Resin vs. Amorolfine vs. Terbinafine Treatment in Onychomycosis

Study Overview
=================
Brief Summary
-----------------
The current study is conducted to corroborate the previous observational clinical trial with more valid methods and a more clinically relevant experimental design. This study aims to compare efficacy, safety, and cost between topically administered 30% resin lacquer for the treatment of dermatophyte toenail onychomycosis and the current best practices: topical 5% amorolfine and systemic terbinafine.

Detailed Description
-----------------
The aim of this prospective, investigator-blinded, randomized and controlled clinical trial is to explore potential differences between 5 % amorolfine and 30 % resin lacquer in topical treatment of onychomycosis. In addition, topical treatment methods are compared with the most effective 'drug of choice' for onychomycosis according the current guidelines i.e. oral medication with terbinafine. Altogether 90 patients (the aim is to collect the 30 patients per group) who have culture or potassium hydroxide (KOH) stain verified dermatophyte onychomycosis are randomly allocated into 3 treatment groups to receive either topical treatment or oral medication for toenail onychomycosis classified as follows: White superficial onychomycosis (WSO) Distal and lateral subungual onychomycosis (DLSO) Proximal subungual onychomycosis (PSO) [Total dystrophic onychomycosis) (TDO)] [Excluded] [Candidal onychomycosis] [Excluded] Participants are randomized into 3 groups to receive: Topical treatment: 30 % resin lacquer (Abicin®) applied once daily for 9 months. Topical treatment: 5 % amorolfine lacquer (Loceryl®) applied once weekly for 9 months. Oral medication: 250 mg terbinafine taken orally once daily for 3 months. All patients visit at outpatient department before the launch of the study, and 3 and 9 months thereafter. Clinical examination is done by 4 physicians. During the 42-week study period, laboratory tests are conducted on samples collected before treatment, at 20 weeks, and at 42 weeks. The tests include a fungal culture, KOH staining of the toenail sample, and blood tests. Cultures and KOH microscopy are performed in an independent, specialised mycology laboratory with standard techniques (Medix Laboratories Ltd., Helsinki, Finland). The blood tests measure plasma γ-glutamyl transferase levels (also at 2 weeks); plasma creatinine levels; the total number of white blood cells, including neutrophils, monocytes, basophils, lymphocytes, and eosinophils; the total number of red blood cells, including erythrocytes and haematocrit; erythrocyte indices, including the mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, and haemoglobin level; and the total number thrombocytes (initially and at 42 weeks). During the control visits, sequential digital photographs of the most disfigured and brittle toenails are acquired. In the three phone calls, patients are asked about potential treatment-related side effects, compliance with treatment, patients' perception of treatment outcome, and their willingness to continue in the study. In each treatment arm, the treatment regimen is discontinued 5 weeks before the last toenail sampling to provide an appropriate washout period before the final culture and KOH analysis. To ensure safety and to assess potential contraindications for the treatment regimens, all patients included in the study undergo a comprehensive medical interview and physical examination. To identify patients who may develop intolerable adverse events due to drug combinations, all concurrent medications are cross-checked to verify compatibility with resin, amorolfine, and terbinafine regimens at the beginning of the study. All patients are informed of the possibility of developing a hypersensitivity to resin, amorolfine, or terbinafine. If patients experienced symptoms that corresponded to any level of hypersensitivity, they are dropped from the study.

Official Title
-----------------
Efficacy of Topical Resin Lacquer, Amorolfine, and Oral Terbinafine for Treating Toenail Onychomycosis: a Prospective, Randomized, Controlled, Investigator-blinded, Parallel-group Clinical Trial

Conditions
-----------------
Onychomycosis

Intervention / Treatment
-----------------
* Device: Resin Lacquer
* Drug: Amorolfine
* Drug: Terbinafine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Positive dermatophyte culture in the beginning of the study obtained from the toenail sample. Positive KOH stain in the beginning of the study obtained from the toenail sample. Exclusion Criteria: Any other nail disease than dermatophyte culture or KOH stain verified onychomycosis Onychomycosis caused by yeasts or nondermatophyte molds Kidney failure determined by plasma creatinine level (P-Krea > 100 μmol/l) Liver failure determined by plasma γ-glutamyltransferase level (P-GT > 120 U/I) Sensitivity or allergy to Resin, Amorolfine or Terbinafine Potential adverse cross-reaction of Terbinafine, Amorolfine or Resin with the patient's permanent medication Presence of total dystrophic onychomycosis (TDO) Any topical or oral antifungal treatment within the 6 months before the beginning of the study (washout period > 6 months).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Resin Lacquer<br>Topical 30% Resin Lacquer applied once daily for 9 months (Abicin® 30% Nail Lacquer). | Device: Resin Lacquer<br>* 30% Resin Lacquer is applied once daily for 9 months (Abicin®) in toenail onychomycosis.<br>* Other names: Resin Lacquer arm;|
| Active Comparator: Amorolfine<br>Topical 5% Amorolfine Lacquer applied once weekly for 9 months (Loceryl® 5% Nail Lacquer). | Drug: Amorolfine<br>* 5% Amorolfine Lacquer is applied once weekly for 9 months (Loceryl®) in toenail onychomycosis.<br>* Other names: Amorolfine Lacquer arm;|
| Active Comparator: Terbinafine<br>250 mg of Terbinafine taken orally once daily for 3 months (Generics). | Drug: Terbinafine<br>* 250 mg of Terbinafine is taken orally once daily for 3 months (Generics) in toenail onychomycosis.<br>* Other names: Terbinafine arm;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mycological Cure | To analyze the rate of complete mycological cure i.e. fungal eradication in terms of negative mycological culture AND negative potassium hydroxide (KOH) stain at 4- and 10 months time-points from the beginning of the study. | At 4- and 10 months time-points from the beginning of the study. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Responses to the Treatments | Clinical responses to treatment were based on the proximal linear growth of healthy nail; thus, the clinical responses were classified as partial (evident proximal linear growth of healthy nail) or complete. Partial responses were defined as significant reductions in onycholysis, subungual hyperkeratosis, and streaks. A complete response was a fully normal appearance of the toenail. | At 4- and 10 months time-points from the beginning of the study. | 
| Cost-effectiveness 1 | Cost analysis was based on the retail price (€) and consumption of a 10 ml bottle of Abicin® 30% resin lacquer, a 5 ml bottle of Loceryl® 5% amorolfine lacquer, and 98 tablets of generic 250 mg terbinafine, sold by the University Pharmacy in Helsinki, Finland, January 2014. The cost was expressed as the average treatment cost per patient; for the total cost, this average was extrapolated to the entire study treatment arm. The results show the treatment costs (€) per day per patient in each group. | At 10-month time-point | 
| Cost-effectiveness 2 | Cost analysis was based on the retail price (€) and consumption of a 10 ml bottle of Abicin® 30% resin lacquer, a 5 ml bottle of Loceryl® 5% amorolfine lacquer, and 98 tablets of generic 250 mg terbinafine, sold by the University Pharmacy in Helsinki, Finland, January 2014. The cost was expressed as the average treatment cost per patient; for the total cost, this average was extrapolated to the entire study treatment arm. The results show the treatment costs (€) during the treatment period per patient in each group. | At 10-month time-point | 
| Compliance to the Treatment | Evaluation of compliance was based on patient self-reports of whether the treatment protocol was followed 100% (complete), 80% (good), 60% (moderate), or 40% (poor) of the time. | At 4-month time-point | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Dermatophyte onychomycosis, Fungal nail infection, Resin Lacquer, Amorolfine, Terbinafine