Ciclopirox Hydrolacquer Therapy For Adult Onychomycosis
Overview
In a Phase III trial, a water-soluble ciclopirox nail hydrolacquer was evaluated for treating toenail fungal infection. Its enhanced penetration delivered higher ciclopirox concentration to the nail compared to existing lacquers. The study compared the hydrolacquer, its base formulation (vehicle), and an active control over 52 weeks.
381 patients with mild to moderate toenail fungal infection participated. Although complete cure rates didn’t significantly differ, at 52 weeks, more ciclopirox hydrolacquer users achieved mycological cure (32.0%) compared to vehicle (23.2%) and the reference product (27%). Similar trends were seen for improvement (mycological cure plus ≥20% reduction in diseased nail).
Importantly, the hydrolacquer outperformed the vehicle in negativizing dermatophyte cultures (p=.039) and prevented recurrence, relapse, or re-infection in fully cured patients during a 4-week follow-up. Safety profile matched the vehicle and reference product, the novel ciclopirox nail hydrolacquer showed improved penetration, demonstrating notable efficacy in achieving mycological cure and negativizing cultures, surpassing the vehicle. It maintained a safety profile similar to existing options.
Introduction
Onychomycosis, a chronic fungal nail infection caused by various pathogens, can lead to discomfort and physical impairment. Its prevalence ranges from 2% to 20% in developed countries, with higher rates among older individuals. Effective treatment focuses on eradicating pathogens to prevent recurrence. Topical treatments are preferred due to their safety and patient acceptance, especially in early-stage disease without nail matrix involvement.
Yet, nail structure limits drug absorption, challenging treatment success. Ciclopirox, a broad-spectrum antifungal, has demonstrated efficacy and safety in onychomycosis treatment for over two decades. Its multifaceted mechanism inhibits fungal growth and possesses antibacterial and anti-inflammatory properties.
Ciclopirox’s effectiveness hinges on its ability to permeate and remain on the nail plate. To enhance this, a novel vehicle named Ciclo-Tech® was developed. This technology employs hydroxypropyl-𝛽-cyclodextrin, sodium lauryl sulfate, and poloxamer 407 to increase drug diffusion, penetration, and action time. The resulting formulation significantly elevates drug concentration compared to traditional lacquers.
Building on this, a water-soluble ciclopirox nail lacquer with moisturizing and film-forming properties was created, allowing increased drug penetration and concentration in the nail. An in vitro study revealed its superior permeability compared to a reference product. Subsequently, a Phase III clinical trial assessed its efficacy and safety for toenail fungal infection treatment, onychomycosis treatment faces challenges due to nail structure and limited drug absorption. Ciclopirox, an established antifungal, remains a prime choice. The novel water-soluble ciclopirox nail lacquer, formulated with advanced technology, aims to enhance drug penetration and concentration, offering promise for effective and safe treatment of toenail fungal infection.
Method
The study design was approved by relevant institutional review boards and regulatory authorities, and written informed consent was obtained from all participants. The investigational product (Ciclopirox nail lacquer 80 mg/g + Ciclo-Tech® technology), the vehicle, and the active comparator (Ciclopirox nail lacquer 80 mg/g + HPCH) were applied topically once daily, and participants were monitored for adverse events and treatment responses.
Inclusion Criteria:
Adult men and women aged ≥18 to ≤75 years with distal mild to moderate onychomycosis (involving ≥20% to ≤60% of the distal bed adherent nail plate without the involvement of the lunula) caused by dermatophyte fungi affecting at least one big toenail were eligible. Positivity for the disease was confirmed through culture and the positive dermatophyte test strip (DTS). Participants needed to be willing to comply with study requirements and provide written informed consent.
Exclusion Criteria:
Patients were excluded if they had allergies to ciclopirox or any component of the study medication, a life expectancy of less than 2 years, regular use of cosmetic lacquer unwilling to be interrupted, pregnancy or breastfeeding, or were using systemic or topical antifungal drugs.
This prospective, randomized, double-blinded, controlled study included 381 eligible patients (out of 1430 screened) recruited from Spain, Mexico, and Latvia. Participants were randomly assigned into three groups (1:1:1): the vehicle group (n=126), the ciclopirox nail hydrolacquer group (n=127), and the reference product group (n=128). The treatment period was 48 weeks with a 4-week follow-up up to week 52. The primary outcome assessed the efficacy of the ciclopirox nail hydrolacquer in terms of complete cure and mycological cure compared to the vehicle for treating toenail onychomycosis. Secondary outcomes included improvement rates and safety endpoints, such as adverse events and laboratory parameters.
Study Design and Statistical Analysis:
To demonstrate the superiority of ciclopirox nail hydrolacquer over the vehicle, the study employed a 1:1 allocation, with a significance level of α = 0.05 and a required power of 80%. Patients were randomly assigned to either ciclopirox nail hydrolacquer, vehicle, or reference product groups. Statistical tests, including parametric and non-parametric tests, were used to analyze differences between variables. Fisher’s exact test was used for categorical variables. Primary endpoint analysis was performed using the intention-to-treat (ITT) population, with the per protocol (PP) population considered supportive. Safety analyses were conducted in the safety population. Statistical analyses were performed using SAS® Software version 9.3.
Assessments
The study comprised 11 visits over 52 weeks, including a screening period, treatment phase, and follow-up. Inclusion and exclusion criteria were reviewed during the selection visit. The target nail was examined, and DTS/KOH and tissue culture tests were conducted. If DTS was positive, fungal culture confirmed the presence of fungi. Randomization and treatment assignment occurred at Visit 2. Clinical cure at visits 3–9 triggered target nail sampling for confirmation. Blood sampling for analytical parameters and ciclopirox level determination was done for the safety subgroup. Efficacy variables, assessed by investigators and a blinded evaluator, included nail photographs and planimetry evaluations. Safety variables encompassed adverse events recording, vital signs, and laboratory parameters.
The study design aimed to demonstrate the superiority of ciclopirox nail hydrolacquer, involving rigorous statistical analyses and thorough assessments to evaluate treatment efficacy and safety over a 52-week period.
Result
Among 1430 screened patients, 381 were treated, 376 were analyzed for efficacy (ITT set), 381 were analyzed for safety, and 255 completed the study. Demographic characteristics were similar among patient groups. Trichophyton rubrum was the most common dermatophyte species identified. At week 52, no statistically significant differences were observed in complete cure rates among groups. Mycological cure rates were higher in the ciclopirox nail hydrolacquer group (32.0%) compared to the reference product (27.0%) and vehicle (23.2%), but the differences were not statistically significant. The ciclopirox nail hydrolacquer showed statistically significant superiority over the vehicle in terms of converting to negative dermatophyte culture (47.2% vs. 34.4%). A higher proportion of patients in the ciclopirox nail hydrolacquer group demonstrated improvement (27.2%) compared to the reference product (20.6%), although the difference was not statistically significant. The ciclopirox nail hydrolacquer group exhibited no recurrences, relapses, or re-infections after complete cure, contrasting with the other groups. Safety profiles were comparable between treatments, with low rates of adverse events (AEs) and mostly mild intensity. Serious AEs were more frequent in the reference product group but not directly related to study drugs. Overall, the active treatments showed efficacy for onychomycosis treatment similar to other published trials.
This study evaluated the efficacy and safety of the new ciclopirox nail hydrolacquer formulation compared to its vehicle and an active comparator for treating toenail fungal infection. While the active treatments exhibited effectiveness, no significant differences were observed compared to the control group, possibly due to higher-than-expected efficacy in the control group. The ciclopirox nail hydrolacquer demonstrated potential benefits, including improved mycological outcomes and absence of relapses, warranting further investigation.
Conclusion
The primary objective of treating onychomycosis is to eliminate the fungus, restore healthy nails, and prevent reinfection. Achieving this is challenging due to the limited penetration of active ingredients through the nail. This study aimed to evaluate the effectiveness of a new ciclopirox formulation, combined with Ciclo-Tech® technology, compared to a vehicle and a reference product for treating toenail fungal infection.
The trial demonstrated that both the new ciclopirox nail hydrolacquer and the reference product were effective in treating onychomycosis over 52 weeks, with similar complete cure rates to published trials. Interestingly, no significant differences were observed compared to the vehicle group, which was intended as a placebo control. This might be due to the active role of the technology in the vehicle.
Cyclodextrins, known for enhancing solubility and bioavailability, could contribute to the antifungal effect by interacting with the fungal membrane. The vehicle’s inclusion in the study might have impacted results positively. Furthermore, the ciclopirox nail hydrolacquer showed higher efficacy in mycological cure and improvement compared to the reference product, indicating the importance of the new vehicle’s role.
Safety profiles were consistent with previous ciclopirox lacquers, and minimal systemic absorption was observed. The new ciclopirox nail hydrolacquer displayed better efficacy in achieving mycological cure, eliminating live fungus, and preventing relapses or reinfections.
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