Investigating the benefits and harms of reduced daily dose oral isotretinoin in the treatment of acne: A parallel group, assessor blind, non-inferiority, multicentre randomised controlled trial, with an internal pilot (Acne-ID)

Research question: Is low-dose daily isotretinoin non-inferior to standard-care dose daily isotretinoin for clearing acne vulgaris (acne), whilst also minimising harms and increasing wider health benefits? Background: Severe acne leads to a significant impact on wellbeing and physical symptoms including (pain and bleeding) and scarring. After topical treatments and oral antibiotics, evidence-based treatment options are limited and most patients with severe acne are treated with oral isotretinoin. Isotretinoin at the standard care dose is a highly effective treatment, but there are potential side effects which impact daily life, can occasionally be serious and may lead to lower treatment satisfaction. Currently, we have limited evidence on a low-dose isotretinoin strategy, which may be an effective, safer and more acceptable treatment. Aims and objectives: Primary: To investigate whether a low-dose isotretinoin strategy is non-inferior to standard-care dose for clearance of acne at the end of treatment. Secondary: (i)To investigate the benefits and harms of a low-dose isotretinoin strategy compared to standard-care dose in relation to side-effects, satisfaction with treatment, quality of life, and acne recurrence (ii)To establish the health economic implications of the two isotretinoin dosing strategies (technical efficiency); (iii)To develop a clinical support tool to aid shared decision making when initiating isotretinoin treatment. Design: A parallel group, assessor blind, non-inferiority, multicentre randomised controlled trial, with an internal pilot and nested qualitative and health economic evaluation studies. Participants and setting: People with severe acne aged 12-30 years who meet MHRA guidance criteria for isotretinoin and attend a UK dermatology department. Intervention: Low-dose strategy 0.2-0.3mg/kg/day. At 6 months, if there has been insufficient improvement, the dose can be increased to <0.5mg/kg/day. Comparator: Standard-care dose strategy =0.5mg/kg/day and dose titration up to 1mg/kg/day over 1-2 months, unless clinically contraindicated. Aim for a minimum of 0.7mg/kg/day. Primary outcome: Proportion of participants achieving clearance of acne, defined by “clear or almost clear” at the end of treatment. Assessed using a blinded Investigator Global Assessment (IGA). Secondary outcomes: (i) Investigator reported acne severity throughout the treatment period; (ii) Patient reported acne severity; (iii) Treatment related side effects and tolerability; (iv) Acne health related quality of life; (v) Patient satisfaction with treatment; (vi) Mood and suicidal ideation; (vii) Relapse in acne within 12 months of stopping oral isotretinoin; (vi) Health care resource use. These will investigate the potential advantages of low-dose isotretinoin Sample size and analysis: 800 participants (400 in each arm) recruiting from 20 dermatology departments. 90% power to conclude non-inferiority based on primary outcome. Timeline: Total duration 60 months. Month 1-9 set-up, month 10-27 recruitment, month 40 finish active treatment phase, month 52 finish follow-up phase, month 53-54 database lock, 55-60 analysis and reporting. Impact and dissemination: this trial will directly inform clinical practice through development of a decision support tool for use in dermatology clinics, dissemination via clinical networks and uptake into national guidelines.