A Phase II, Randomized, Double-blind, Placebo-controlled, Dose-ranging Study to Evaluate the Efficacy and Safety of VT-1161 Oral Tablets in the Treatment of Patients With Distal and Lateral Subungual Onychomycosis of the Toenail

B. Elewski; S. Brand; T. Degenhardt; S. Curelop; R. Pollak; R. Schotzinger; A. Tavakkol

Disclosures

The British Journal of Dermatology. 2021;184(2):270-280. 

In This Article

Patients and Methods

Trial Design

This was a multicentre, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study (ClinicalTrials.gov identifier NCT02267356). Patients were randomized to one of four dosing regimens of VT-1161 or matching placebo, as indicated in Figure 1. The study consisted of three phases: (i) a loading phase, where patients began the study with a daily dosing regimen for 14 days, (ii) a treatment phase, with a once-weekly dose (same strength as in the loading phase) for either 10 or 22 weeks, and (iii) a follow-up phase lasting through 60 weeks.

Figure 1.

Trial design schematic.

Patients were assessed at baseline for the extent of clear nails, and subsequently for both efficacy and safety at weeks 2, 4, 8, 12, 18, 24, 36, 48 and 60 (end-of-study visit). Telephone contacts were performed to assess for adverse events (AEs) at weeks 30, 42 and 54.

Participants

The study protocol was approved by an institutional review board and was executed using good clinical practices as per the relevant FDA and International Conference on Harmonisation guidelines. Informed consent was obtained from all patients prior to the commencement of any study procedures. The study was conducted between February 2015 and October 2016, and patients were recruited from 34 dermatology, podiatry and internal medicine clinical sites in the USA.

Eligible men and women ≥ 18 and ≤ 70 years of age were enrolled who had a clinical diagnosis of moderate-to-severe distal and lateral subungual onychomycosis of at least one great toenail, affecting ≥ 25% to ≤ 75% of the target toenail (TGT) and confirmed by positive baseline KOH microscopy and culture for dermatophytes. The TGT was required to have been ≤ 3 mm thick at the distal end with ≥ 2 mm of clear nail measured from the proximal nailfold.

Exclusion criteria included presence of subungual haematoma or melanonychia, nail streaks, severe onychorrhexis or significant dystrophy or anatomical abnormalities of the TGT, involvement of the nail matrix, exclusively lateral-edge involvement of the great toenail(s), and presence of other diseases of the foot that would interfere with clinical evaluation of onychomycosis. Patients were also excluded if onychomycosis was caused by Candida species, if they had used any systemic antifungal therapy within 3 months of screening, or if they had used a topically applied antifungal on their toenail or feet within 1 month of screening.

Interventions

Patients were randomized (1 : 1 : 1 : 1 : 1) to one of the four dosing regimens of VT-1161 or matching placebo for a 2-week once-daily loading dose, followed by a once-weekly dose for either 10 or 22 weeks, then a nontreatment period of 36 weeks, for a total participation period up to 60 weeks.

Efficacy Evaluations

The large toenail most affected was selected as the TGT for clinical assessment at baseline and evaluation throughout the study. Signs and symptoms of onychomycosis were evaluated at each clinic visit for onycholysis, subungual hyperkeratosis and percentage of toenail involvement. Digital photographs of the nail (to document clear nail growth) were obtained at all visits and were analysed by Canfield Scientific, Inc., Parsippany, NJ, USA. All screening photographs were reviewed by an independent expert reviewer, designated by the sponsor, to ensure the consistency of key inclusion and exclusion criteria across the study sites. A sample of subungual debris was sent to a central laboratory (Center for Medical Mycology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA) for mycological evaluation by performing a KOH wet mount test and culture.

Safety and Tolerability Evaluations

Physical examinations, vital signs, electrocardiograms, clinical laboratory tests and AEs were monitored throughout the study to assess safety and tolerability. All AEs were assessed in a blinded manner and were graded according to the Division of Microbiology and Infectious Diseases (DMID) Adult Toxicity table (November 2007, modified). For AEs involving a body system or laboratory value not addressed in the DMID table, the Common Terminology Criteria for Adverse Events version 4·0 was used. Safety assessments included any relevant changes that occurred after the start of study drug, regardless of whether the change was an examination finding, test result or symptom reported by a patient, and regardless of presumed relationship to the study drug. The patient was followed clinically until the event was resolved or deemed stable.

Outcomes

The primary efficacy outcome was the proportion of patients with complete cure of the TGT, defined as both clinical cure (0% nail involvement, Investigator's Global Assessment = 0) and mycological cure (defined as both negative KOH and negative dermatophyte culture) at week 48. Additional efficacy outcomes were (i) the proportion of patients with complete cure of the TGT at week 60 [end of study (EOS)]; (ii) the proportion of patients with therapeutic success, defined as having mycological cure (negative KOH and negative culture) and ≤ 10% (Investigator's Global Assessment = 1) nail involvement of the TGT at weeks 48 and 60 (EOS); (iii) the proportions of patients with mycological cure (negative KOH and negative culture) of the TGT at weeks 48 and 60 (EOS); (iv) the proportions of patients with clinical cure (0% nail involvement) of the TGT at weeks 48 and 60 (EOS) and (v) the percentage change in mycotic nail involvement of the TGT from baseline to week 48.

Sample Size

A sample size of approximately 40 patients per treatment group was estimated to provide ≥ 80% power to show a treatment difference of 25% between an active treatment and the placebo group in complete cure rates at week 48 (Fisher's exact test, two-sided alpha = 0·05 and assuming 5% of patients on placebo were completely cured). Based on an estimated 20% discontinuation rate, approximately 250 patients in total were to be randomized to provide approximately 200 evaluable patients.

Randomization and blinding

This was a double-blinded study. Patients were randomized in a 1 : 1 : 1 : 1 : 1 ratio using a computer-generated randomization schedule programmed by the blinded statistician using PROC PLAN in SAS version 9·2 (SAS Institute Inc., Cary, NC, USA). The clinical sites accessed the randomization codes through an interactive web response system, which assigned the patients to one of four dosing regimens of oral VT-1161 or matching placebo. The patients, study investigators and staff, the clinical staff members within Viamet, the clinical study monitor and the study medical monitor remained blinded to the individual treatment assignments until database lock after week 60. No patients were unblinded prior to the end of the study due to AEs or any other reason.

Statistical Methods

Efficacy data are presented for both the intent-to-treat (ITT) and per protocol populations. The ITT population was defined as all patients who were randomized and received at least one dose of study medication. The per protocol population was defined as all ITT patients who additionally completed week 48 without any missing clinical cure data or any protocol deviations that would have impacted treatment outcome and who were also compliant with the study treatment. Additional post hoc assessments were performed to evaluate VT-1161 cure rates vs. terbinafine cure rates, as reported in the Lamisil® FDA summary basis of approval (SBA). Every effort was made to obtain required data at each scheduled evaluation from all patients randomized. In situations where it was not possible to obtain all data for the primary efficacy analysis and key secondary analysis endpoints, missing data were imputed using last observation carried forward.

Subgroup analyses were conducted for clinical cure, therapeutic success, mycological cure and clinical cure according to the following subgroups: age (18–49 years vs. ≥ 50 years), baseline severity (percentage of nail affected 25–50% vs. > 50%) and sex.

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