Atopic Dermatitis, Atopic Dermatitis and Related Conditions, Atopic Dermatitis Eczema, Eczema
Conditions
Keywords
atopic dermatitis, eczema, dupilumab, atopic eczema
Brief summary
This is a single-arm, open-label study to examine the effect of dupilumab on the immunologic and genetic environment within atopic dermatitis skin lesions.
Detailed description
Fifteen subjects with moderate to severe AD will receive dupilumab for a treatment period of 52 weeks (i.e. last injection on week 50). Biopsy samples from AD subjects and surgical discard samples will undergo molecular profiling. Skin swabs and stool samples will be collected and banked for future analysis. The reason to treat patients for 52 weeks is to have the ability to correlate early molecular events with clinical outcomes at week 52.
Interventions
DRUGDupilumab
Dupilumab treatment
Sponsors
Regeneron Pharmaceuticals
Sanofi
University of California, San Francisco
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Ability to provide written informed consent and comply with the protocol. * At least 18 years of age. * Diagnosis of chronic atopic dermatitis for at least 3 years prior to enrollment. * Subject is considered a candidate for phototherapy or systemic therapy * Eczema Area and Severity Index (EASI) score ≥ 12 * Investigator Global Assessment (IGA) ≥ 3 * 10% body surface area (BSA) or greater * Subject is unlikely to conceive due to male, post-menopausal, or using adequate contraceptive (barrier, hormonal, implant, or permanent sterilization methods). * Physical exam within clinically acceptable limits.
Exclusion criteria
* Subject is unable to provide written informed consent or comply with the protocol. * Subject is younger than 18 years of age. * Subject has had atopic dermatitis for less than 3 years prior to enrollment. * Subject with mild atopic dermatitis (EASI\<12 and IGA\<3) or is not a candidate for phototherapy or systemic treatments. * Subject with current, or a history of, severe atopic dermatitis well controlled on current therapy. * Serious known infection. * History of immunosuppression (including human immunodeficiency virus (HIV)) * History of malignancy within 5 years before the screening visit, except completely treated in situ carcinoma of the cervix, completely treated and resolved non-metastatic squamous or basal cell carcinoma of the skin. * Severe concomitant illnesses. * Having used immunosuppressive/immunomodulating drugs (eg, systemic corticosteroids, cyclosporine, mycophenolate-mofetil, IFN-γ, Janus kinase inhibitors, azathioprine, methotrexate, etc.) or phototherapy within 4 weeks before the baseline visit. * Treatment with topical corticosteroid or topical calcineurin inhibitor within 1 week before the baseline visit. * Treatment with any cell-depleting agents including but not limited to rituximab: within 6 months before the baseline visit, or until lymphocyte count returns to normal, whichever is longer, or use of other biologics: within 5 half-lives (if known) or 16 weeks prior to baseline visit, whichever is longer. * Physical or laboratory exam not within clinically acceptable limits. * Subjects possess other diagnoses that, in the investigator's opinion, preclude him/her from safely participating in this study or interfere with the evaluation of the subject's atopic dermatitis. * History of known or suspected intolerance to any of the ingredients of the investigational study product. * Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (\>10 mIU/mL).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in CD4+ T Effector Cells Expressing IL4 in Dupilumab-treated Subjects at Week 12 vs Week 0 | 12 weeks | The percent change in CD4+ T effector cells expressing IL-4 in dupilumab-treated subjects at week 12 vs week 0 was calculated as follows. A single value was derived for the entire population with pooled samples from pre- and post-intervention time points, which was then used to calculate a percent change between the two periods. Specifically, the mean M1 across subjects of the percentage of CD4+ T effector cells expressing IL4 was computed at week 0. The mean M2 across subjects of the percentage of CD4+ T effector cells expressing IL4 was computed at week 12. The final result was calculated as: (M1-M2)/M1\*100. Therefore, the result is a number and there is no central tendency metric. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Differentially Expressed Genes in Cutaneous CD4+ T Cells Between Week 0 and Week 12 in Dupilumab-treated Subjects | 12 weeks | A single value was derived for the entire population with pooled samples from pre- and post-intervention time points, which was then used to calculate an percent change between the two periods. Specifically, single cell RNA-sequencing was used to calculate the number of differentially expressed genes in cutaneous CD4+ T cells between week 0 and week 12 in dupilumab-treated subjects. The calculation was performed in the software package Seurat (RRID:SCR\_016341) using the FindMarkers function, which utilizes a non-parametric Wilcoxon rank-sum test. Genes were considered significantly differentially expressed if the adjusted p-value \< 0.05 and the absolute value of log2(Fold Change) \> 1.0. Therefore, this measure is reported as a number and there is no central tendency metric. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dupilumab Treatment 14 subjects competed (3 withdrew during course of study). Subjects will received dupilumab for a treatment period of 52 weeks (i.e. last injection on week 50). All subjects will undergo skin biopsies for molecular profiling.
Dupilumab: Dupilumab treatment | 17 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Dupilumab Treatment |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants |
| Age, Continuous | 38.1 years |
| EASI score | 21.98 units on a scale |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 10 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) White | 3 Participants |
| Region of Enrollment United States | 17 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 17 |
| other Total, other adverse events | 10 / 17 |
| serious Total, serious adverse events | 0 / 17 |
Outcome results
Primary
Percent Change in CD4+ T Effector Cells Expressing IL4 in Dupilumab-treated Subjects at Week 12 vs Week 0
The percent change in CD4+ T effector cells expressing IL-4 in dupilumab-treated subjects at week 12 vs week 0 was calculated as follows. A single value was derived for the entire population with pooled samples from pre- and post-intervention time points, which was then used to calculate a percent change between the two periods. Specifically, the mean M1 across subjects of the percentage of CD4+ T effector cells expressing IL4 was computed at week 0. The mean M2 across subjects of the percentage of CD4+ T effector cells expressing IL4 was computed at week 12. The final result was calculated as: (M1-M2)/M1\*100. Therefore, the result is a number and there is no central tendency metric.
Time frame: 12 weeks
Population: Number of subjects with atopic dermatitis with single cell data
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dupilumab Treatment | Percent Change in CD4+ T Effector Cells Expressing IL4 in Dupilumab-treated Subjects at Week 12 vs Week 0 | Percent change in lesional skin | 68.4 Percent change |
| Dupilumab Treatment | Percent Change in CD4+ T Effector Cells Expressing IL4 in Dupilumab-treated Subjects at Week 12 vs Week 0 | Percent change in non-lesional skin | 100.0 Percent change |
Secondary
Number of Differentially Expressed Genes in Cutaneous CD4+ T Cells Between Week 0 and Week 12 in Dupilumab-treated Subjects
A single value was derived for the entire population with pooled samples from pre- and post-intervention time points, which was then used to calculate an percent change between the two periods. Specifically, single cell RNA-sequencing was used to calculate the number of differentially expressed genes in cutaneous CD4+ T cells between week 0 and week 12 in dupilumab-treated subjects. The calculation was performed in the software package Seurat (RRID:SCR\_016341) using the FindMarkers function, which utilizes a non-parametric Wilcoxon rank-sum test. Genes were considered significantly differentially expressed if the adjusted p-value \< 0.05 and the absolute value of log2(Fold Change) \> 1.0. Therefore, this measure is reported as a number and there is no central tendency metric.
Time frame: 12 weeks
Population: Number of subjects with atopic dermatitis with single cell data available
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dupilumab Treatment | Number of Differentially Expressed Genes in Cutaneous CD4+ T Cells Between Week 0 and Week 12 in Dupilumab-treated Subjects | DEG in lesional skin | 81 differentially expressed genes |
| Dupilumab Treatment | Number of Differentially Expressed Genes in Cutaneous CD4+ T Cells Between Week 0 and Week 12 in Dupilumab-treated Subjects | DEG in non-lesional skin | 186 differentially expressed genes |
Comparison: Single cell RNA-sequencing was used to calculate the number of differentially expressed genes in cutaneous CD4+ T cells between week 0 and week 12 in dupilumab-treated subjects. The calculation was performed in the software package Seurat (RRID:SCR\_016341) using the FindMarkers function, which utilizes a non-parametric Wilcoxon rank-sum test. Genes were considered significantly differentially expressed if the adjusted p-value \< 0.05 and the absolute value of log2(Fold Change) \> 1.0.p-value: <0.05Wilcoxon (Mann-Whitney)