Resin vs. Amorolfine vs. Terbinafine Treatment in Onychomycosis

• ClinicalTrials.gov Identifier: NCT01851590
• Recruitment Status: Completed
• First Posted: May 10, 2013
• Results First Posted: November 30, 2015
• Last Update Posted: November 30, 2015
• Sponsor: Helsinki University Central Hospital
• Collaborator: Repolar Ltd.
• Information provided by (Responsible Party): Janne J. Jokinen, Helsinki University Central Hospital

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Onychomycosis	Device: Resin Lacquer; Drug: Amorolfine; Drug: Terbinafine	Phase 4

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:

1. White superficial onychomycosis (WSO)
2. Distal and lateral subungual onychomycosis (DLSO)
3. Proximal subungual onychomycosis (PSO)
4. [Total dystrophic onychomycosis) (TDO)] [Excluded]
5. [Candidal onychomycosis] [Excluded]

Participants are randomized into 3 groups to receive:

1. Topical treatment: 30 % resin lacquer (Abicin®) applied once daily for 9 months.
2. Topical treatment: 5 % amorolfine lacquer (Loceryl®) applied once weekly for 9 months.
3. 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 129 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Investigator)
• Primary Purpose: Treatment
• 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
• Study Start Date: October 2013
• Actual Primary Completion Date: October 2014
• Actual Study Completion Date: October 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: Resin Lacquer; Topical 30% Resin Lacquer applied once daily for 9 months (Abicin® 30% Nail Lacquer).	Device: Resin Lacquer; 30% Resin Lacquer is applied once daily for 9 months (Abicin®) in toenail onychomycosis.; Other Name: Resin Lacquer arm
Active Comparator: Amorolfine; Topical 5% Amorolfine Lacquer applied once weekly for 9 months (Loceryl® 5% Nail Lacquer).	Drug: Amorolfine; 5% Amorolfine Lacquer is applied once weekly for 9 months (Loceryl®) in toenail onychomycosis.; Other Name: Amorolfine Lacquer arm
Active Comparator: Terbinafine; 250 mg of Terbinafine taken orally once daily for 3 months (Generics).	Drug: Terbinafine; 250 mg of Terbinafine is taken orally once daily for 3 months (Generics) in toenail onychomycosis.; Other Name: Terbinafine arm

Outcome Measures

Primary Outcome Measures :

1. Mycological Cure [ Time Frame: At 4- and 10 months time-points from the beginning of the study. ]
   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.

Secondary Outcome Measures :

1. Clinical Responses to the Treatments [ Time Frame: At 4- and 10 months time-points from the beginning of the study. ]
   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.
2. Cost-effectiveness 1 [ Time Frame: At 10-month time-point ]
   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.
3. Cost-effectiveness 2 [ Time Frame: At 10-month time-point ]
   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.
4. Compliance to the Treatment [ Time Frame: At 4-month time-point ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 90 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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).

Contacts and Locations

Locations

Finland

Vääksyn Lääkärikeskus

Vääksy, Finland, FI-17200

Sponsors and Collaborators

Helsinki University Central Hospital

Repolar Ltd.

Investigators

• Principal Investigator: Janne J. Jokinen, MD, PhD; Department of Cardiac Surgery, Heart and Lung Centre, Helsinki University Hospital, FI-00029, Helsinki, Finland

More Information

Publications:

Sigurgeirsson B et al. Efficacy of amorfine nail lacquer for the prophylaxis of onychomycosis over 3 years. J Eur Acad Dermatol Venereol 2010;24: 910-5. Rautio M et al. Antibacterial effects of home-made resin salve from Norway spruce (Picea abies). APMIS 2007;115: 335-340. Rautio M et al. In vitro fungistatic effects of natural coniferous rosin from Norway spruce (Picea abies). Eur J Clin Microbiol Infect Dis 2012;31:1783-9. Sipponen A et al. Effects of Norway spruce (Picea abies) resin on cell wall and cell membrane of Staphylococcus aureus. Ultrastruct Pathol 2009;33: 128-135. Sipponen P et al. Natural coniferous resin lacquer in treatment of toenail onychomycosis: an observational study. Mycoses 2012, Accepted. Roberts DT et al. British Association of Dermatologists. Guidelines for treatment of onychomycosis. Br J Dermatol 2003;148:402-10. Baran R et al. A new classification of onychomycosis. Br J Dermatol 1998;139: 567-71.

• Responsible Party: Janne J. Jokinen, Consultant Cardiothoracic Surgeon, Helsinki University Central Hospital
• ClinicalTrials.gov Identifier: NCT01851590
• Other Study ID Numbers: 334/13/03/01/2012; 2012-004822-48 ( EudraCT Number )
• First Posted: May 10, 2013
• Results First Posted: November 30, 2015
• Last Update Posted: November 30, 2015
• Last Verified: October 2015

Keywords provided by Janne J. Jokinen, Helsinki University Central Hospital:

Dermatophyte onychomycosis; Fungal nail infection; Resin Lacquer; Amorolfine; Terbinafine

Additional relevant MeSH terms:

Onychomycosis; Tinea; Dermatomycoses; Skin Diseases, Infectious; Infection; Mycoses; Nail Diseases; Skin Diseases; Terbinafine; Amorolfine; Antifungal Agents; Anti-Infective Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action