Efficacy and Safety of Tralokinumab in Adolescents With Moderate to Severe Atopic Dermatitis: The Phase 3 ECZTRA 6 Randomized Clinical Trial

Abstract

Importance: Safe and effective long-term treatments for adolescents with moderate to severe atopic dermatitis (AD) are limited.

Objective: To evaluate the efficacy and safety of interleukin-13-targeted treatment with tralokinumab monotherapy in adolescents with AD.

Design, setting, and participants: The 52-week, randomized, double-blinded, placebo-controlled, phase 3 ECZTRA 6 trial was conducted from July 17, 2018, through March 16, 2021, at 72 centers across 10 countries in North America, Europe, Asia, and Australia. Enrolled patients were 12 to 17 years old with moderate to severe AD (Investigator's Global Assessment [IGA] score ≥3; Eczema Area and Severity Index [EASI] ≥16).

Interventions: Patients were randomized (1:1:1) to tralokinumab (150 or 300 mg) or placebo every 2 weeks for 16 weeks. Patients with an IGA score of 0 (clear) or 1 (almost clear) and/or 75% or higher improvement in EASI (EASI 75) at week 16 without rescue medication received maintenance treatment; other patients switched to open-label tralokinumab, 300 mg, every 2 weeks.

Main outcomes and measures: Primary end points at week 16 were an IGA score of 0 or 1 and/or achieving EASI 75. Key secondary end points were a reduction of Adolescent Worst Pruritus Numeric Rating Scale of 4 or more, change in SCORing AD, and change in Children's Dermatology Life Quality Index from baseline to week 16. Safety end points were the number of adverse events and serious adverse events.

Results: Of 301 patients randomized, 289 comprised the full analysis set (median [IQR] age, 15.0 [13.0-16.0] years; 149 [51.6%] male). More patients receiving tralokinumab, 150 mg, (n = 98), and tralokinumab, 300 mg (n = 97), achieved an IGA score of 0 or 1 without rescue medication at week 16 (21 [21.4%] and 17 [17.5%], respectively) vs placebo (n = 94; 4 [4.3%]) (adjusted difference, 17.5% [95% CI, 8.4%-24.6%]; P < .001 and 13.8% [95% CI, 5.3%-22.3%]; P = .002, respectively). More patients receiving tralokinumab, 150 mg (28 [28.6%]), and tralokinumab, 300 mg, (27 [27.8%]) vs placebo (6 [6.4%]) achieved EASI 75 without rescue at week 16 (adjusted difference, 22.5% [95% CI, 12.4%-32.6%]; P < .001 and 22.0% [95% CI, 12.0%-32.0%]; P < .001, respectively). Proportions of patients with Adolescent Worst Pruritus Numeric Rating Scale reduction of 4 or more from baseline were greater with tralokinumab, 150 mg (23.2%), and tralokinumab, 300 (25.0%), vs placebo (3.3%), and adjusted mean changes were greater in SCORing AD with tralokinumab, 150 mg (-27.5%), and tralokinumab, 300 mg (-29.1%), vs placebo (-9.5%) and in Children's Dermatology Life Quality Index with tralokinumab, 150 mg (-6.1%), and tralokinumab, 300 mg (-6.7%), vs placebo (-4.1%) at week 16. At week 52, tralokinumab efficacy was maintained without rescue in more than 50% of patients meeting primary end point(s) at week 16. In the open-label phase, IGA score of 0 or 1 and EASI 75 were achieved in 33.3% and 57.8%, respectively, at week 52. Tralokinumab was well tolerated, without frequency of conjunctivitis increasing through week 52.

Conclusions and relevance: In this randomized clinical trial, tralokinumab was efficacious and well tolerated, supporting its value for treating adolescents with moderate to severe AD.

Trial registration: ClinicalTrials.gov Identifier: NCT03526861.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Paller reported institutional grants from LEO Pharma during the conduct of the study; grants from AbbVie, AnaptysBio, Eli Lilly, Incyte, Janssen, Krystal Biotech, LEO Pharma, Regeneron, and UCB; and personal fees from AbbVie, Acrotech, Almirall, Amgen, Amryt, Arcutis, Arena, Azitra, BioCryst, BiomX, Boehringer Ingelheim, Botanix, BridgeBio, Bristol Myers Squibb, Castle Biosciences, Catawba, Eli Lilly, Exicure, Gilead, Incyte, Janssen, Kamari, LEO Pharma, Novartis, Pfizer, Pierre Fabre, RAPT, Regeneron, Sanofi/Genzyme, Seanergy, UCB, Union, Abeona, Bausch + Lomb, Galderma, InMed, and Novan. Prof Flohr reported institutional funding from Sanofi/Genzyme and Pfizer; serving as chief investigator of the UK National Institute for Health Research-funded TREAT (ISRCTN15837754) and SOFTER (NCT03270566) trials, as well as the UK-Irish Atopic Eczema Systemic Therapy Register (ISRCTN11210918); serving as a principal investigator in the European Union Horizon 2020-funded BIOMAP Consortium; and leading the EU Trans-Foods consortium. Prof Cork reported nonfinancial support from Ashfield MedComms, funded by LEO Pharma; research funding from Bayer; institutional research grants from Hyphens Pharma, Johnson & Johnson, Kymab (now Sanofi), Pfizer, Sanofi/Genzyme, L’Oréal, LEO Pharma, Perrigo (ACO Nordic), and Regeneron; personal fees from Astellas, Boots, Eli Lilly, Hyphens Pharma, Johnson & Johnson, Procter & Gamble, Regeneron, L’Oréal, LEO Pharma, Novartis, Perrigo (ACO Nordic), Pfizer, Regeneron, Sanofi/Genzyme, and Stiefel; serving as a clinical trial investigator for Astellas, Galapagos, Johnson & Johnson, LEO Pharma, La Roche-Posay, MSD, Novartis, Perrigo, Regeneron, Sanofi/Genzyme, and Stiefel; serving as an advisory board member, consultant, and/or invited lecturer for Pfizer, Amgen, Astellas, Bayer, Johnson & Johnson, LEO Pharma, L’Oréal, MSD, Novartis, Regeneron, Sanofi/Genzyme, Stiefel, and Unilever; and serving in uncompensated roles as a member of the board of the European Academy of Dermatology and Venereology, a voluntary medical adviser to the National Eczema Society, and an editorial board member for JEADV Clinical Practice. Prof Bewley reported grants from Janssen; personal fees from AbbVie, Almirall, Eli Lilly, Galderma, Janssen, LEO Pharma, Novartis, Sanofi, UCB, and Pfizer; serving as president of the European Society for Dermatology and Psychiatry and adviser in the UK to ISG; and work with Changing Faces, the Psoriasis Association, and NES. Dr Blauvelt reported receiving honoraria as a speaker for AbbVie, Bristol Myers Squibb, Eli Lilly, Pfizer, Regeneron, and Sanofi; receiving honoraria as a scientific adviser for AbbVie, Abcentra, Aclaris, Affibody, Aligos, Almirall, Alumis, Amgen, AnaptysBio, Arcutis, Arena, Aslan, Athenex, Bluefin Biomedicine, Boehringer Ingelheim, Bristol Myers Squibb, Cara Therapeutics, Dermavant, EcoR1, Eli Lilly, Escient, Evelo, Evommune, Forte, Galderma, HighlightII Pharma, Incyte, Innovent Bio, Janssen, Landos, LEO Pharma, Merck, Novartis, Pfizer, Rani, Rapt, Regeneron, Sanofi/Genzyme, Spherix Global Insights, Sun Pharma, TLL Pharmaceutical, TrialSpark, UCB, Union, Vibliome, and Xencor; and acting as a clinical study investigator receiving institutional clinical study funds for AbbVie, Acelyrin, Almirall, Alumis, Amgen, Arcutis, Athenex, Boehringer Ingelheim, Bristol Myers Squibb, Concert, Dermavant, Eli Lilly, Evelo, Evommune, Galderma, Incyte, Janssen, LEO Pharma, Merck, Novartis, Pfizer, Regeneron, Sun Pharma, and UCB. Dr Hong reported grants from AbbVie, Amgen, Arcutis, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Dermavant, Eli Lilly, Galderma, Incyte, Janssen, LEO Pharma, Novartis, Pfizer, Regeneron, Sanofi, and UCB, as well as serving as a researcher, consultant, and/or adviser for AbbVie, Amgen, Arcutis, Bausch Health, Boehringer Ingelheim, Celgene, Dermavant, Dermira, DS Biopharma, Galderma, GSK, Incyte, Janssen, LEO Pharma, Lilly, MedImmune, Novartis, Pfizer, Regeneron, Roche, Sanofi/Genzyme, Sun Pharma, and UCB. Prof Imafuku reported personal fees from LEO Pharma during the conduct of the study and serving as a researcher, consultant, or speaker for AbbVie, Amgen, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eisai, GSK, Janssen, Kyowa Kirin, LEO Pharma, Lilly, Maruho, Novartis, Pfizer, Taiho Yakuhin Kogyo, Mitsubishi Tanabe, Tsumura, Torii, and UCB. Dr Schuttelaar reported support from LEO Pharma as an investigator during the conduct of the study; grants from Sanofi/Genzyme; and support as an adviser from Lilly, AbbVie, and Galderma. Dr Simpson reported grants and personal fees from LEO Pharma during the conduct of the study; personal fees from Advances in Cosmetic Medical Derm Hawaii, AbbVie, Amgen, AOBiome, Arcutis, Arena Pharmaceuticals, Aslan Pharma, Boehringer Ingelheim, Boston Consulting Group, Bristol Myers Squibb, Collective Acumen, CorEvitas, Dermira, Eli Lilly, Evelo Biosciences, Evidera, Excerpta Medica, FIDE, Forte Bio RX, Galderma, Gesellschaft Z, GSK, Incyte, Janssen, Johnson & Johnson, Kyowa Kirin, LEO Pharma, Medscape, Merck, Maui Derm, MLG Operating, MJH Healthcare Holding, Pfizer, Physicians World, PRImE, Regeneron, Revolutionizing Atopic Dermatitis, Roivant, Sanofi/Genzyme, Trevi Therapeutics, Valeant, Vindico Medical Education, and WebMD; grants from AbbVie, Amgen, Arcutis, Aslan, Castle Biosciences, Celegene, CorEvitas, Dermavant, Dermira, Eli Lilly, Galderma, Incyte, Kymab, Kyowa Hakko Kirin, LEO Pharma, Merck, Novartis, Pfizer, Regeneron, Sanofi, Target RWE, and National Jewish Health; and serving as a consultant and investigator for Regeneron, Sanofi, Dermira, Menlo Pharmaceuticals, Lilly, AbbVie, Genentech, MedImmune, GSK, LEO Pharma, Celgene, and Pfizer. Dr Soong reported grants from LEO Pharma during the conduct of the study; personal fees from LEO Pharma, Regeneron, Sanofi, Genentech, Lilly, AbbVie, Pfizer, Amgen, and AstraZeneca; grants from Regeneron, Genentech, Lilly, Glenmark, Allakos, AbbVie, Pfizer, Incyte, Aslan, and Amgen; serving on the advisory boards of and receiving research grants from Incyte, Lilly, Genentech, Novartis, and UCB; serving on the advisory boards, receiving research grants, and serving as a speaker for AbbVie, LEO Pharma, Amgen, AstraZeneca, Pfizer, Regeneron, and Sanofi; and receiving research grants from Allakos, Dermavant, and Galderma. Dr Arlert reported nonfinancial support from Ashfield MedComms, funded by LEO Pharma, and is an employee of LEO Pharma, the trial sponsor. Ms Lophaven reported nonfinancial support from Ashfield MedComms, funded by LEO Pharma, and is an employee of LEO Pharma, the trial sponsor. Dr Kurbasic reported nonfinancial support from Ashfield MedComms, funded by LEO Pharma, and is an employee of LEO Pharma, the trial sponsor. Dr Soldbro reported nonfinancial support from Ashfield MedComms, funded by LEO Pharma, and is an employee of LEO Pharma, the trial sponsor. Ms Vest reported nonfinancial support from Ashfield MedComms, funded by LEO Pharma; is an employee of LEO Pharma, the trial sponsor; and holds shares in LEO Pharma. Prof Wollenberg reported nonfinancial support from Ashfield MedComms, funded by LEO Pharma; personal fees from AbbVie, Aileens, Almirall, Amgen, Beiersdorf, Bristol Myers Squibb, Galderma, Glenmark, GSK, Janssen, LEO Pharma, Eli Lilly, L’Oréal, MSD, Novartis, Pfizer, Regeneron, Sanofi, and UCB; grants from Pierre Fabre; and other support from Bioderma, Chugai, Galapagos, Hans Karrer, Maruho, MedImmune, Merck, and Santen.

Figures

Figure 1.. CONSORT Diagram

Q2W indicates every 2 weeks. aWithdrew from the trial prior to first dosing.

Figure 2.. Tralokinumab Efficacy vs Placebo Across Primary and Key Secondary End Points up to Week 16 (Initial Treatment Period), Full Analysis Set

Primary end points were Investigator’s Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) (A) and 75% or more improvement in the Eczema Area and Severity Index (EASI 75) (B) by visit up to week 16 (initial treatment period) in the full analysis set. Secondary end points included the proportion of patients with a reduction in weekly average Adolescent Worst Pruritus Numeric Rating Scale (NRS) of 4 or more from baseline by visit (C), change from baseline in SCORing Atopic Dermatitis (SCORAD) by visit (D), change from baseline in Children’s Dermatology Life Quality Index (CDLQI) by visit in the initial treatment period up to week 16 (E), and proportion of patients with a CDLQI reduction of 6 or more from baseline by visit (F). For binary end points, patients who received rescue medication after week 2 were considered nonresponders, and those with missing values at week 16 were imputed as nonresponders. For continuous end points, data collected after permanent discontinuation of tralokinumab or initiation of rescue medication after week 2 were not included. Q2W indicates every 2 weeks. aP < .01 vs placebo. bP < .001 vs placebo. cP < .05 vs placebo.

Figure 3.. Tralokinumab Efficacy During Weeks 16-52 of the Open-label Phase

The response rates for Investigator’s Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) (A) and 75% or more improvement in the Eczema Area and Severity Index (EASI 75) (B) by visit up to week 52 in the open-label treatment period (open-label analysis set) included all patients from the initial treatment period who did not meet the primary end point without rescue medication at week 16. All patients received open-label tralokinumab, 300 mg, every 2 weeks (Q2W) plus optional topical corticosteroids. Patients could use weak to moderate potency topical corticosteroids and/or topical calcineurin inhibitors as needed on lesional skin at the investigator’s discretion. Patients who received high-potency topical calcineurin inhibitor or systemic atopic dermatitis treatment during open-label treatment were considered nonresponders, and patients with missing data were imputed as nonresponders.