Randomized, Placebo-controlled, Phase 3 Study of Itraconazole for the Treatment of Onychomycosis

July 2013 | Volume 12 | Issue 7 | Original Article | 758 | Copyright © July 2013

Stuart Maddin MD,a John Quiring PhD,b and Lynne Bulgerc

aDepartment of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada
bQST Consultations, LTD, Allendale, MI
cStiefel, a GSK company, Ontario, Canada

BACKGROUND: Itraconazole, approved for treatment of toenail fungal infection onychomycosis, provides antifungal activity at a dosage requiring once-daily (QD) administration of 2 100-mg capsules for 12 weeks. Utilizing the Meltrex® technology delivery system, a novel 200-mg formulation of itraconazole was developed delivering the same dosage as 2 capsules in a single tablet.
METHODS: This phase 3, randomized, placebo-controlled trial investigated the noninferiority of 1 itraconazole 200-mg tablet to 2 itraconazole 100-mg capsules dosed QD for 12 weeks, with a 40-week follow-up period. Clinical Cure (Investigator’s Global Assessment plus mycological examination) was the primary outcome measure and Clinical Improvement was a secondary endpoint. Safety and efficacy of itraconazole 200-mg tablets were also compared with placebo.
RESULTS: Significantly more patients in the intent-to-treat per-protocol populations on itraconazole (200-mg tablet or 2 100-mg capsules) achieved Complete Cure and Clinical Improvement compared with placebo. For both endpoints, itraconazole 200-mg tablet QD was noninferior to itraconazole 100-mg capsules and superior to placebo. All treatment groups demonstrated a similar safety profile with no new safety signals identified.
LIMITATIONS: Absolute patient blinding was not possible; the number of tablets versus capsules differed, and the appearance of the active drugs could not be masked. However, efficacy was based on objective assessments from blinded investigators.
CONCLUSIONS: Once-daily itraconazole 200-mg was well-tolerated, and may be an effective alternative to 2 itraconazole 100-mg capsules for the treatment of toenail onychomycosis. The convenience of a simpler dosing regimen may improve patient compliance (ClinicalTrials.gov number, NCT00356915).

J Drugs Dermatol. 2013;12(7):758-763.


Onychomycosis is a common fungal infection of the nail beds or nail plates. As the most common nail disorder in adults, onychomycosis affects >10% of Western populations. Its prevalence increases with age, with some reports suggesting that as many as 50% of individuals over 70 years of age have onychomycosis.1 In addition to age, other risk factors for onychomycosis include a family history of onychomycosis, sports participation, immune suppression, diabetes, peripheral vascular disease, and mycoses, such as tinea capitis or tinea pedis.1 In >90% of cases affecting toenails and 350% of those affecting fingernails, onychomycosis is caused primarily by the dermatophytes Trichophyton rubrum and Trichophyton mentagrophytes. Less commonly, nondermatophyte molds and yeasts (eg, Candida albicans) have been implicated in onychomycosis onset, and occasionally a mixture of dermatophytes and nondermatophytes may be responsible for onychomycosis development.2
Treating onychomycosis may involve topical and/or systemic antifungal agents. Overall, systemic agents have consistently demonstrated higher efficacy rates compared with those observed with topical antifungals.3 For this reason, topical agents generally are reserved for milder onychomycosis infections, and systemic agents for moderate-to-severe cases.4 Currently, the most commonly used, approved treatments for onychomycosis include oral itraconazole and terbinafine hydrochloride.4 Itraconazole has been marketed since the mid-1990s in a dosage form requiring once-daily (QD) administration of 2 100-mg capsules for 12 weeks for the treatment of toenail onychomycosis.5
A novel formulation of itraconazole (200-mg tablet with the Meltrex® technology delivery system) was developed to deliver the same dosage as 2 capsules in a single tablet. This tablet, currently the only oral antifungal developed using this particular technology, delivers itraconazole in a “solid solution” format that may improve bioavailability, although this has not been validated.6 The purpose of this phase 3, placebo-controlled, randomized clinical trial was to evaluate the noninferiority of 1 itraconazole 200-mg tablet dosed QD to 2 itraconazole 100-mg capsules dosed QD, and to examine the safety and efficacy of the itraconazole 200-mg tablet compared with a placebo tablet in patients with onychomycosis of the great toenail.


Study Design

This phase 3, randomized, multicenter, parallel group, placebo-controlled, evaluator-blinded study comprised 2 distinct periods: a 12-week dosing period and a 40-week follow-up period. The dosing period lasted 12 weeks, which is the approved treatment