Clinical Trial Designs for Topical Antifungal Treatments of Onychomycosis and Implications on Clinical Practice

Onychomycosis is a fungal nail infection primarily caused by dermatophytes.¹ If left untreated, the infection can cause nail destruction and deformities,¹ resulting in pain and discomfort,² impaired foot mobility,³ and an overall reduced quality of life.¹ Onychomycosis is a chronic condition that requires long treatment periods due to the slow growth rates of toenails.¹ To successfully cure the condition, fungal eradication must be achieved.

Prior to the US Food and Drug Administration (FDA) approval of tavaborole and efinaconazole, ciclopirox was the only approved topical treatment for onychomycosis.⁴ The recent approval of tavaborole and efinaconazole has increased treatment options available to patients and has started to pave the way for future topical treatments. This article discusses the 3 approved topical treatments for onychomycosis and focuses on the design of the phase 3 clinical trials that led to their approval.

Topical Agents Used to Treat Onychomycosis

Tavaborole, efinaconazole, and ciclopirox have undergone extensive clinical investigation to receive FDA approval. Results from pivotal phase 3 studies establishing the efficacy and safety of each agent formed the basis for regulatory submission. Although it may seem intuitive to compare the relative performance of these agents based on their respective phase 3 clinical trial data, there are important differences in study methodology, conduct, and populations that prevent direct comparisons. The FDA provides limited guidance to the pharmaceutical industry on how to conduct clinical trials for potential onychomycosis treatments. Comparative efficacy and safety claims are limited based on cross-study comparisons. The details of the phase 3 trial designs are summarized in the Table.

Tavaborole
Tavaborole is a boron-based treatment with a novel mechanism of action.⁵ Tavaborole binds to the editing domain of leucyl–transfer ribonucleic acid synthetase via an integrated boron atom and inhibits fungal protein synthesis.⁶ Two identical randomized, double-blind, vehicle-controlled, parallel-group, phase 3 clinical trials evaluating tavaborole were performed.⁵ The first study (registered at www.clinicaltrials.gov with the identifier NCT01270971) included 594 participants from27 sites in the United States and Mexico and was conducted between December 2010 and November 2012. The second study (NCT01302119) included 604 participants from 32 sites in the United States and Canada and was conducted between February 2011 and January 2013.

Eligible participants 18 years and older had distal subungual onychomycosis (DSO) of the toenails affecting 20% to 60% of 1 or more target great toenails (TGTs), tested positive for fungus using potassium hydroxide (KOH) wet mounts and positive for Trichophyton rubrum and Trichophyton mentagrophytes on fungal culture diagnostic tests, had distal TGT thickness of 3 mm or less, and had 3 mm or more of clear nail between the proximal nail fold and the most proximal visible mycotic border.⁵ Those with active tinea pedis requiring treatment or with a history of chronic moccasin-type tinea pedis were excluded. Participants were randomized to receive either tavaborole or vehicle (2:1). Treatments were applied once daily to all infected toenails for a total of 48 weeks, and nail debridement (defined as partial or complete removal of the toenail) was not permitted. Notably, controlled trimming of the nail was allowed to 1 mm of the leading nail edge. Regular assessments of each toenail for disease involvement, onycholysis, and subungual hyperkeratosis were made at screening, baseline, week 2, week 6, and every 6 weeks thereafter until week 52. Subungual TGT samples were taken at screening and every 12 weeks during the study for examination at a mycology laboratory, which performed KOH and fungal culture tests. A follow-up assessment was made at week 52.⁵

The primary end point was complete cure of the TGT at week 52, with secondary end points of completely or almost clear TGT nail (≤10% dystrophic nail), completely or almost clear TGT nail (≤10% dystrophic nail) plus negative mycology, and negative mycology of TGT.⁵ Examples of TGTs in participants who achieved complete cure and almost clear nails with negative mycology before and after treatment with tavaborole are shown in Figure 1. An example of a patient considered to have treatment failure is shown in Figure 2. This patient showed marked improvement in nail appearance and had a negative culture result but had a positive KOH test, which demonstrates the stringency in which topical agents are judged in onychomycosis trials.⁵

Figure 1. Illustrative case of toenail onychomycosis before (A) and at week 52 (B) in tavaborole phase 3 clinical trials. Almost clear nail with negative mycology was achieved at week 52 after 48 weeks of treatment with tavaborole.

Figure 2. Clinical example of a treatment failure from the tavaborole phase 3 clinical trials. A patient before treatment (A) and at week 52 (B) who achieved an almost completely clear nail plus negative culture but positive potassium hydroxide preparation results after 48 weeks of treatment with tavaborole.

Efinaconazole
Efinaconazole is a topical triazole antifungal specifically indicated to treat onychomycosis. Two identical randomized, vehicle-controlled, double-blind, multicenter trials were performed to assess the safety and efficacy of efinaconazole solution 10%^.7 The first study (NCT01008033) involved 870 participants and was conducted at a total of 74 sites in Japan (33 sites), Canada (7 sites), and the United States (34 sites) between December 2009 and September 2011. The second study (NCT01007708) had 785 participants and was conducted at 44 sites in Canada (8 sites) and the United States (36 sites) between December 2009 and October 2011.

Participants aged 18 to 70 years with a clinical diagnosis of DSO affecting 1 or more TGT were eligible to participate.⁷ Other eligibility criteria included an uninfected toenail length 3 mm or more from the proximal nail fold, a maximum toenail thickness of 3 mm, positive KOH wet mounts, and positive dermatophyte or mixed dermatophyte/candida cultures. Dermatophytes included T rubrum and T mentagrophytes. Those with severe moccasin-type tinea pedis were excluded. Participants were randomized to receive efinaconazole or vehicle (3:1). Once-daily treatments were self-applied to nails for 48 weeks. Clinical assessments were made at baseline and every 12 weeks until week 48, with a follow-up assessment at week 52. No nail trimming protocol was provided.⁷

The primary end point of the efinaconazole phase 3 trials was complete cure at week 52, with secondary end points including mycologic cure, treatment success (≤5% mycotic nail), and complete or almost complete cure (negative culture and KOH, ≤5% mycotic nail). An example of a complete cure from baseline to week 52 is shown in Figure 3.⁷

Figure 3. Representative clinical example of an onychomycosis patient before (A) and after treatment with efinaconazole for 48 weeks (B) with a trimmed nail, achieving complete cure. Reprinted from the Journal of the American Academy of Dermatology, Copyright 2013, with permission from Elsevier.7

Ciclopirox
Ciclopirox was the first topical therapy to be approved for the treatment of onychomycosis. Ciclopirox is a broad-spectrum antifungal agent that inhibits metal-dependent enzymes, which are responsible for the degradation of toxic peroxides in fungal cells. The safety and efficacy of ciclopirox nail lacquer topical solution 8% also was investigated in 2 identical phase 3 clinical trials.⁸ The first study was conducted at 9 sites in the United States between June 1994 and June 1996 and included 223 participants. The second study was conducted at 9 sites in the United States between July 1994 and April 1996 and included 237 participants.

Eligible participants were required to have DSO in at least one TGT, positive KOH wet mount with positive dermatophyte culture, and 20% to 65% nail involvement.⁸ Those with tinea pedis were not excluded. Participants were randomized to receive once-daily treatment with ciclopirox or vehicle (1:1)(applied to all toenails and affected fingernails) for 48 weeks. The product was to be removed by the patient with alcohol on a weekly basis. Trimming was allowed as necessary, and mechanical debridement by the physician could be performed monthly. Assessments were made every 4 weeks, and mycologic examinations were performed every 12 weeks. Participants who were clinically cured were assessed further in a 12- to 24-week posttreatment follow-up period.⁸

The primary end point of complete cure and secondary end points of treatment success (negative culture and KOH, ≤10% mycotic nail), mycologic cure, and negative mycologic culture were assessed at week 48.⁸