Efficacy of Fractional CO2 laser as adjunct treatment for Onychomycosis: An Intra-individual, Open-label, Randomized Controlled Trial

Study Title

Efficacy of Fractional CO2 Laser as adjunct treatment for Onychomycosis An Intra individual Open Label Randomized Controlled Trial

Rationale

Onychomycosis is a chronic fungal nail infection commonly caused by dermatophytes non dermatophyte molds and yeasts. Standard treatments include systemic antifungals itraconazole terbinafine fluconazole. Topical agents ciclopirox or amorolofine nail lacquer are recommended as monotherapy in mild onychomycosis as combination therapy or as maintenance therapy. Nevertheless low cure rates and high rates of recurrence are known. Fractional CO2 laser therapy a novel adjunct therapy for onychomycosis helps by creating micro channels in the nail plate enhancing drug penetration. It also exerts thermal effects on fungal elements and stimulates nail repair. Preliminary studies suggest that laser assisted drug penetration can improve treatment outcomes and reduce recurrences. However controlled trials with standard recommended therapy for onychomycosis are missing. This study aims to evaluate the efficacy of fractional CO2 laser in improving nail outcomes in patients on combination antifungal therapy potentially offering an effective multimodality strategy for managing onychomycosis.

Aim

To assess the efficacy of fractional CO2 laser in improving cure rates in onychomycotic nails of patients on combination antifungal therapy systemic plus topical

Primary Objective

To compare the decline in Onychomycosis Severity Index OSI score between nails treated with fractional CO2 laser as compared to laser untreated nails in patients with onychomycosis on combination antifungal therapy systemic itraconazole plus topical ciclopirox 8 percent nail lacquer

Secondary Objectives

1 To evaluate and compare the mycological cure rates between the two groups at 6 months of treatment

2 To evaluate and compare recurrence rates between the two groups at 6 months of post treatment follow up

3 To evaluate clinical improvement based on Physician Global Assessment PGA scale

4 To evaluate treatment related adverse effects

5 To correlate the treatment response with fungal species isolated

Study Setting

Departments of Dermatology and STD Microbiology and Pathology University College of Medical Sciences and Guru Teg Bahadur Hospital Delhi

Study design

Intra individual open label randomized controlled trial

Sampling method

Simple randomization

Informed consent

Informed written consent will be taken from patients prior to initiating therapy after explaining the study protocol

Study duration

August 2025 to November 2026

Study participants

Adult patients with clinically suspected primary onychomycosis visiting Dermatology OPD

Inclusion criteria

1 Confirmed diagnosis of onychomycosis based on at least 2 of 4 investigations being positive onychoscopy direct microscopy fungal culture and nail clipping for PAS staining

2 Moderate to severe onychomycosis involving at least two nails based on OSI score

3 Normal kidney and liver function

4 Consenting to adhere to the study protocol and complete the requisite follow up

Exclusion criteria

1 Pregnant and lactating ladies

2 Presence of liver disease renal impairment or cardiac disease

3 History of recent systemic or topical antifungal treatment within the past 3 months or 1 month respectively

4 Secondary onychomycosis

5 Uncontrolled diabetes or immunocompromised status

6 Active bacterial or viral infections around nail

7 History of hypersensitivity to the systemic and or topical drugs

Sample size

The minimum sample size was estimated based on a study by Ranjan et al 2023 which reported the outcome of interest in two interest groups. Using a two tailed alternative hypothesis a significance level of 5 percent power of 99 percent and equal allocation between groups and assuming a standard deviation of 5 the calculated minimum sample size was 24 participants 12 in each group. Based on available resources feasibility time and to accommodate for attrition we have decided to enroll a minimum of 30 participants

Methods

The study will commence after obtaining clearance from the Institutional Ethics Committee. An informed written consent will be taken from all participants after explaining the study protocol.

For all patients with suspected primary onychomycosis a complete history will be taken and a thorough muco cutaneous examination including all 20 nails will be done under good lighting. The findings will be recorded in the pre designed case record form. Clinical pictures will be stored in jpeg format. The specific changes seen in the nails will be recorded. This will be followed by onychoscopy of all nails to identify features in favor of onychomycosis. These images will also be stored.

This will be followed by nail clippings for direct microscopy and fungal culture taken from the most representative nail. Nail plate biopsy nail clippings more than 4 mm in size will be processed for histopathological examination and PAS staining. A complete hemogram blood sugar estimation and estimation of liver and kidney function will be done for all participants

For patients confirmed to have onychomycosis at least 2 of the above 4 tests reported positive involving at least two nails the severity will be recorded for each affected nail as OSI score. The affected nails will be then randomized into 2 groups. In the first patient group A and B will be decided by lottery method then alternated in subsequent patients. In each patient among the total number of affected nails the right or left half of nails will be assigned to Group A and the other half to Group B to receive treatment as follows

Group A Standard therapy

Oral Itraconazole 200 mg BID 1 week per month 2 or 3 pulses for fingernails or 3 or 4 pulses for toenails

Ciclopirox 8 percent nail lacquer applied daily

Group B Intervention group

Standard therapy as above

Fractional CO2 laser every 4 weeks for a maximum of 6 months

Treatment end point

6 months

Follow up duration

6 months of follow up with continuing ciclopirox application

Treatment Monitoring

OSI scoring will be done at baseline and every 4 weeks till 12 months end of follow up

Local adverse effects including pain changes in surrounding skin and discoloration of nail plate will be recorded at each session

Renal and liver function tests will be done at baseline at 1 month and at 3 months. Patients with significant derangement or any severe drug reaction will be withdrawn from therapy

Mycological testing direct microscopy and fungal culture will be done at baseline treatment end point 6 months and follow up end point 12 months. It will also be done for nails where an increase in OSI will be seen during follow up period

Evaluation of clinical improvement by 2 independent physicians as per Physician Global Assessment scale will be done at treatment end point 6 months and follow up end point 12 months

Outcome measures

Primary outcome measure Significance of difference in the decline in OSI score between laser treated and laser untreated nails

Secondary outcome measures

1 Difference in mycological cure rates between the two groups at treatment end point 6 months

2 Difference in recurrence rates between the two groups at follow up end point 12 months

3 Difference in Physician Global Assessment scale in both groups at 6 months and 12 months

4 Frequency of treatment related adverse effects

5 Correlation of mycological cure rates and recurrence rates with the etiological fungi

Statistical analysis

All data will be managed using Microsoft Excel. Quantitative data will be presented as mean plus or minus standard deviation SD while qualitative data will be expressed as frequency and percentage. The normality of continuous variables will be assessed using the Kolmogorov Smirnov test. Based on the distribution of the data either Pearsons correlation coefficient for normally distributed data or Spearmans rank correlation coefficient for non normally distributed data will be used to evaluate correlations between continuous variables.

Comparisons between two independent groups will be performed using the independent t test for normally distributed data or the Mann Whitney U test for non normally distributed data. Survival curves for the event of interest recurrence of infection will be constructed using the Kaplan Meier method and log rank test will be applied to assess significant differences between the survival curves. A p value less than 0.05 will be considered statistically significant. All analyses will be two tailed and will be conducted using IBM SPSS Statistics software