Dermatitis, Atopic Dermatitis
Conditions
Keywords
Atopic Dermatitis, Atopic Eczema
Brief summary
A study to evaluate the efficacy and safety of apremilast (CC-10004) in subjects with moderate to severe atopic dermatitis
Interventions
DRUGApremilast
Orally twice a day (BID)
DRUGPlacebo
Orally twice a day (BID)
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Males or females, aged ≥ 18 years (≥ 20 for Japanese subjects) at the time of consent. 2. Have a diagnosis of atopic dermatitis for ≥ 12 months. 3. Have moderate to severe atopic dermatitis which is considered inappropriate for topical therapy or which cannot be adequately controlled by topical therapy. 4. Meet the laboratory criteria as defined per protocol 5. Females of Childbearing Potential (FCBP) must have a negative pregnancy test at Screening and Baseline. Sexually active FCBP must use one of the approved contraceptive options required per protocol while on and for at least 28 days after the last dose of study medication 6. Male subjects (including those who have had a vasectomy) who engage in activity in which conception is possible must use barrier contraception while on and for at least 28 days after the last dose of study medication.
Exclusion criteria
1. Active tuberculosis (TB) or a history of inadequately treated tuberculosis. 2. Positive for hepatitis B surface antigen or hepatitis C antibody 3. Pregnant or breast feeding 4. History of allergy to any component of the study medication. 5. Active skin infection requiring systemic antimicrobials at Baseline.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change From Baseline in the Eczema Area and Severity Index (EASI) Score at Week 12. | Baseline to Week 12 | EASI is a validated composite scoring system integrating the proportion of the body region (area) involved and the intensity of key signs of atopic dermatitis (AD). A representative lesion is selected for each of the four body regions for assessing the intensity of each of the four signs (erythema, induration /papulation, excoriation, and lichenification). Symptoms (eg, pruritus) and secondary signs (eg, xerosis, scaling) are excluded from the assessment. The total EASI score ranges from 0 to 72. A higher score indicated worse disease status, and a negative change from baseline indicated improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved a Score of 0 (Cleared) or 1 (Almost Cleared) and at Least a 2-point Reduction From Baseline in a Static Physician's Global Assessment of Acute Signs (sPGA-A) at Week 12. | Baseline to Week 12 | The sPGA-A is intended to assess the global severities (ie, a visual average integrating all areas of AD) of key acute clinical signs of AD, including erythema, induration/papulation, oozing/crusting (lichenification excluded) based on a 5-point scale of cleared (0), almost cleared (1), mild (2), moderate (3) and severe (4). |
| Percentage of Participants Who Achieved at Least a 50% Reduction From Baseline in the EASI Score (EASI 50) at Week 12 | Baseline to Week 12 | The EASI 50 reduction (defined as ≥ 50% reduction from baseline in EASI score) was selected to serve as the key responder endpoint. A ≥ 50% improvement is clinically meaningful for this population. |
| The Percentage Change From Baseline in the Average Weekly Pruritus Numerical Rating Scale (NRS) Score at Week 4 | Baseline to Week 4 | The participant completed a daily diary recording the average intensity of pruritus they experienced during the preceding 24 hrs. The intensity of pruritus was assessed using a validated 11-point NRS, ranging from 0 (no pruritus) to 10 (the worst pruritus imaginable). It should be noted that this NRS is distinct from the pruritus, Visual Analogue Scale (VAS) in the Modified SCORAD Index with respect to recall period (three days for the VAS). The weekly NRS score was calculated as the average of the NRS scores over 7 days within the specified week. A higher score indicated worse disease status, and a negative change from baseline indicated improvement. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Placebo Controlled Period | Baseline to Week 12 | A TEAE is an adverse event with a start date on or after the date of the first dose of IP and no later than 28 days after the last dose of IP for participants who discontinued early. An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values, regardless of etiology. Any worsening (ie, any clinically significant adverse change in the frequency or intensity of a pre existing condition) should be considered an AE. A serious AE is any which results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect; constitutes an important medical event. |
| Number of Participants With TEAEs During the Apremilast Exposure Period | Baseline to Week 24; median duration of apremilast 30 mg was 23.3 weeks and 22.4 weeks for apremilast 40 mg | A TEAE is an adverse event with a start date on or after the date of the first dose of investigational product (IP) and no later than 28 days after the last dose of IP. An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values, regardless of etiology. Any worsening (ie, any clinically significant adverse change in the frequency or intensity of a pre existing condition) should be considered an AE. A serious AE is any which results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect; constitutes an important medical event. |
Countries
Canada, Japan, United States
Participant flow
Pre-assignment details
Treatment assignment was stratified by geographic region and within each region, by the Eczema Area and Severity Index (EASI) score (≤ 20 or \> 20). Six participants were excluded from analysis due to unsigned case books; a total of 185 participants were included in the final analyses.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants initially randomized to identically matching placebo (PBO) tablets twice daily BID during the Placebo-controlled Phase (Weeks 0-16) | 64 |
| Apremilast 30 mg Participants initially randomized to receive 30 mg apremilast tablets twice daily in the 12-week placebo-controlled phase. | 58 |
| Apremilast 40 mg Participants initially randomized to receive 40 mg apremilast tablets twice daily in the 12-week placebo-controlled phase. | 63 |
| Total | 185 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Active Treatment Phase Week 12-24 | Adverse Event | 0 | 1 | 2 | 0 | 1 |
| Active Treatment Phase Week 12-24 | Lack of Efficacy | 0 | 3 | 1 | 1 | 0 |
| Active Treatment Phase Week 12-24 | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 |
| Active Treatment Phase Week 12-24 | Other-Unspecified | 0 | 0 | 1 | 1 | 0 |
| Active Treatment Phase Week 12-24 | Withdrawal by Subject | 0 | 0 | 1 | 0 | 0 |
| Placebo-Controlled Phase Week 0-12 | Adverse Event | 1 | 2 | 6 | 0 | 0 |
| Placebo-Controlled Phase Week 0-12 | Lack of Efficacy | 8 | 7 | 4 | 0 | 0 |
| Placebo-Controlled Phase Week 0-12 | Lost to Follow-up | 1 | 0 | 1 | 0 | 0 |
| Placebo-Controlled Phase Week 0-12 | Protocol Violation | 0 | 1 | 0 | 0 | 0 |
| Placebo-Controlled Phase Week 0-12 | Withdrawal by Subject | 4 | 2 | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | Apremilast 30 mg | Apremilast 40 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 37.7 years STANDARD_DEVIATION 14.71 | 39.2 years STANDARD_DEVIATION 15.8 | 38.3 years STANDARD_DEVIATION 14.74 | 38.4 years STANDARD_DEVIATION 15 |
| Sex: Female, Male Female | 39 Participants | 27 Participants | 32 Participants | 98 Participants |
| Sex: Female, Male Male | 25 Participants | 31 Participants | 31 Participants | 87 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 14 / 64 | 22 / 58 | 30 / 63 | 30 / 82 | 45 / 86 |
| serious Total, serious adverse events | 0 / 64 | 1 / 58 | 2 / 63 | 2 / 82 | 3 / 86 |
Outcome results
Primary
Percentage Change From Baseline in the Eczema Area and Severity Index (EASI) Score at Week 12.
EASI is a validated composite scoring system integrating the proportion of the body region (area) involved and the intensity of key signs of atopic dermatitis (AD). A representative lesion is selected for each of the four body regions for assessing the intensity of each of the four signs (erythema, induration /papulation, excoriation, and lichenification). Symptoms (eg, pruritus) and secondary signs (eg, xerosis, scaling) are excluded from the assessment. The total EASI score ranges from 0 to 72. A higher score indicated worse disease status, and a negative change from baseline indicated improvement.
Time frame: Baseline to Week 12
Population: All participants who were randomized as specified per protocol and who received at least one dose of IP with a baseline and at least 1 post baseline value at or before week 12; A missing value at Week 12 was imputed by last observation carried forward (LOCF), including the value obtained at the Early Termination Visit prior to Week 12.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percentage Change From Baseline in the Eczema Area and Severity Index (EASI) Score at Week 12. | -10.98 percent change | Standard Error 6.873 |
| Apremilast 30 mg | Percentage Change From Baseline in the Eczema Area and Severity Index (EASI) Score at Week 12. | -25.99 percent change | Standard Error 7.106 |
| Apremilast 40 mg | Percentage Change From Baseline in the Eczema Area and Severity Index (EASI) Score at Week 12. | -31.57 percent change | Standard Error 6.82 |
p-value: 0.130895% CI: [-34.52, 4.5]ANCOVA
p-value: 0.034795% CI: [-39.7, -1.5]ANCOVA
Secondary
Number of Participants With TEAEs During the Apremilast Exposure Period
A TEAE is an adverse event with a start date on or after the date of the first dose of investigational product (IP) and no later than 28 days after the last dose of IP. An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values, regardless of etiology. Any worsening (ie, any clinically significant adverse change in the frequency or intensity of a pre existing condition) should be considered an AE. A serious AE is any which results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect; constitutes an important medical event.
Time frame: Baseline to Week 24; median duration of apremilast 30 mg was 23.3 weeks and 22.4 weeks for apremilast 40 mg
Population: Safety population includes all participants who received at least one dose of IP. These were Apremilast participants as treated.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With TEAEs During the Apremilast Exposure Period | TEAE | 49 participants |
| Placebo | Number of Participants With TEAEs During the Apremilast Exposure Period | Drug-related TEAE | 29 participants |
| Placebo | Number of Participants With TEAEs During the Apremilast Exposure Period | Severe TEAE | 1 participants |
| Placebo | Number of Participants With TEAEs During the Apremilast Exposure Period | Serious TEAE (SAE) | 2 participants |
| Placebo | Number of Participants With TEAEs During the Apremilast Exposure Period | Drug-related SAE | 0 participants |
| Placebo | Number of Participants With TEAEs During the Apremilast Exposure Period | TEAE Leading to Drug Interruption | 0 participants |
| Placebo | Number of Participants With TEAEs During the Apremilast Exposure Period | TEAE Leading to Drug Withdrawal | 3 participants |
| Placebo | Number of Participants With TEAEs During the Apremilast Exposure Period | Death | 0 participants |
| Apremilast 30 mg | Number of Participants With TEAEs During the Apremilast Exposure Period | TEAE Leading to Drug Withdrawal | 9 participants |
| Apremilast 30 mg | Number of Participants With TEAEs During the Apremilast Exposure Period | TEAE | 61 participants |
| Apremilast 30 mg | Number of Participants With TEAEs During the Apremilast Exposure Period | Drug-related SAE | 2 participants |
| Apremilast 30 mg | Number of Participants With TEAEs During the Apremilast Exposure Period | Drug-related TEAE | 38 participants |
| Apremilast 30 mg | Number of Participants With TEAEs During the Apremilast Exposure Period | Death | 0 participants |
| Apremilast 30 mg | Number of Participants With TEAEs During the Apremilast Exposure Period | Severe TEAE | 1 participants |
| Apremilast 30 mg | Number of Participants With TEAEs During the Apremilast Exposure Period | TEAE Leading to Drug Interruption | 8 participants |
| Apremilast 30 mg | Number of Participants With TEAEs During the Apremilast Exposure Period | Serious TEAE (SAE) | 3 participants |
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Placebo Controlled Period
A TEAE is an adverse event with a start date on or after the date of the first dose of IP and no later than 28 days after the last dose of IP for participants who discontinued early. An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values, regardless of etiology. Any worsening (ie, any clinically significant adverse change in the frequency or intensity of a pre existing condition) should be considered an AE. A serious AE is any which results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect; constitutes an important medical event.
Time frame: Baseline to Week 12
Population: Safety population includes all participants who received at least one dose of IP.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Placebo Controlled Period | TEAE | 30 participants |
| Placebo | Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Placebo Controlled Period | Drug-related TEAE | 8 participants |
| Placebo | Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Placebo Controlled Period | Severe TEAE | 0 participants |
| Placebo | Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Placebo Controlled Period | Serious TEAE (SAE) | 0 participants |
| Placebo | Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Placebo Controlled Period | Drug-related SAE | 0 participants |
| Placebo | Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Placebo Controlled Period | TEAE Leading to Drug Interruption | 3 participants |
| Placebo | Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Placebo Controlled Period | TEAE Leading to Drug Withdrawal | 1 participants |
| Placebo | Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Placebo Controlled Period | Death | 0 participants |
| Apremilast 30 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Placebo Controlled Period | Severe TEAE | 0 participants |
| Apremilast 30 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Placebo Controlled Period | TEAE Leading to Drug Withdrawal | 2 participants |
| Apremilast 30 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Placebo Controlled Period | Serious TEAE (SAE) | 1 participants |
| Apremilast 30 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Placebo Controlled Period | Drug-related SAE | 0 participants |
| Apremilast 30 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Placebo Controlled Period | TEAE Leading to Drug Interruption | 0 participants |
| Apremilast 30 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Placebo Controlled Period | TEAE | 36 participants |
| Apremilast 30 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Placebo Controlled Period | Drug-related TEAE | 26 participants |
| Apremilast 30 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Placebo Controlled Period | Death | 0 participants |
| Apremilast 40 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Placebo Controlled Period | Severe TEAE | 1 participants |
| Apremilast 40 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Placebo Controlled Period | Drug-related TEAE | 27 participants |
| Apremilast 40 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Placebo Controlled Period | TEAE | 44 participants |
| Apremilast 40 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Placebo Controlled Period | Serious TEAE (SAE) | 2 participants |
| Apremilast 40 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Placebo Controlled Period | TEAE Leading to Drug Withdrawal | 6 participants |
| Apremilast 40 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Placebo Controlled Period | TEAE Leading to Drug Interruption | 4 participants |
| Apremilast 40 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Placebo Controlled Period | Drug-related SAE | 1 participants |
| Apremilast 40 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Placebo Controlled Period | Death | 0 participants |
Secondary
Percentage of Participants Who Achieved a Score of 0 (Cleared) or 1 (Almost Cleared) and at Least a 2-point Reduction From Baseline in a Static Physician's Global Assessment of Acute Signs (sPGA-A) at Week 12.
The sPGA-A is intended to assess the global severities (ie, a visual average integrating all areas of AD) of key acute clinical signs of AD, including erythema, induration/papulation, oozing/crusting (lichenification excluded) based on a 5-point scale of cleared (0), almost cleared (1), mild (2), moderate (3) and severe (4).
Time frame: Baseline to Week 12
Population: ITT includes all participants who were randomized as specified per protocol and received at least one dose of IP. LOCF for missing data handling.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Who Achieved a Score of 0 (Cleared) or 1 (Almost Cleared) and at Least a 2-point Reduction From Baseline in a Static Physician's Global Assessment of Acute Signs (sPGA-A) at Week 12. | 6.3 percentage of participants |
| Apremilast 30 mg | Percentage of Participants Who Achieved a Score of 0 (Cleared) or 1 (Almost Cleared) and at Least a 2-point Reduction From Baseline in a Static Physician's Global Assessment of Acute Signs (sPGA-A) at Week 12. | 3.4 percentage of participants |
| Apremilast 40 mg | Percentage of Participants Who Achieved a Score of 0 (Cleared) or 1 (Almost Cleared) and at Least a 2-point Reduction From Baseline in a Static Physician's Global Assessment of Acute Signs (sPGA-A) at Week 12. | 14.3 percentage of participants |
p-value: 0.493895% CI: [-10.2, 4.8]Cochran-Mantel-Haenszel
p-value: 0.136895% CI: [-2.3, 18.2]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Who Achieved at Least a 50% Reduction From Baseline in the EASI Score (EASI 50) at Week 12
The EASI 50 reduction (defined as ≥ 50% reduction from baseline in EASI score) was selected to serve as the key responder endpoint. A ≥ 50% improvement is clinically meaningful for this population.
Time frame: Baseline to Week 12
Population: ITT includes all participants who were randomized as specified in the protocol and received at least one dose of IP. LOCF.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Who Achieved at Least a 50% Reduction From Baseline in the EASI Score (EASI 50) at Week 12 | 32.8 percentage of participants |
| Apremilast 30 mg | Percentage of Participants Who Achieved at Least a 50% Reduction From Baseline in the EASI Score (EASI 50) at Week 12 | 31.0 percentage of participants |
| Apremilast 40 mg | Percentage of Participants Who Achieved at Least a 50% Reduction From Baseline in the EASI Score (EASI 50) at Week 12 | 42.9 percentage of participants |
p-value: 0.858995% CI: [-18, 14.9]Cochran-Mantel-Haenszel
p-value: 0.247695% CI: [-6.7, 26.6]Cochran-Mantel-Haenszel
Secondary
The Percentage Change From Baseline in the Average Weekly Pruritus Numerical Rating Scale (NRS) Score at Week 4
The participant completed a daily diary recording the average intensity of pruritus they experienced during the preceding 24 hrs. The intensity of pruritus was assessed using a validated 11-point NRS, ranging from 0 (no pruritus) to 10 (the worst pruritus imaginable). It should be noted that this NRS is distinct from the pruritus, Visual Analogue Scale (VAS) in the Modified SCORAD Index with respect to recall period (three days for the VAS). The weekly NRS score was calculated as the average of the NRS scores over 7 days within the specified week. A higher score indicated worse disease status, and a negative change from baseline indicated improvement.
Time frame: Baseline to Week 4
Population: All participants who were randomized as specified in the protocol and who received at least one dose of IP with a baseline and at least 1 postbaseline value at or before Week 4 were included. LOCF.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | The Percentage Change From Baseline in the Average Weekly Pruritus Numerical Rating Scale (NRS) Score at Week 4 | -4.83 percent change | Standard Error 5.657 |
| Apremilast 30 mg | The Percentage Change From Baseline in the Average Weekly Pruritus Numerical Rating Scale (NRS) Score at Week 4 | -10.00 percent change | Standard Error 5.911 |
| Apremilast 40 mg | The Percentage Change From Baseline in the Average Weekly Pruritus Numerical Rating Scale (NRS) Score at Week 4 | -9.00 percent change | Standard Error 5.85 |
p-value: 0.528695% CI: [-21.34, 10.99]ANCOVA
p-value: 0.609295% CI: [-20.22, 11.88]ANCOVA