI 100) at Week 16 | 7.9 percentage of participants |
| Upadacitinib 30 mg QD | Percentage of Participants Achieving a 100% Reduction From Baseline in EASI Score (EASI 100) at Week 16 | 28.4 percentage of participants |
p-value: <0.00195% CI: [14.8, 26]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Achieving a 75% Reduction From Baseline in EASI Score at Week 2
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 2
Population: Intent-to-treat population; Non-responder imputation while incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dupilumab 300 mg EOW | Percentage of Participants Achieving a 75% Reduction From Baseline in EASI Score at Week 2 | 18.2 percentage of participants |
| Upadacitinib 30 mg QD | Percentage of Participants Achieving a 75% Reduction From Baseline in EASI Score at Week 2 | 44.3 percentage of participants |
p-value: <0.00195% CI: [19.3, 32.7]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Achieving a 90% Reduction From Baseline in EASI Score (EASI 90) at Week 16
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
Population: Intent-to-treat population; non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dupilumab 300 mg EOW | Percentage of Participants Achieving a 90% Reduction From Baseline in EASI Score (EASI 90) at Week 16 | 40.3 percentage of participants |
| Upadacitinib 30 mg QD | Percentage of Participants Achieving a 90% Reduction From Baseline in EASI Score (EASI 90) at Week 16 | 61.6 percentage of participants |
p-value: <0.00195% CI: [13.8, 28.6]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Achieving a Reduction of ≥ 4 Points From Baseline in Worst Pruritus NRS at Week 16
The Worst Pruritus NRS is an assessment tool that participants used to report the intensity of their pruritus during a 24-hour recall period using an electronic hand-held device. Participants were asked to rate itch (pruritus) intensity at its worst during the past 24 hours on an 11-point scale from 0 (no itch) to 10 (worst imaginable itch).
Time frame: Baseline and Week 16
Population: Intent-to-treat population with Worst Pruritus NRS ≥ 4 at Baseline; non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dupilumab 300 mg EOW | Percentage of Participants Achieving a Reduction of ≥ 4 Points From Baseline in Worst Pruritus NRS at Week 16 | 36.4 percentage of participants |
| Upadacitinib 30 mg QD | Percentage of Participants Achieving a Reduction of ≥ 4 Points From Baseline in Worst Pruritus NRS at Week 16 | 56.1 percentage of participants |
p-value: <0.00195% CI: [12.4, 27.3]Cochran-Mantel-Haenszel
Secondary
Percent Change From Baseline in Worst Pruritus Numerical Rating Scale (NRS) Score at Week 1
The Worst Pruritus NRS is an assessment tool that participants used to report the intensity of their pruritus during a 24-hour recall period using an electronic hand-held device. Participants were asked to rate itch (pruritus) intensity at its worst during the past 24 hours on an 11-point scale from 0 (no itch) to 10 (worst imaginable itch). The percent change from Baseline was calculated from a rolling weekly average; a negative change from Baseline indicates improvement.
Time frame: Baseline (Week 0) to Week 1
Population: Intent-to-treat population with non-missing Baseline and at least one post-baseline value; 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dupilumab 300 mg EOW | Percent Change From Baseline in Worst Pruritus Numerical Rating Scale (NRS) Score at Week 1 | -8.94 percent change | Standard Error 1.831 |
| Upadacitinib 30 mg QD | Percent Change From Baseline in Worst Pruritus Numerical Rating Scale (NRS) Score at Week 1 | -31.96 percent change | Standard Error 1.772 |
p-value: <0.00195% CI: [-28.03, -18.02]Mixed Effect Model Repeated Measurement
Secondary
Percent Change From Baseline in Worst Pruritus Numerical Rating Scale (NRS) Score at Week 16
The Worst Pruritus NRS is an assessment tool that participants used to report the intensity of their pruritus during a 24-hour recall period using an electronic hand-held device. Participants were asked to rate itch (pruritus) intensity at its worst during the past 24 hours on an 11-point scale from 0 (no itch) to 10 (worst imaginable itch). The percent change from Baseline was calculated from a rolling weekly average; a negative change from Baseline indicates improvement.
Time frame: Baseline (Week 0) to Week 16
Population: Intent-to-treat population with non-missing Baseline and at least one post-baseline value; 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dupilumab 300 mg EOW | Percent Change From Baseline in Worst Pruritus Numerical Rating Scale (NRS) Score at Week 16 | -49.58 percent change | Standard Error 1.986 |
| Upadacitinib 30 mg QD | Percent Change From Baseline in Worst Pruritus Numerical Rating Scale (NRS) Score at Week 16 | -67.78 percent change | Standard Error 1.906 |
p-value: <0.00195% CI: [-23.61, -12.8]Mixed Effect Model Repeated Measurement
Secondary
Percent Change From Baseline in Worst Pruritus Numerical Rating Scale (NRS) Score at Week 4
The Worst Pruritus NRS is an assessment tool that participants used to report the intensity of their pruritus during a 24-hour recall period using an electronic hand-held device. Participants were asked to rate itch (pruritus) intensity at its worst during the past 24 hours on an 11-point scale from 0 (no itch) to 10 (worst imaginable itch). The percent change from Baseline was calculated from a rolling weekly average; a negative change from Baseline indicates improvement.
Time frame: Baseline (Week 0) to Week 4
Population: Intent-to-treat population with non-missing Baseline and at least one post-baseline value; 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dupilumab 300 mg EOW | Percent Change From Baseline in Worst Pruritus Numerical Rating Scale (NRS) Score at Week 4 | -32.39 percent change | Standard Error 2.288 |
| Upadacitinib 30 mg QD | Percent Change From Baseline in Worst Pruritus Numerical Rating Scale (NRS) Score at Week 4 | -60.41 percent change | Standard Error 2.204 |
p-value: <0.00195% CI: [-34.25, -21.78]Mixed Effect Model Repeated Measurement