Clinical trial NCT03814343: Topical Amphotericin B in 30% Dimethylsulphoxide in Treating of Non-dermatophytes Onychomycosis
Official title: Comparison of Effectiveness of Topical Amphotericin B in 30% Dimethylsulphoxide and 30% Dimethylsulphoxide in Treating of Non-dermatophytes Onychomycosis: Randomized Double Blind Controlled Trial Pilot Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Fungal Infection
Onychomycosis
Fungus, Nail
Keywords: fungal infection
onychomycosis
amphotericin B
Dimethylsulphoxide
non-dermatophyte
randomized double blind controlled trial
Lead sponsor: Mahidol University
Sponsor class: OTHER
First posted: 2019-01-24
Enrollment: 19
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized double blind controlled trial pilot study
Primary purpose: TREATMENT

Brief summary: The randomized control trial study aimed to evaluate effectiveness and safety of amphotericin B in 30% DMSO solution comparing with 30% DMSO solution in NDMs onychomycosis treatment.

Detailed description: Introduction Onychomycosis caused by non-dermatophyte molds (NDMs) have become more common in clinical practice, particularly in tropical and subtropical area. With worldwide prevalence as high as 10-24% for nail infection, more recent studies have focused on the treatment regimens for NDMs onychomycosis, especially of Neoscytalidium spp and Fusarium spp. etiology. However, there has been no consensus to-date regarding standard treatment of choice for NDMs onychomycosis.

NDMs onychomycosis was considered to be recalcitrant infection. Previous in vitro study in Malaysia reported high susceptibility of Neoscytalidium dimidiatum in amphotericin B, voriconazole, and miconazole treatment.Different therapeutic approaches such as oral antifungal agents, keratolytic agents, combined oral antifungal agents with keratolytic agents, or surgical nail avulsion, have been implemented but none has been considered a gold standard protocol in NDMs onychomycosis.

Amphotericin B is the polyene class of antimicrobial compounds. Its properties are fungicidal and have a broad spectrum with a low rate of resistance. In in vitro study, amphotericin B was reported to have better efficacy of treating N. dimidiatum infection followed by terbinafine and voricanazole. The mechanism of action is the interaction with ergosterol of fungi membrane resulting in forming permeable channels in cellular membrane of targeted fungi. This causes impairing membrane barrier function. In addition, it also causes growth inhibition. Amphotericin B is often used in treating disseminated fungal infection and visceral leishmaniasis. However, Amphotericin B can cause several side effects including nephrotocixicity, fever, chills, nausea, vomiting, headache, anemia, electrolytes imbalance (hypokalemia and hypomagnesaemia). Oral amphotercin B has poor bioavailability. Topical forms are not commonly used due to its highly lipophilic property. As a consequence, topical amphotericin B is not well absorbed through mucosa or skin resulting in low efficacy. High dose of topical amphotericin B had been developed but the results didn't work well because it caused severe adverse events such as blistering, itching, redness, peeling or severe irritation of the skin and did not even achieve the goal of treatment.

Dimethylsulphoxide (DMSO) is a promising vehicle to enhance the penetration of the drugs to animal or human skin. In addition, DMSO also has fungicidal activity. In vitro release study of amphotericin B from amphotericin B in 30% DMSO solution conducted in Siriraj Hospital revealed adequate amphotericin B concentration in the nails.

Since skin and nail infections caused by NDMs especially N. dimidiatum has been diagnosed in many countries with the majority cases being reported from Thailand, it could be implied that N. dimidiatum was endemic pathogens in this area. Published data on treatment regimens of NDMs nail infection using amphotericin B are still limited. According to the high antifungal property and low rate of drug resistance of amphotericin B, this randomized control trial study aimed to evaluate effectiveness and safety of amphotericin B in 30% DMSO solution comparing with 30% DMSO solution.

Objectives

1. To evaluate effectiveness including mycological cure of amphotericin B in 30% DMSO solution comparing with 30% DMSO solution in NDMs onychomycosis treatment
2. To evaluate safety of amphotericin B in 30% DMSO solution comparing with 30% DMSO solution in NDMs onychomycosis treatment

Material and Methods Patients Since there was no previous study that compared amphotericin B in 30% DMSO with pure 30% DMSO in treating of NDMs onychomycosis, this study designated a total of 20 patients into two groups as 10 patients with NDMs onychomycosis treated with 30% DMSO (control group) and another 10 Patients with NDMs onychomycosis treated with amphotericin B in 30% DMSO. NDMs onychomycosis was diagnosed with diagnostic criteria for NDM onychomycosis proposed by Gupta et al. Patients with any systemic or topical antifungal agents at least 3 months prior to the study were excluded from this study.

Design of medication Drugs were prepared in two solutions. First, amphotericin B (Alpharma, Denmark) was mixed with 30% DMSO (Sigma- Aldrich, Buchs, Switzerland) in 50:50 ratio. A final concentration of amphotericin B was 2 mg/ml. Later solution was pure 30% DMSO without amphotericin B. Those two final solutions had the same appearance, odor and texture. The solution will be kept in amber glass bottles with aluminum foil together with dropper. The drug regimen is to apply 1-3 drops of the solution once a day to each affected nail and briefly let the solution evaporate before continuing their usual activities.

Treatment, Follow-up and measurement A randomized control trial study conducted in outpatient nail clinic, Siriraj Hospital. Patients will be divided into two groups by mixed block of randomization. First groups will be treated with amphotericin B in 30% DMSO solution. Another group will be given only 30% DMSO solution. Each patient is subjected to continuously apply his/ her own drugs followed instruction given for 12 weeks. They will be followed up at 12 weeks, 24 weeks and 36 weeks for re-evaluation of clinical, mycological laboratories, adherence to the drug and adverse events. Effectiveness was evaluated by clinical improvement and mycological cure as well as median time to mycological cure. Clinical evaluation would be assessed by two treatment-blind dermatologists. Regarding mycological cure, it was defined as negative KOH and fungal culture. Data were analyzed using PASW Statistics version 18 (SPSS, Inc., Chicago, IL, USA).

Duration of study: 1 year

Study design: Randomized double blind control trial

Eligibility criteria: Inclusion Criteria:

1. Patients with non-dermatophyte onychomycosis.
2. Patients aged more than 18 years.
3. Patients has not been treated with any oral/ IV/ topical antifungal therapy within 36 weeks before enrolled.

Exclusion Criteria:

1. Patients had concomitant nail diseases.
2. Immunocompromised host.
3. Patients with dermatophyte onychomycosis.

Primary outcomes:
measure: Effectiveness of amphotericin B in 30% DMSO solution comparing with 30% DMSO solution in NDMs onychomycosis treatment
timeFrame: 36 weeks
measure: Median time to mycological cure of patients with amphotericin B in 30% DMSO solution comparing with 30% DMSO solution in NDMs onychomycosis treatment
timeFrame: 36 weeks
Secondary outcomes:
measure: Clinical cure of amphotericin B in 30% DMSO solution comparing with 30% DMSO solution in NDMs onychomycosis treatment
timeFrame: 36 weeks
measure: Median time to clinical cure of patients with amphotericin B in 30% DMSO solution comparing with 30% DMSO solution in NDMs onychomycosis treatment
timeFrame: 36 weeks
measure: Evaluate side effects of amphotericin B in 30% DMSO solution comparing with 30% DMSO solution in NDMs onychomycosis treatment
timeFrame: 12 weeks
Other outcomes:
Locations:
city: Bangkoknoi
country: Thailand
facility: Department of Dermatology Siriraj Hospital
state: Bangkok
Study officials:
affiliation: Mahidol University
name: Sumanas Bunyaratavej, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Mahidol University
name: Charussri Leeyaphan, MD
role: STUDY_DIRECTOR
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