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Clinical Trial
. 2024 Nov 1;160(11):1161-1170.
doi: 10.1001/jamadermatol.2024.3121.

Roflumilast Cream, 0.15%, for Atopic Dermatitis in Adults and Children: INTEGUMENT-1 and INTEGUMENT-2 Randomized Clinical Trials

Eric L Simpson  1 , Lawrence F Eichenfield  2 , Javier Alonso-Llamazares  3 , Zoe D Draelos  4 , Laura K Ferris  5 , Seth B Forman  6 , Melinda Gooderham  7   8 , Mercedes E Gonzalez  9 , Adelaide A Hebert  10 , Leon H Kircik  11   12   13   14 , Mark Lomaga  15   16 , Angela Moore  17   18 , Kim A Papp  19   20 , Vimal H Prajapati  21   22 , Diane Hanna  23 , Scott Snyder  23 , David Krupa  23 , Patrick Burnett  23 , Erin Almaraz  23 , Robert C Higham  23 , David H Chu  23 , David R Berk  23
Affiliations
Clinical Trial

Roflumilast Cream, 0.15%, for Atopic Dermatitis in Adults and Children: INTEGUMENT-1 and INTEGUMENT-2 Randomized Clinical Trials

Eric L Simpson et al. JAMA Dermatol. .

Erratum in

  • Error in Supplement 2.
    [No authors listed] [No authors listed] JAMA Dermatol. 2025 Jun 1;161(6):669-670. doi: 10.1001/jamadermatol.2025.1153. JAMA Dermatol. 2025. PMID: 40266584 Free PMC article. No abstract available.

Abstract

Importance: Safe, effective, and well-tolerated topical treatment options available for long-term use in patients with atopic dermatitis (AD) are limited and associated with low adherence rates.

Objective: To evaluate efficacy and safety of once-daily roflumilast cream, 0.15%, vs vehicle cream in patients with AD.

Design, setting, and participants: Two phase 3, randomized, double-blind, vehicle-controlled trials (Interventional Trial Evaluating Roflumilast Cream for the Treatment of Atopic Dermatitis 1 and 2 [INTEGUMENT-1 and INTEGUMENT-2]), included patients from sites in the US, Canada, and Poland. Participants were 6 years or older with mild to moderate AD based on Validated Global Assessment for Atopic Dermatitis (assessed on a 5-point scale ranging from 0 [clear] to 4 [severe]).

Intervention: Patients were randomized 2:1 to receive roflumilast cream, 0.15%, or vehicle cream once daily for 4 weeks.

Main outcomes and measures: The primary efficacy end point was Validated Investigator Global Assessment for Atopic Dermatitis success at week 4, defined as a score of 0 or 1 plus at least a 2-grade improvement from baseline. Secondary end points included Eczema Area and Severity Index and Worst Itch Numeric Rating Scale. Safety and local tolerability were also evaluated.

Results: Among 1337 patients (654 patients in INTEGUMENT-1 and 683 patients in INTEGUMENT-2), the mean (SD) age was 27.7 (19.2) years, and 761 participants (56.9%) were female. The mean body surface area involved was 13.6% (SD = 11.6%; range, 3.0% to 88.0%). Significantly more patients treated with roflumilast than vehicle achieved the primary end point (INTEGUMENT-1: 32.0% vs 15.2%, respectively; P < .001; INTEGUMENT-2: 28.9% vs 12.0%, respectively; P < .001). At week 4, statistically significant differences favoring roflumilast also occurred for the achievement of at least 75% reduction in the Eczema Area and Severity Index (INTEGUMENT-1: 43.2% vs 22.0%, respectively; P < .001; INTEGUMENT-2: 42.0% vs 19.7%, respectively; P < .001). Roflumilast was well tolerated with low rates of treatment-emergent adverse events. At each time point, investigators noted no signs of irritation at the application site in 885 patients who were treated with roflumilast (≥95%), and 885 patients who were treated with roflumilast (90%) reported no or mild sensation at the application site.

Conclusions and relevance: In 2 phase 3 trials enrolling adults and children, once-daily roflumilast cream, 0.15%, improved AD relative to vehicle cream, based on multiple efficacy end points, with favorable safety and tolerability.

Trial registration: ClinicalTrials.gov Identifiers: NCT04773587, NCT04773600.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Simpson reported grants and personal fees from Arcutis Biotherapeutics during the study; personal fees from AbbVie, Amgen, Areteia Therapeutics, Bristol Myers Squibb, CorEvitas, Corvus, Dermira, Eli Lilly, Evelo Biosciences, FIDE, Forte Bio RX, Galderma, GlaxoSmithKline, Gilead Sciences, Impetus Healthcare, Incyte, Innovaderm Reche, Janssen, Johnson & Johnson, Kyowa Kirin, Leo, Merck, NUMAB Therapeutics AG, Pfizer, Physicians World LLC, PRImE, Recludix Pharma, Regeneron, Roivant, Sanofi-Genzyme, SITRYX Therapeutics, Trevi Therapeutics, and Valeant; and grants from AbbVie, Acrotech, Amgen, ASLAN, Castle, CorEvitas, Dermavant, Dermira, Incyte, Eli Lilly, Kymab, Kyowa Kirin, Leo, Pfizer, Regeneron, Sanofi, Target, and VeriSkin outside the submitted work. Amy Simpson (spouse) is a sub-investigator for AbbVie, Allakos, Amgen, Arcutis, Aslan, BMS, Dermavant, DermBiont, Eli Lilly, Galderma, Hallux, Incyte, Leo, Moberg, Technoderma, and UCB. Dr Eichenfield reported grants and personal fees from Arcutis during the study; other from Amgen, AbbVie, Dermavant, Galderma, Incyte, Eli Lilly, Pfizer, Regeneron, and Sanofi outside the submitted work. Dr Alonso-Llamazares reported serving as a PI of clinical trials for Abbott, AbbVie, Aclaris, Actavis, Allergan, Almirall, Amgen, Apogee Therapeutics, Arcutis, Aristea, ASLAN, Bristol Myers Squibb, Celldex Therapeutics, Clexio Biosciences, Dermavant, DermBiont, Dermira, DiCE Therapeutics, Dr. Reddy's Laboratories, Eli Lilly, Glenmark, Incyte, Janssen, Leo, MedImmune, Menlo Therapeutics, Moberg, Palvella, Pfizer, Prollenium, RAPT, RXI Pharmaceutical, Sanofi, Takeda, TARO, Valeant (not Otho Dermatologics), Viamet Pharmaceuticals, Vyne Therapeutics, UBC, and Xencor. Dr Draelos reported grants from Arcutis during the study. Dr Ferris reported grants from Arcutis, Galderma, Regeneron, Amgen, Sanofi, AbbVie; and personal fees from Arcutis, Regeneron, Sanofi, Amgen outside the submitted work. Dr Gooderham reported non-financial support from Arcutis during the study; and personal fees from Aceylrin, AbbVie, Arcutis, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, Galderma, Incyte, Janssen, LEO Pharma, Meiji, Dermavant, Moonlake, Nektar, Nimbus, Novartis, Pfizer, Regeneron, Sanofi, Sun Pharma, Tarsus, Takeda, UCB, Union, Ventyx, Apogee, AnaptysBio, Aristea, and L'Oreal outside the submitted work. Dr Gonzalez reported personal fees from Regeneron Pharmaceuticals, Sanofi Genzyme, Arcutis Biotherapeutics, Dermavant Sciences, AbbVie, Verrica Pharmaceuticals, Eli Lilly, Anterogen, Nielsen Biosciences, and Amgen outside the submitted work. Dr Hebert reported grants to UTHealth McGovern Medical School during the study; and personal fees from Pfizer, Arcutis, Dermavant, Leo, Amgen, and honoraria from Pfizer, Arcutis, Dermavant, Incyte, and Leo outside the submitted work. Dr Kircik reported grants from Arcutis, Dermavant, Leo, Sanofi, Galderma, L'Oreal, Incyte, Dermira, Anacor, Pfizer, Eli Lilly, Aslan, and Biosion during the study. Dr Moore reported grants from Arcutis outside the submitted work. Dr Papp reported personal fees from AbbVie, Acelyrin, Akros, Alumis, Arcutis, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Can-Fite Biopharma, Celltrion, Concert Pharmaceuticals, Dermavant, Dermira, DiCE Pharmaceuticals, Eli Lilly, Evelo, Forbion, Galderma, Horizon, Incyte, Janssen, Kymab, Kyowa Hakko Kirin, Leo Pharma, Meiji Seika, Mitsubishi, Nimbus, Novartis, Pfizer, Reistone Biopharma, Sanofi, Sandoz, Sun Pharma, Takeda, UCB Pharma, and Zai Lab outside the submitted work; and roles as Deputy Editor at Journal of Cutaneous Medicine and Surgery and Contributing Editor at The Chronicle of Skin & Allergy. Dr Prajapati reported personal fees from AbbVie, Amgen, Apogee Therapeutics, Arcutis, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Eli Lilly, Galderma, Incyte, JAMP Pharma, J&J Innovative Medicines, Janssen, LEO Pharma, Novartis, Organon, Pfizer, Sanofi Genzyme, Sun Pharma, UCB, Reistone, Nektar Therapeutics, AnaptysBio, Arena, Asana, Dermavant, Dermira, Meiji Pharma, Nimbus Lakshmi, RAPT Therapeutics, Regeneron, and Takeda outside the submitted work. Dr Hanna reported employment with Arcutis Biotherapeutics. Dr Snyder reported employment and stock ownership at Arcutis Biotherapeutics. Mr Krupa reported personal fees from Arcutis Biotherapeutics outside the submitted work and employment with Arcutis Biotherapeutics. Dr Burnett reported personal fees from Arcutis Biotherapeutics during the study; personal fees and a patent for Arcutis Biotherapeutics outside the submitted work. Mr Higham reported employment and stock ownership at Arcutis Biotherapeutics. Dr Chu reported salary, stock/options, and a patent from Arcutis Biotherapeutics during and outside the study. Dr Berk reported personal fees from Arcutis Biotherapeutics during and outside the study, with a patent for Arcutis Biotherapeutics. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. INTEGUMENT-1 and INTEGUMENT-2 Flow Diagrams
INTEGUMENT indicates Interventional Trial Evaluating Roflumilast Cream for the Treatment of Atopic Dermatitis. ITT, intention-to-treat; PCP, primary care physician.
Figure 2.
Figure 2.. Percentage of Patients Achieving vIGA-AD Success and at Least 75% Improvement in EASI Score
Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) was evaluated on a 5-point scale: 0 (clear), 1 (almost clear), 2 (mild), 3 (moderate), and 4 (severe). vIGA-AD success was defined as a score of 0 or 1 plus at least a 2-grade improvement from baseline. EASI-75 indicates at least a 75% reduction in Eczema Area and Severity Index score from baseline. aP values are nominal.
Figure 3.
Figure 3.. Percentage of Patients With Worst Itch Numeric Rating Scale (WI-NRS) Success and Daily Changes
WI-NRS was evaluated on an 11-point scale ranging from 0 (no itch) to 10 (worst itch imaginable). WI-NRS success was defined as at least a 4-point reduction in WI-NRS from baseline in patients 12 years or older. CFB indicates change from baseline; LS, least squares. aEvaluated in patients 12 years or older with baseline WI-NRS score of at least 4. bEvaluated in all patients, not just those with baseline WI-NRS scores of at least 4. cNominal P = .004 (INTEGUMENT-1) and P < .001 (INTEGUMENT-2) at 24 hours following the first application, and P < .05 at all subsequent time points, for difference vs vehicle.
Figure 4.
Figure 4.. Clinical Images of Atopic Dermatitis in Patients Treated With Roflumilast Cream, 0.15%, Over 4 Weeks
vIGA-AD indicates Validated Investigator Global Assessment for Atopic Dermatitis; WI-NRS, Worst Itch Numeric Rating Scale. vIGA-AD and WI-NRS are global measures.
See this image and copyright information in PMC

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