Topical and device-based treatments for fungal infections of the toenails

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the clinical and mycological effects of topical drugs and device-based therapies for onychomycosis.

Background

Please see Table 1 for a glossary of unfamiliar terms.

Table 1. Glossary of terms
TermDefinition
AllylamineClass of antifungal molecules used to treat skin and nails. Examples include butenafine and terbinafine
AzoleClass of antifungal compounds used to treat skin and nails, characterised by a 5-membered nitrogen heterocyclic ring. Examples include ketoconazole and fluconazole
BenzoxaboroleClass of small molecules characterised by a boron atom. The antifungal tavaborole is a member of this class
Cross-contaminationUnintentional transfer of a micro-organism from 1 object or person to another
DermatophytesInfectious fungi that feed on the keratin present in the skin, hair, and nails, which usually cause an inflammatory response at the site of infection
DistalAway from the cuticle, toward the end of the nail
DystrophicProgressive damage or deformity characterised by the wasting away of tissue or both
FungicidalTo kill fungal cells
FungistaticTo impede the growth and reproduction of fungal cells
HydroxypyridoneClass of compounds with antifungal properties used to treat skin and nails. Example: ciclopirox
HyponychiumThe skin beneath the distal free edge of the nail
IontophoresisA method whereby ionic medicinal compounds are introduced into the body by applying an electrical current to the skin
keratinA key protein in the structure of skin, hair, and nails
LateralTo the sides (of the nail)
ProximalClose to (the cuticle)
MetalloproteasesEnzymes in the body that break down proteins and contain a metal ion to aid in this process
Morpholine derivativeAn antifungal based on the organic compound morpholine. Example: amorolfine
MycologicalConcerning fungi
Nail apparatusRefers to the nail and associated underlying structures (Figure 1)
OnycholysisDetachment of the nail from the nail bed
SubungualUnderneath the nail
SynthetaseA biological enzyme that acts in the body to combine molecules or compounds together
Tinea pedisAlso known as "athlete's foot", an infection of skin of the feet typically caused by dermatophytes

Description of the condition

Onychomycosis is a fungal infection of the nail apparatus (Zaias 1972). It is primarily caused by dermatophytes, which are Infectious fungi that feed on the keratin present in the skin, hair, and nails, that usually cause an inflammatory response at the site of infection (Welsh 2010). Yeasts and non-dermatophyte moulds can also cause onychomycosis either alone or in combination with dermatophytes (Gupta 2012; Welsh 2010). Many people seek treatment for cosmetic purposes, but onychomycosis is an infectious condition, so it is critical that it is treated to prevent cross-contamination and secondary complications (Szepietowski 2006). Patients with onychomycosis report decreased quality of life and may restrict their activities because of embarrassment about the aesthetic appearance of their nails (Reich 2011).

Clinical presentation

Onychomycosis has several clinical presentations, including distal and lateral subungual (under the nail) onychomycosis (DLSO), proximal subungual onychomycosis, superficial white onychomycosis, and total dystrophic onychomycosis (Hay 2011). DLSO is the most common form of onychomycosis and often presents secondary to tinea pedis (Hay 2011). DLSO affects the nail plate; nail bed; and hyponychium, which is the skin beneath the distal free edge of the nail, and may present with streaks of pigmentation in the nail and uneven borders, which distinguishes it from simple onycholysis, where the nail detaches from the nail bed (Hay 2011). Proximal subungual onychomycosis is initiated at the proximal nail fold and is usually whitish in colour, while superficial white onychomycosis is localised to the centre of the nail plate with a white, chalky appearance (Hay 2011). Total dystrophic onychomycosis is the most severe form of onychomycosis; it affects the entire nail plate and results in nail thickening along with complete loss of normal nail architecture (Hay 2011).

Figure 1 presents the anatomy of the nail, including the distal, lateral, and proximal areas of the nail.

Figure 1.

Anatomy of the nail

Epidemiology

Onychomycosis accounts for approximately 50% of reported nail disorders (Faergemann 2003). A recent systematic review, Sigurgeirsson 2014, reported the population-based prevalence of onychomycosis as 4.3% in Europe and North America and found it was more prevalent in men in North America and Europe and women in South America. The review reported that onychomycosis was more common in toenails than fingernails, and the primary causative organism was Trichophyton rubrum (44.9%), followed by yeasts (21.2%) and moulds (13.3%).

Comorbidities

Onychomycosis is associated with a number of medical conditions and advancing age (Baran 2011). For example, there is an increased prevalence of onychomycosis in individuals with psoriasis, diabetes, immunosuppression, peripheral vascular disease, and obesity (Baran 2011; Döner 2011; Gupta 1997; Gupta 2000). It is critical to treat onychomycosis in individuals with these conditions, as they are at an increased risk of secondary complications. These patients may also have contraindications for the oral antifungals terbinafine and itraconazole due to drug-drug interactions or a higher risk of adverse events (Baran 2008; Barber 2006).

Description of the intervention

Topical drugs for onychomycosis generally come in the form of lacquers or solutions directly applied to the surface of the nail (Gupta 2013). Device-based therapies may include, but are not limited to, laser systems, iontophoresis, photodynamic therapy, and ultrasound (Gupta 2013). We will consider device-based therapies with a topical component or in combination with a topical therapy. Oral treatments for fungal infections of the toenails are also commonly used (Gupta 2015); however, they are outside the scope of this review.

How the intervention might work

Topical drugs

Antifungal drugs can either be fungistatic, preventing further growth of fungal cells, or fungicidal, killing fungal cells entirely. Most antifungal drugs inhibit cell membrane synthesis, but others target protein translation and fungal proteases (Gupta 2013). Topical drugs are usually applied daily for six months or longer in order to allow the normal nail to grow and replace the regions damaged by infection (Gupta 2014b). Drugs formulated for topical application in onychomycosis include those from the allylamine, azole, hydroxypyridone, morpholine-derivative, and benzoxaborole classes (Gupta 2013; Gupta 2014). The azoles, allylamines, and morpholine-derivative drugs inhibit ergosterol biosynthesis, an essential component of the cell wall (Gupta 1994). The hydroxypyridone-class drug ciclopirox inhibits metalloproteases by binding metal ions (Valeant 2004). The benzoxaborole-class drugs inhibit protein translation by inhibiting the fungal leucine transfer ribonucleic acid (tRNA) synthetase (Rock 2007).

Devices

Devices have diverse mechanisms of action. Laser device systems are thought to act via selective photothermolysis, which is the conversion of light energy into heat energy that is confined to a specific target (Anderson 1983). Iontophoresis devices use an electrical current to increase the penetration of a topically applied drug into the nail plate (Amichai 2010). Photodynamic therapy uses a narrow-spectrum light source to activate topically applied photosensitisers (Piraccini 2008). This Cochrane Review may also identify new devices with novel mechanisms of action.

Why it is important to do this review

A Cochrane review on dermatophyte infections of the feet and nails was published in 2007 (Crawford 2007). Since then, a substantial amount of research on topical drugs and device-based therapies for the treatment of onychomycosis has emerged in the scientific literature, warranting a review exclusively on toenails. Topical drugs and devices are important therapeutic options for mild to moderate onychomycosis. The advantage of effective topical therapies for onychomycosis is that they are not distributed throughout the body systemically so may mean there is less likelihood of drug interactions or adverse events.

As these categories of therapies increase, it is important that healthcare professionals have accurate information about the optimal dosage and treatment regimens, so they can effectively treat patients with new drugs and devices.

Objectives

To assess the clinical and mycological effects of topical drugs and device-based therapies for onychomycosis.

Methods

Criteria for considering studies for this review

Types of studies

The review will include randomised controlled trials (RCTs) of topical and device-based therapies for onychomycosis.

Types of participants

We will include men and women over 18 years of age who have onychomycosis of the toenails. Diagnosis of nail samples must have occurred using direct microscopic examination (potassium hydroxide), culture, periodic acid-Schiff stain (PAS), or molecular biology.

Types of interventions

We will include RCTs that compare a topical or device-based therapy with placebo, no treatment, or an active comparator that must be topical or device based.

Types of outcome measures

We will assess outcomes based on the following time points: ≤ 12 weeks, > 12 and ≤ 36 weeks, > 36 and ≤ 52 weeks, and > 52 weeks. We will exclude studies with a duration of less than 12 weeks. We will present our primary outcomes in a 'Summary of findings' table.

Primary outcomes
  1. Complete cure rate: the proportion of participants with 0% nail plate involvement and mycological cure at follow-up.

  2. Adverse events: the proportion of participants who reported at least one event, whether related or not to the intervention. In addition and where possible, we will also evaluate adverse events based on the likelihood of their being related to the interventions, as judged by the study investigator(s).

Secondary outcomes
  1. Mycological cure rate: the proportion of participants who achieved negative mycological testing as defined by the study at follow-up.

  2. Clinical cure rate: the proportion of participants who achieved 0% nail plate involvement at follow-up.

  3. Compliance: the proportion of participants who completed the study protocol without deviations, as defined by study investigators.

  4. Time to recurrence.

  5. Quality of life: this will be descriptive based on measures included by study investigators.

  6. Pharmacoeconomics: the cost of the treatment will be descriptive.

Search methods for identification of studies

We aim to identify all relevant RCTs regardless of language or publication status (published, unpublished, in press, or in progress).

Electronic searches

We will search the following databases for relevant trials:

  • the Cochrane Skin Group Specialised Register;

  • the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library;

  • MEDLINE via Ovid (from 1946);

  • EMBASE via Ovid (from 1974); and

  • LILACS (Latin American and Caribbean Health Science Information database, from 1982).

We have devised a draft search strategy for RCTs for MEDLINE (Ovid), which is displayed in Appendix 1. This will be used as the basis for search strategies for the other databases listed.

Trials registers

We will search the following trials registers using the following terms: onychomycosis or tinea unguium.

Searching other resources

References from published studies

We will check the bibliographies of included and excluded studies for additional references to relevant RCTs.

We will handsearch the Mycoses journal from 1957 to 1990 for additional studies. (Later editions of the journal are indexed in MEDLINE and EMBASE, so it is not necessary to handsearch them.)

Unpublished literature

We will conduct online searches of pharmaceutical company websites and the U.S. Food and Drug Administration (FDA) website.

We will contact experts in the field of dermatology regarding unpublished trials.

Conference proceedings

We will handsearch the following conference proceedings for relevant trials from years that the Cochrane Skin Group have not already handsearched:

  • the British Association of Dermatologists (1982 to 2013);

  • the Annual Meetings of the American Academy of Dermatology (1990 to 2013);

  • the European Academy of Dermatology and Venereology (1996 to 2013);

  • the European Society for Dermatological Research (1970 to 2012); and

  • the Australasian College of Dermatologists (1996 to 2013).

Adverse effects

We will not perform a separate search for adverse effects of the target intervention. However, we will examine data on adverse effects from the included studies that we identify.

Data collection and analysis

Selection of studies

We will manage the studies using Microsoft Excel 2010 software. At least two individuals, FS, DD, DL, or MP, will screen the references and each perform independent study selection. We will pilot the study selection criteria on a subsample of the articles (approximately 10) in order to validate the criteria and ensure that they are consistently interpreted for all studies. We will examine all articles and documents retrieved to determine if they comply with the inclusion and exclusion criteria.

Data extraction and management

Two review authors, FS, DD, DL, or MP, will independently extract the data for each included study using a standard form, including the study design, number of participants randomised into each treatment group, baseline characteristics, health intervention, treatment regimen and duration, treatment success and failure, safety, tolerability, the number of participants lost to follow up, the duration of follow-up, and pharmacoeconomic data. We will pilot the forms on a small group of studies to ensure completeness. We will discuss disagreements in order to reach a consensus. If we cannot reach consensus, a third author will perform additional data extraction to break a split decision. The first individual, FS, will enter the data into Review Manager (Review Manager 2014), and the second author, DD, DL, or MP, will verify the data. We will not be blinded to authors, institutions, or journals during data extraction.

Assessment of risk of bias in included studies

Two authors, KF and DD, will independently evaluate risk of bias in individual studies using Cochrane's 'Risk of bias' tool (Higgins 2011), resolving disagreements by discussion. The 'Risk of bias' ('RoB') table will include domains on the following: sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, and within-study selective outcome reporting.

Measures of treatment effect

We will analyse dichotomous outcomes using a risk ratio (RR) with a 95% confidence interval (CI).

We will quantify significantly different outcomes as a number needed to treat to benefit (NNTB) based on the following formula: NT = 1/ARC * (1-RR) (Centre for Evidence-Based Medicine). We will use the RRs from the meta-analysis and the moderate assumed control risk (ARC) calculated in GRADEpro (Grading of Recommendations Assessment, Development and Evaluation profiler) GDT (Guideline Development Tool) (GRADEPro).

We will analyse continuous outcomes as a mean difference (MD) with a 95% CI.

We will measure time to recurrence using the hazard ratio and collect standard errors from Cox proportional hazards models.

Unit of analysis issues

The participant will be the unit of analysis, with clinical trials designating one target toenail per participant as the unit of analysis. We will not consider nail data in clinical studies that use individual nails as the unit of analysis, including multiple toenails per participant in their data set, and we will not consider participant-controlled data. We will exclude cross-over trials as the aim of any treatment for onychomycosis is cure.

Dealing with missing data

If data are missing or in a format that precludes extraction, we will contact the study authors to request that information. We will prioritise intention-to-treat (ITT) data and convert per-protocol data into ITT data wherever possible. In the event that we are unable to acquire all missing data, we will perform analyses with the available data.

Assessment of heterogeneity

We will assess the heterogeneity of the included studies for clinical and statistical factors. Clinical factors may include population age, comorbidities, and disease severity. We will quantify statistical heterogeneity using the I² statistic (Higgins 2011). Higgins provides a range of values for moderate (30% to 60%), substantial (50% to 90%), and considerable (75% to 100%) heterogeneity.

An I² value greater than 75% will indicate substantial heterogeneity, and we will not report meta-analyses for comparisons where I² is greater than 75%.

Assessment of reporting biases

We will investigate selective reporting of outcomes in analyses with 10 studies or more (Dwan 2008). We will generate funnel plots of the data to determine if reporting asymmetry is present.

Data synthesis

We will calculate risk ratios (dichotomous data) using the Mantel-Haenszel model, and we will calculate mean differences (continuous data) using the inverse-variance model. Where meta-analysis is possible (e.g., at least three trials), we will conduct the analyses using a random-effects model. Where results are estimated for individual studies with low numbers of events (less than 10 in total) or where the total sample size is less than 30 participants and a risk ratio is used, we will report the proportion of events in each group together with a P value from a Fisher's Exact test.

We will summarise time to recurrence by calculating random-effects estimates of the pooled hazard ratio using the generic inverse-variance method.

If meta-analysis is not possible due to the number of trials (less than three) or considerable heterogeneity (greater than 75%), we will assess the studies for the data collected qualitatively.

Subgroup analysis and investigation of heterogeneity

When moderate statistical heterogeneity is present (I² statistic greater than 50%), we will conduct subgroup analysis. We will analyse any clinical sources of heterogeneity, such as participant age and onychomycosis severity, if sufficient studies are present (at least two studies with a combined sample size of 30 or larger for each group being compared (Dijkman 2009)).

Sensitivity analysis

In analyses with considerable heterogeneity (I² statistic greater than 75%), we will conduct sensitivity analysis to determine if removing studies with identified risk of bias contributes to the overall heterogeneity.

We will perform sensitivity analyses to determine the impact of removing studies with missing data to examine if they contributed to the risk of bias.

'Summary of findings' table

We will present the data for the primary outcomes in at least one 'Summary of findings' table. If further subgroup analyses merit their own 'Summary of findings' table, we will include further tables.

We will assess the quality of the evidence across the outcome measures that we will report in the 'Summary of findings' tables using the GRADE assessment and GRADEpro GDT software (GRADEPro).

Acknowledgements

The authors wish to acknowledge Dr Jessie L Carviel for creation of Figure 1 and Melissa A MacLeod, MSc, for guidance regarding referees' comments.

The Cochrane Skin Group editorial base wishes to thank Esther van Zuuren who was the Cochrane Dermatology Editor and Methods Editor for this protocol; Ben Carter who was the Statistical Editor; the clinical referee, Ignacio Garcia-Doval; and the consumer referee, David Potter.

Appendices

Appendix 1. Draft search strategy for MEDLINE (OVID)

1. exp Onychomycosis/
2. ((fungal or fungus) adj4 (toenail$ or toe$ or nail$)).mp.
3. (ringworm adj4 (toenail$ or toe$ or nail$)).mp.
4. Onychomycos$.mp.
5. tinea unguium.mp.
6. or/1-5
7. randomized controlled trial.pt.
8. controlled clinical trial.pt.
9. randomized.ab.
10. placebo.ab.
11. clinical trials as topic.sh.
12. randomly.ab.
13. trial.ti.
14. 7 or 8 or 9 or 10 or 11 or 12 or 13
15. exp animals/ not humans.sh.
16. 14 not 15
17. 6 and 16

[Lines 7-16: Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE: sensitivity- and precision-maximizing version (2008 revision)]

Contributions of authors

KF was the contact person with the editorial base.
AKG co-ordinated the contributions from the co-authors and wrote the final draft of the protocol.
FS, DD, and EV worked on the methods sections.
AKG, FS, and KF drafted the clinical sections of the background and responded to the clinical comments of the referees.
AKG, DD, and EV responded to the methodological and statistical comments of the referees.
AKG, FS, and DD contributed to writing the protocol.
DJ was the consumer co-author and checked the protocol for readability and clarity. He also ensured that the outcomes are relevant to consumers.
AKG is the guarantor of the final review.

Disclaimer

This project was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to the Cochrane Skin Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.

Declarations of interest

Aditya Gupta, Deanne Daigle, Kelly Foley, and Fiona Simpson are employed by Mediprobe Research Inc. Mediprobe Research Inc. is not a commercial organization, nor is it a contract research organization.

In addition to Dr Gupta's dermatology practice, he conducts clinical trials and these are done through Dr AK Gupta Medicine Professional Corporation, previously known as Mediprobe Research. In Canada, all physicians work through Professional Corporations, and Dr Gupta does the same. Mediprobe Research is the name we continue to use because we have done so for years, but the official corporate entity is Dr AK Gupta Medicine Professional Corporation. We have not conducted clinical trials for tinea pedis in the past three years, and Dr Gupta is currently recruiting for a trial using a plasma-based device for use in onychomycosis.

Elmer Villanueva: nothing to declare.
Denny John: nothing to declare.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • The National Institute for Health Research (NIHR), UK.

    The NIHR, UK, is the largest single funder of the Cochrane Skin Group.

Ancillary