Dupilumab Effect on Pruritus Neuro-mechanisms in Patients With Atopic Dermatitis

Sanofi54 enrolled

Overview

Primary Objective: \- Assess change in neuronal architecture following long term treatment with dupilumab in skin biopsies from atopic dermatitis (AD) participants with chronic pruritus. Secondary Objectives: * Assess change in neuronal architecture following short term treatment with dupilumab and during follow-up in skin biopsies from AD participants with chronic pruritus. * To evaluate the efficacy of dupilumab in AD participants with chronic pruritus. * To evaluate the safety of dupilumab in adult participants with moderate-to-severe AD.

AD participants: A 20-week Observation Period including 16 weeks of treatment for AD participants and a 4-week follow-up period; Healthy participants: 8 days observation period.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

NONE

Enrollment

Conditions

Dermatitis Atopic

Interventions

Dupilumab (SAR231893)DRUG

Pharmaceutical form: solution for injection Route of administration: subcutaneous

Eligibility

Sex: ALLMin age: 18 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion criteria: For AD participants * Male or female of greater than or equal to (\>=)18 years of age inclusive, at the time of signing the informed consent form (ICF). * Diagnosed with moderate-to-severe chronic AD for at least 1 year before screening. * Eligible to be treated with dupilumab according to product monograph. * Pruritus lasting 6 or more weeks before baseline (Day 1). * Eczema Area and Severity Index (EASI) score \>=12 at baseline. * Pruritus numerical rating scale (NRS) \>=4 at baseline. * Investigator global assessment (IGA) score of \>=3 at screening (on the 0 to 4 scale) at baseline. * Atopic dermatitis active lesions on the upper limbs or lower limbs suitable for a skin biopsy without oozing, bleeding, or infection on upper limbs or trunk. * Participants with acute AD lesions as determined by Investigator's judgment. * Stable treatment with non-prohibited medication or therapy during the study. For Healthy participants * Male or female of \>=18 years of age inclusive, at the time of signing the ICF. * Certified as generally healthy by a comprehensive clinical assessment. Exclusion criteria: For AD participants * Previous treatment with dupilumab stopped within 6 months of baseline due to inadequate response to dupilumab. * Skin conditions other than AD that can confound assessments in the opinion of the investigator. * Regular use (\>2 visits per week) of a tanning booth/parlor within 4 weeks of the Screening Visit. * Severe concomitant illness(es) that, in the Investigator's judgment, would adversely affect the participant's participation in the study. * Participants with active tuberculosis (TB) or non-TB mycobacterial infection, or a history of incompletely treated TB unless it is well documented the participant has been adequately treated and can now start treatment with a biologic agent * Diagnosed with, suspected of, or at high risk of endoparasitic infection, and/or use of antiparasitic drug within 2 weeks before the Screening Visit (Visit 1) or during the Screening Period. * Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, or antifungals within 2 weeks before the Screening Visit (Visit 1) or during the Screening Period. * Known or suspected immunodeficiency, including history of invasive opportunistic infections. * Active malignancy or history of malignancy within 5 years before the Baseline Visit, except completely treated in situ carcinoma of the cervix and completely treated and resolved non-metastatic squamous or basal cell carcinoma of the skin. * Ocular disorder that in the opinion of the Investigator could adversely affect the individual's risk for study participation. Examples include, but are not limited to, individuals with a history of active cases of herpes keratitis, Sjogren's syndrome, keratoconjunctivitis sicca or dry eye syndrome that require daily use of supplemental lubrication or individuals with ocular conditions that require the use of ocular corticosteroids or cyclosporine. * History of systemic hypersensitivity or anaphylaxis to dupilumab or any other biologic therapy, including any excipient. * Participant with any other medical or psychological condition including relevant laboratory or electrocardiogram abnormalities at screening. For healthy participants * Regular use (\>2 visits per week) of a tanning booth/ parlor within 4 weeks of the Screening Visit. * Treatment with the following concomitant medications and procedures is prohibited within 4 weeks before the Screening Visit or 5 half-lives (whichever is longer) until End of Study Visit: * Topical medication * Analgesics * Immunomodulators * Antidepressants * Anti-anxiety drugs * Any Type 2 immune disorders uncontrolled Type 2 diabetes mellitus, Type 1 diabetes mellitus, neuropathy or any other neurological disease. * Any concomitant illness(es) or conditions that, in the Investigator's judgment, would adversely affect the participant's participation in the study or potentially affect any skin biopsy related read out. * Positive test for immunoglobulin E (IgE) antibodies. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Locations (3)

Investigational Site Number 8400001

Miami, Florida, United States

Investigational Site Number 8400002

East Windsor, New Jersey, United States

Investigational Site Number 2760001

Münster, Germany

Outcomes

Primary Outcomes

Change From Baseline in Intraepidermal Nerve Fiber Density on Lesional Skin at Week 17

Skin biopsies were used to analyze the epidermal nerve fiber density. Nerve fibers were visualized by staining consecutive sections for the pan-axonal marker protein gene product 9.5 (PGP9.5); and the basement membrane was visualized by staining for collagen type 4. Quantification of intraepidermal nerve fiber density was calculated by assessing nerve fibers crossing the basement membrane per square millimeter (F/mm\^2). Data for this outcome measure was not planned to be collected and analyzed for "healthy participant" arm as pre-specified in protocol.

Time frame: Baseline, Week 17

Percentage of Participants With Change From Baseline in Nerve Fiber Branching on Lesional Skin at Week 17

Skin biopsies were used to analyze the epidermal nerve fiber branching. Nerve fibers were visualized by staining consecutive sections for the pan-axonal marker PGP9.5; and the basement membrane was visualized by staining for collagen type 4. Branching of epidermal nerve fibers was assessed semi-quantitatively by classifying participants into 4 groups depending on the predominant intraepidermal nerve fiber branching pattern as follows: only linear (100% linear), mainly linear (\>60% linear), mainly branched (\>60% branched), only branched (100% branched). Percentage of participants with change in nerve fiber branching status from baseline on lesional skin at Week 17 are reported in this outcome measure.

Time frame: Baseline, Week 17

Secondary Outcomes

Change From Baseline in Intraepidermal Nerve Fiber Density on Lesional Skin at Weeks 3 and 21

Skin biopsies were used to analyze the epidermal nerve fiber density. Nerve fibers were visualized by staining consecutive sections for the pan-axonal marker PGP9.5; and the basement membrane was visualized by staining for collagen type 4. Quantification of intraepidermal nerve fiber density was calculated by assessing nerve fibers crossing the basement membrane per square millimeter (F/mm\^2).

Time frame: Baseline, Weeks 3 and 21

Data from ClinicalTrials.gov

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Change From Baseline in Nerve Fiber Branching on Lesional Skin at Weeks 3 and 21

Time frame: Baseline, Weeks 3 and 21

Change From Baseline in Peak Pruritus Assessed by Numeric Rating Scale (NRS) Scores at Weeks 17 and 21

Peak Pruritus NRS was an assessment tool used to report the intensity of participant's pruritus (itch) during a daily recall period. Participants were asked to rate their worst itch on a 0 ("No itch") to 10 ("Worst itch imaginable") NRS by answering the following question: "On a scale of 0 to 10, with 0 being 'no itch' and 10 being the 'worst itch imaginable', how would you rate your itch at the worst moment during the previous 24 hours?". Higher scores indicated greater severity.