Transcriptomic Skin Analysis for Atopic Dermatitis

(LEADS Trial)

Recruiting at 9 trial locations

Age: Any Age

Sex: Any

Trial Phase: Phase 4

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Must be taking: Dupilumab

Must not be taking: Systemic immunosuppressants, Biologics

Disqualifiers: HIV, Skin diseases, Immunosuppression, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 10

Duration: 24 weeks

431 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a multi-center, longitudinal study which will characterize the gene expression profiles and transcriptomic endotypes that underlie mild and moderate-severe Atopic dermatitis (AD) and will determine changes in these expression patterns and endotypes in response to standard-of-care treatment. Participants will complete up to ten scheduled study visits with assessment of topical steroid response and dupilumab response (if uncontrolled with topical steroids). Skin samples will be collected at all study visits to determine the gene expression profiles and transcriptomic endotypes that underlie mild vs. moderate-severe AD disease. The investigators will also evaluate the lipidomic, metabolomic, proteomic, and microbiome profiles of AD skin endotypes associated with mild and moderate-severe AD disease. Non-AD participants will serve as a control population. The primary objective of this study is to determine if the type 2-high non-lesional skin (skin tape) endotype is associated with current mild versus moderate-severe AD disease.

Will I have to stop taking my current medications?

The trial requires participants to stop using certain medications before joining. You must not use systemic immunosuppressive therapies, certain biologics, or specific topical treatments for a specified period before the study starts. Check with the study team to see if your current medications are affected.

What data supports the effectiveness of the drug Dupilumab for treating atopic dermatitis?

Dupilumab has been shown to significantly improve skin inflammation and itching in patients with moderate-to-severe atopic dermatitis by blocking key inflammatory pathways, with studies demonstrating rapid and sustained improvements in clinical outcomes and a favorable safety profile. ^{1 2 3 4 5}

Is the treatment safe for humans?

Dupilumab has shown remarkable effectiveness and safety in treating moderate-to-severe atopic dermatitis, with limited drug-related adverse events. However, there is a small risk of local Staphylococcus aureus infection during treatment. ^{1 6 7 8 9}

What makes the drug Dupilumab unique for treating atopic dermatitis?

Dupilumab is unique because it is the first targeted biological therapy for atopic dermatitis, working by blocking specific proteins (interleukin-4 and interleukin-13) involved in the immune response, which helps improve skin barrier function and reduce inflammation. ^{3 8 10 11 12}

Research Team

Max A. Seibold, Ph.D.

Principal Investigator

National Jewish Health: Division of Pediatric Allergy and Clinical Immunology

Donald Leung, M.D., Ph.D.

Principal Investigator

National Jewish Health: Division of Pediatric Allergy and Clinical Immunology

Eligibility Criteria

This trial is for individuals with mild to moderate-severe Atopic Dermatitis (AD). Eligible participants must understand and consent to the study, use FDA-approved birth control if applicable, apply Vanicream moisturizer twice daily, and adhere to asthma medications if they have asthma. Participants should not be pregnant or breastfeeding, have a history of certain cancers or keloids (adults), require systemic immunosuppressants recently, or have used other biologics or phototherapy close to the baseline visit.

Inclusion Criteria

Parent or guardian must be able to understand and complete study-related questionnaires.

I will continue my asthma medication throughout the study.

I agree to use approved birth control methods during the study.

Exclusion Criteria

I only have Atopic Dermatitis and no other skin conditions affecting my skin's outer layer.

You have a history of heavy drinking or drug abuse within the past 2 years.

I have never had keloids form after an injury or surgery.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive standard-of-care treatment including topical corticosteroids and dupilumab, with skin samples collected at all study visits to determine gene expression profiles.

24 weeks

10 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with final assessments and skin sample collection.

4-8 weeks

Treatment Details

Interventions

• Dupilumab
• Triamcinolone Acetonide

Trial Overview The study aims to analyze gene expression in skin samples from AD patients responding to standard treatments like topical steroids and Dupilumab. It will compare these profiles between mild and severe cases over ten visits. Non-AD participants are controls. The primary goal is seeing if a specific skin endotype correlates with AD severity.

Participant Groups

Group I: Experienced Dupilumab atopic dermatitis participants Experimental Treatment 1 Intervention

AD participants already on dupilumab (for \>= 4 months prior to study entry (20 children, 40 adults)) at the start of the study will continue treatment with dupilumab as prescribed by their physician outside of the study. They may also continue treatment with other prescribed topical AD medications outside of the specified target skin area throughout the study; they may continue treatment with other prescribed topical AD medications within the specified target area from Day 7 through Day 140. Long-term dupilumab participants will apply Vanicream™ beginning at Day 0 through Day 7. Long-term dupilumab participants will return for assessment visits at Day 63 and 140. At Day 140, participants will resume application of Vanicream™ through the End of Study Assessment (Day 168).

Group II: Dupilumab-naïve atopic dermatitis participants Experimental Treatment 4 Interventions

On Day 7, dupilumab-naïve AD participants will begin applying topical corticosteroids twice daily to their specified target area, as well as to active lesions on non-target skin. Dupilumab-naïve AD participants will return for a Steroid Assessment Visit at Day 35, when response to topical corticosteroids will be evaluated at the target site by TAA and targeted EASI scoring, and overall management of AD body-wide by topical steroid/moisturizer treatment will be evaluated by EASI score. Participants who are responsive to topical corticosteroids will continue to use them body-wide through Day 140. Participants who are non-responsive to topical corticosteroids at any time before Day 91 will begin use of dupilumab through their penultimate scheduled visit (Day 140-Day 196) and may continue use of topical corticosteroids outside of their specified target area as needed.

Group III: Non-atopic dermatitis participants Active Control 1 Intervention

Approximately 150 will be non-AD controls (including approximately 50 children, 6-17 years of age, and 100 adults, = 18 years of age) Non-AD control participants will apply Vanicream™ beginning at Day 0 through Day 7. Non-AD control participants will return for assessment visits at Day 35, 91, and 140. At Day 140, participants will resume application of Vanicream™ through the End of Study Assessment (Day 168).

Dupilumab is already approved in United States, European Union for the following indications:

Approved in United States as Dupixent for:

• Atopic dermatitis
• Asthma
• Chronic rhinosinusitis with nasal polyps
• Eosinophilic esophagitis

Approved in European Union as Dupixent for:

• Atopic dermatitis
• Asthma
• Chronic rhinosinusitis with nasal polyps
• Eosinophilic esophagitis

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

Findings from Research

Dupilumab significantly improved asthma control and sinonasal symptoms in adult patients with moderate to severe atopic dermatitis, as shown by improvements in ACQ-5 and SNOT-22 scores compared to placebo in a study involving 2444 patients.

The treatment also effectively reduced signs and symptoms of atopic dermatitis across all patient subgroups, demonstrating its efficacy in managing multiple related conditions simultaneously.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dupilumab Improves Asthma and Sinonasal Outcomes in Adults with Moderate to Severe Atopic Dermatitis. Boguniewicz, M., Beck, LA., Sher, L., et al.[2022]

Dupilumab significantly improved the SCORing Atopic Dermatitis (SCORAD) scores in adults with moderate-to-severe atopic dermatitis as early as Week 1 or 2, demonstrating its rapid efficacy compared to placebo.

In a post hoc analysis of 2,444 patients from four phase 3 trials, dupilumab showed sustained improvements in SCORAD outcomes, regardless of whether it was used alone or with topical corticosteroids, indicating its effectiveness in managing this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dupilumab provides rapid and sustained improvement in SCORAD outcomes in adults with moderate-to-severe atopic dermatitis: combined results of four randomized phase 3 trials. Barbarot, S., Wollenberg, A., Silverberg, JI., et al.[2022]

Dupilumab is the first targeted biological therapy approved for moderate-to-severe atopic dermatitis in patients aged 6 and older, effectively blocking interleukin-4 and interleukin-13 signaling, which are key players in the disease's immune response.

Clinical trials have shown that dupilumab not only improves symptoms of atopic dermatitis but also helps restore the skin's barrier function and corrects the underlying immune dysregulation associated with the condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dupilumab for Atopic Dermatitis-From Clinical Trials to Molecular and Cellular Mechanisms. Cabanillas, B.[2023]

Dupilumab, a monoclonal antibody targeting the IL-4 receptor, has shown rapid and significant improvements in adults with moderate-to-severe atopic dermatitis (AD) in Phase I and II studies, both as a standalone treatment and in combination with topical corticosteroids.

The treatment not only improved clinical symptoms and patient-reported outcomes but also demonstrated a favorable safety profile with no dose-limiting toxicity, confirming the role of IL-4 and IL-13 in the inflammation associated with AD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug evaluation review: dupilumab in atopic dermatitis. Hamilton, JD., Ungar, B., Guttman-Yassky, E.[2022]

In a study of 60 patients with atopic dermatitis treated with dupilumab, serum TARC and LDH levels were strongly associated with changes in disease activity, indicating their potential as effective markers for monitoring treatment response.

The study highlights that the relevance of laboratory markers, such as IgE and eosinophil counts, varies depending on the treatment used, suggesting that dupilumab alters the relationship between these markers and disease activity compared to untreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association study of transition of laboratory marker levels and transition of disease activity of atopic dermatitis patients treated with dupilumab. Mizuno, M., Horiguchi, G., Teramukai, S., et al.[2022]

Dupilumab is the first biological medication approved for treating moderate-to-severe atopic dermatitis, demonstrating significant effectiveness and a favorable safety profile.

Despite its overall safety, there have been rare cases of local Staphylococcus aureus infections reported in patients undergoing dupilumab treatment for atopic dermatitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Case report: Dupilumab leads to an increased chance of head and neck Staphylococcus aureus infection in atopic dermatitis patients. Chen, M., Gao, K., Ali, K., et al.[2023]

In a real-life study of 241 adults with atopic dermatitis treated with dupilumab, significant improvements were observed in skin severity scores after 3 months, with 48.8% of patients achieving a ≥75% improvement in the Eczema Area and Severity Index (EASI).

However, the study also found a higher incidence of conjunctivitis (38.2% of patients) and increased eosinophilia (57% during follow-up) compared to baseline, indicating potential safety concerns associated with dupilumab treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of dupilumab for the treatment of atopic dermatitis in a real-life French multicenter adult cohort. Faiz, S., Giovannelli, J., Podevin, C., et al.[2019]

Dupilumab significantly reduced the severity of atopic dermatitis in children aged 6-11, with a notable decrease in SCORAD scores after 3 months of treatment, indicating its effectiveness in real-world settings.

While dupilumab was generally safe, with a low incidence of serious side effects, some children experienced conjunctivitis and injection site reactions, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of dupilumab in the treatment of atopic dermatitis in children (6-11 years): data from a French multicentre retrospective cohort in daily practice. Lasek, A., Bellon, N., Mallet, S., et al.[2022]

In a study of 210 adult patients with treatment-refractory atopic dermatitis, dupilumab treatment led to a significant reduction in eczema severity, with a 70% improvement in symptoms by week 16 and 76.6% by week 52.

The most common side effect reported was conjunctivitis, affecting 34% of patients, but only 8.1% discontinued treatment, indicating that dupilumab is generally well-tolerated over the long term.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dupilumab shows long-term effectiveness in a large cohort of treatment-refractory atopic dermatitis patients in daily practice: 52-Week results from the Dutch BioDay registry. Ariëns, LFM., van der Schaft, J., Spekhorst, LS., et al.[2021]

This study analyzed the transcriptome of peripheral blood mononuclear cells (PBMCs) from 56 Chinese patients with moderate-to-severe atopic dermatitis (AD) before and after 16 weeks of dupilumab treatment, revealing significant changes in immune pathways.

Two specific genes, MAP2K3 and UBE2L3, were identified as potential predictors of dupilumab efficacy, suggesting that they could help determine which patients are likely to benefit from this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Peripheral blood mononuclear cell- transcriptome signatures of atopic dermatitis and prediction for the efficacy of dupilumab. Wang, Y., Wu, Y., Gu, C., et al.[2023]

Dupilumab is the first targeted biological therapy approved for moderate-to-severe atopic dermatitis in patients aged 6 and older, effectively blocking interleukin-4 and interleukin-13 signaling, which are key players in the disease's immune response.

Clinical trials have shown that dupilumab not only improves symptoms of atopic dermatitis but also helps restore the skin's barrier function and corrects the underlying immune dysregulation associated with the condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dupilumab for Atopic Dermatitis-From Clinical Trials to Molecular and Cellular Mechanisms. Cabanillas, B.[2022]

In a study of 59 patients with severe atopic dermatitis treated with dupilumab over 36 months, the treatment showed high efficacy, with over 94% of patients achieving significant improvement in their Eczema Area and Severity Index (EASI) scores at various time points.

Dupilumab was well-tolerated, with mild adverse events reported in only 20.3% of patients, indicating a favorable safety profile alongside its effectiveness in reducing symptoms like itching and sleep disturbances.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Dupilumab for the Treatment of Severe Atopic Dermatitis in Clinical Practice: A Single Center Experience. Martínez-Doménech, A., Zaragoza-Ninet, V., Esteve-Martínez, A., et al.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

Dupilumab Improves Asthma and Sinonasal Outcomes in Adults with Moderate to Severe Atopic Dermatitis. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Dupilumab provides rapid and sustained improvement in SCORAD outcomes in adults with moderate-to-severe atopic dermatitis: combined results of four randomized phase 3 trials. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Dupilumab for Atopic Dermatitis-From Clinical Trials to Molecular and Cellular Mechanisms. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Drug evaluation review: dupilumab in atopic dermatitis. [2022]

5. Australia pubmed.ncbi.nlm.nih.gov

Association study of transition of laboratory marker levels and transition of disease activity of atopic dermatitis patients treated with dupilumab. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Case report: Dupilumab leads to an increased chance of head and neck Staphylococcus aureus infection in atopic dermatitis patients. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of dupilumab for the treatment of atopic dermatitis in a real-life French multicenter adult cohort. [2019]

8. England pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of dupilumab in the treatment of atopic dermatitis in children (6-11 years): data from a French multicentre retrospective cohort in daily practice. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Dupilumab shows long-term effectiveness in a large cohort of treatment-refractory atopic dermatitis patients in daily practice: 52-Week results from the Dutch BioDay registry. [2021]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Peripheral blood mononuclear cell- transcriptome signatures of atopic dermatitis and prediction for the efficacy of dupilumab. [2023]

11. United States pubmed.ncbi.nlm.nih.gov

Dupilumab for Atopic Dermatitis-From Clinical Trials to Molecular and Cellular Mechanisms. [2022]

12. Spain pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Dupilumab for the Treatment of Severe Atopic Dermatitis in Clinical Practice: A Single Center Experience. [2023]