These articles have been accepted for publication in the British Journal of Dermatology and are currently being edited and typeset. Readers should note that articles published below have been fully refereed, but have not been through the copy-editing and proof correction process. Wiley-Blackwell and the British Association of Dermatologists cannot be held responsible for errors or consequences arising from the use of information contained in these articles; nor do the views and opinions expressed necessarily reflect those of Wiley-Blackwell or the British Association of Dermatologists This article is protected by copyright. All rights reserved. Accepted Date : 08-Jun-2014 Article type : Therapeutics A treatment for severe nodular acne: A randomised investigator-blinded, controlled, non-inferiority trial comparing fixed-dose adapalene/BPO plus doxycycline vs oral isotretinoin Authors: J. Tan,1 S. Humphrey,2 R. Vender,3 B. Barankin,4 M. Gooderham,5 N. Kerrouche,6 F. Audibert,6 C. Lynde,7 on behalf of the POWER study group Author affiliations: 1University of Western Ontario and Windsor Clinical Research Inc., Ontario, Canada; 2Department of Dermatology & Skin Science, The University of British Columbia, Vancouver, Canada; 3Dermatrials Research Inc., Hamilton, Ontario, Canada; 4 Toronto Research Centre, Toronto, Ontario, Canada; 5SKiN Centre for Dermatology, Peterborough, Ontario, Canada; 6Galderma R&D SNC, Sophia Antipolis, France; 7Lynderm Clinical Research, Markham, Ontario, Canada Corresponding author: Jerry Tan, MD, FRCPC University of Western Ontario, Windsor Clinical Research Inc. 2224 Walker Rd. Suite 300 Windsor, Canada Tel: (519) 971-9519 Fax: (519) 971-7594 E-mail: [email protected] Funding sources: This study was funded by Galderma. ClinicalTrials.gov Identifier: NCT01474590 Conflicts of interest statement: Drs. Tan, Humphrey, Vender, Barankin, Gooderham, and Lynde received investigator fees for the study. Mr. Kerrouche and Mr. Audibert are employees of Galderma. Dr. Jerry Tan has served as an advisor (advisory board), consultant, investigator and speaker for Galderma. Dr. Shannon Humphrey has served as an advisor (advisory board), speaker and investigator for Galderma. Dr. Ronald Vender has served as an advisor (advisory board), investigator and speaker for Galderma. Dr. Benjamin Barankin is a speaker for Galderma. Dr. Melinda Gooderham is an investigator and speaker for Galderma. Dr. Charles Lynde has served as an advisor (advisory board), consultant and investigator for Galderma. Running head: Doxycycline + adapalene/benzoyl peroxide: Alternative to isotretinoin

This article is protected by copyright. All rights reserved.

What’s Known/What Does this Study Add: What's already known about this topic? • Oral isotretinoin (ISO) is the gold standard for treatment of severe nodular acne.

What does this study add? • Oral doxycycline plus adapalene/benzoyl peroxide (D+A/BPO) gel was efficacious and safe in treatment of severe nodular acne over 20 weeks • D+A/BPO is an option for treatment of severe nodular acne and may offer an alternative for patients unable, unwilling or intolerant of oral ISO.

Abstract Background: Oral isotretinoin (ISO) is the gold standard for severe nodular acne. However, as some patients are unwilling, unable, or intolerant to ISO, other options are needed. Objective: To compare efficacy and safety of oral ISO versus doxycycline 200 mg plus adapalene 0.1%/benzoyl peroxide 2.5% gel (D+A/BPO) in severe nodular acne over 20 weeks. Methods: Multicentre, randomised, controlled, non-inferiority investigator-blinded study involving 266 subjects. Results: D+A/BPO showed a significantly earlier onset of action in reducing nodules, papules/pustules, and total lesions at week 2. ISO was superior in reducing nodules (95.6% vs. 88.7%), papules/pustules (95.2% vs. 79.6%) and total lesions (92.9% vs. 78.2%; all p