Results of a Phase III, Double-Blind, Randomized, Parallel-Group, Non-Inferiority Study Evaluating the Safety and Efficacy of Isotretinoin-Lidose in Patients With Severe Recalcitrant Nodular Acne
June 2014 | Volume 13 | Issue 6 | Original Article | 665 | Copyright © June 2014
Guy F. Webster MD PhD,a James J. Leyden MD,b and Jason A. Gross PharmDc
aDepartment of Dermatology, Jefferson Medical College, Philadelphia, PA
bDepartment of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, PA
cCipher Pharmaceutical Inc., Mississauga, Ontario, Canada
Abstract
BACKGROUND: Isotretinoin-Lidose, the first new formulation of isotretinoin in 30 years, differs from previously approved isotretinoin formulations in that it is less dependent on the presence of fat in the gut for absorption.
OBJECTIVE: Evaluate the safety profiles of isotretinoin-Lidose and food-dependent generic isotretinoin in the largest clinical study with isotretinoin—925 randomized patients from 49 study sites. Determine if the efficacy of this new formulation is noninferior to an existing isotretinoin.
METHODS: Multicenter, double-blind, randomized, parallel-group, noninferiority trial. Study medication was taken with meals twice daily for 20 weeks. Patients were followed for 4 weeks after the last dose. Safety evaluations included recordings of adverse events, assessments for depression, anxiety, emergent psychotic symptoms, and suicidal ideation/behavior, as well as DEXA and X-ray evaluations and changes in bone age. Two co-primary efficacy outcomes were measured to assess noninferiority: a) change in total nodular facial and truncal lesion count at from baseline to week 20 and b) percentage of patients who experienced at least 90% reduction in nodular facial and truncal lesion count from baseline to week 20.
LIMITATIONS: Although isotretinoin-Lidose can be taken without meals, it was given with food because the absorption of both formulations in the study had to be similar to detect noninferiority.
RESULTS: The safety profile of the 2 formulations was comparable. Criteria for noninferiority for both co-primary efficacy outcomes were met based on predetermined margins.
CONCLUSION: Safety and efficacy of isotretinoin-Lidose is similar and noninferior to food-dependent generic isotretinoin, respectively.
J Drugs Dermatol. 2014;13(6):665-670.
INTRODUCTION
Isotretinoin is indicated for treating severe recalcitrant nodular acne; approved dosage of 1 mg/kg/d is typically prescribed for 20 weeks to achieve a cumulative dose of 120 mg/kg to 150 mg/kg. Cumulative doses falling short of this range have been associated with higher relapse rate and the need for additional treatment.1 One factor that could possibly influence the outcome of isotretinoin therapy is failure to take it with food, particularly fat. Isotretinoin is poorly solubilized in the gastrointestinal (GI) tract in the absence of food. Recently, the Food and Drug Administration (FDA and Health Canada) approved a new formulation of isotretinoin that uses Lidose technology to improve bioavailability of poorly soluble products.
Isotretinoin-Lidose is designed to increase the absorption of isotretinoin in the absence of meals, which was demonstrated in previous pharmacokinetic studies (Unpublished data, Cipher Pharmaceuticals Inc.). A drug with less dependence on the presence of dietary fat in the gut may have a different safety profile. To determine if the safety of isotretinoin-Lidose is comparable and its efficacy is noninferior to that of food-dependent generic isotretinoin formulations, the present trial compared these formulations when both were administered twice daily with meals, as recommended for the comparator formulation of isotretinoin. This study, one of the largest to assess any formulation of isotretinoin, is highly relevant in today’s treatment of severe acne, as it closely monitored psychiatric- and bone-related adverse events in addition to evaluating isotretinoin efficacy in nearly 1000 patients.
Methodology
This Phase III trial was a multicenter (49 sites), double-blind, randomized, parallel-group, noninferiority study that compared the safety and efficacy of isotretinoin-Lidose with a food-dependent generic isotretinoin product in patients with severe recalcitrant nodular acne. The study protocol was reviewed and approved by the Institutional Review Boards/Independent
