An Evaluation of the Safety and Pharmacokinetics of Tavaborole Topical Solution for the Treatment of Fungal Disease of the Toenail in Children and Adolescents

An Open-label Study To Evaluate The Safety, Tolerability, And Pharmacokinetics Of Kerydin (Registered) (Tavaborole) Topical Solution, 5% In The Treatment Of Onychomycosis Of The Toenail In Pediatric Subjects Ages 6 To 16 Years And 11 Months

This was an open-label study to evaluate the safety and pharmacokinetics of tavaborole 5% topical solution in treating distal subungual onychomycosis (a fungal infection) of the toenail in children and adolescents (ages 6 to 16 years).

Following confirmation of eligibility, including laboratory evidence of a fungal organism in the toenail, tavaborole topical solution was applied once daily to all affected toenails for a 48-week treatment period.

Clinical assessment of the extent of infection and safety assessments were performed periodically throughout the 48-week treatment period, and again at 52 weeks (4 weeks after stopping the treatment).

A subgroup of enrolled subjects applied the topical solution to all 10 toenails and a small area of surrounding skin during the first 28 days. These subjects had blood samples analyzed to evaluate the pharmacokinetics (how the drug moves in the body) of tavaborole topical solution in children and adolescents.

Study Overview

• Status: Completed
• Conditions: Onychomycosis; Tinea Unguium
• Intervention / Treatment: Drug: Tavaborole 5% Topical Solution

Detailed Description

This was an open-label study to evaluate the safety, tolerability, and pharmacokinetics of tavaborole 5% topical solution in treating distal subungual onychomycosis (DSO) of the toenail in pediatric subjects aged 6 to 16 years and 11 months. An eligible subject had a target great toenail (TGT) with at least 20% involvement, with a positive potassium hydroxide (KOH) wet mount and positive fungal culture for T. rubrum or T. mentagrophytes.

Eligible subjects applied tavaborole 5% topical solution, once daily to all affected toenails (the TGT as well as all other toenails having the clinical characteristics of onychomycosis) throughout the 48 week treatment period.

Subjects were evaluated at Screening, Baseline (Day 1), and at Weeks 2, 4, 8, 16, 24, 32, 40, 48, and 52. Each evaluation included a clinical assessment of the AEs and local tolerability evaluation.

Additional procedures were performed as follows:

• Mycology sampling at Screening, Week 24, and Week 52/early termination (ET);
• Clinical disease severity of the TGT at Screening, Week 24, and Week 52/ET;
• Safety laboratory testing at Baseline, Week 24, and Week 52/ET;

In this study, there was a PK subgroup of evaluable subjects aged 12 to 16 years and 11 months studied under maximal use conditions. Subjects in this maximal use subgroup applied the study drug on all 10 toenails, including up to 2 mm of the surrounding skin, for 28 days. On Day 15, a predose PK sample was collected to assess steady state trough level. On Day 29, the study drug application was done at the study site, and PK samples were collected prior to dosing, as well as 4, 6, 8, and 24 hours postdose on Days 29 to 30.

• Study Type: Interventional
• Enrollment (Actual): 55
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • California
    • Madera, California, United States, 93637
      • Madera Family Medical Group
    • Palo Alto, California, United States, 94304
      • Stanford University School of Medicine
  • District of Columbia
    • Washington, District of Columbia, United States, 20016
      • MedStar Health Research Institute - MedStar Georgetown University Hospital
  • Florida
    • South Miami, Florida, United States, 33143
      • Doctors Research Network
  • New York
    • Brooklyn, New York, United States, 11203
      • University Hospital, SUNY Downstate Medical Center
    • New York, New York, United States, 10155
      • Skin Specialty Dermatology
  • Oregon
    • Gresham, Oregon, United States, 97030
      • Cyn3rgy Research
    • Portland, Oregon, United States, 97210
      • Oregon Dermatology & Research Center
  • Texas
    • Houston, Texas, United States, 77055
      • West Houston Clinical Research Services LLC
    • San Antonio, Texas, United States, 78218
      • Texas Dermatology and Laser Specialists
  • Utah
    • West Jordan, Utah, United States, 84088
      • Jordan Valley Dermatology Center
  • Virginia
    • Burke, Virginia, United States, 22015
      • PI Coor Clinical Research, LLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 16 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• males or females, ages >/= 6 years and </= 16 years and 11 months
• clinical diagnosis of distal subungual onychomycosis affecting at least 20% of one of the great toenails (target nail); and with positive KOH and positive culture for T. rubrum or T. mentagrophytes from either great toenail

Exclusion Criteria:

• the target toenail has proximal subungual onychomycosis, onychomycosis involving the nail lunula, superficial white onychomycosis, dermatophytoma, exclusively lateral disease, or yellow or brown spikes, or has co-infection with certain fungi or molds
• anatomic abnormalities of the toes or toenail
• current or past history of chronic moccasin-type tinea pedis
• current or past history of psoriasis or lichen planus
• history of significant chronic fungal disease (other than onychomycosis)
• diabetes
• immunodeficiency

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tavaborole 5% Topical Solution; All study participants apply study drug	Drug: Tavaborole 5% Topical Solution; topical solution for application to toenails; Other Names: Kerydin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Local Tolerability Reactions by Severity	Local tolerability reactions consisted of burning/stinging, induration/edema, oozing and crusting, pruritus, erythema, and scaling. Here 0 indicates None, 1 (Mild), 2 (Moderate) and 3 (severe). Grading details are as follows: Burning/Stinging (0: no stinging/burning, 1: slight warm, 2: definite warm, 3: hot); Induration/Edema (0: no elevation, 1: barely perceptible elevation, 2: clearly perceptible elevation but not extensive, 3: marked and extensive elevation); Oozing and Crusting (0: absent, 1: faint signs of oozing, 2: definite oozing, 3: marked and extensive oozing); Pruritus (0: no pruritus, 1: occasional, slight itching, 2: constant itching which is not disturbing sleep, 3: severe bothersome itching/scratching which is disturbing sleep); Erythema (0: no redness present, 1: faintly detectable erythema; very light pink, 2: dull red, 3: deep/dark red); Scaling (0: no scaling, 1: barely perceptible shedding, 2: obvious but not profuse scaling, 3: heavy scale production).	Baseline up to Week 52
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. AEs included both serious and non-serious AEs.	Baseline up to 28 days after last dose of study drug (up to Week 52)
Number of Participants With Adverse Events (AEs) By Severity	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AEs were classified as mild, moderate and severe based on severity assessment by investigator and defined as: Mild = symptoms barely noticeable to the participant or does not make the participant uncomfortable; moderate = symptoms of a sufficient severity to make the participant uncomfortable; severe = symptoms of a sufficient severity to cause the participant severe discomfort.	Baseline up to 28 days after last dose of study drug (up to Week 52)
Change From Baseline in Hematology Parameters (Leukocytes: Basophils, Eosinophils, Lymphocytes, Monocytes and Neutrophils) at Week 24		Baseline, Week 24
Change From Baseline in Hematology Parameters (Leukocytes: Basophils, Eosinophils, Lymphocytes, Monocytes and Neutrophils) at Week 52		Baseline, Week 52
Change From Baseline in Hematology Parameter (Hematocrit) at Week 24		Baseline, Week 24
Change From Baseline in Hematology Parameter (Hematocrit) at Week 52		Baseline, Week 52
Change From Baseline in Hematology Parameter (Erythrocytes) at Week 24		Baseline, Week 24
Change From Baseline in Hematology Parameter (Erythrocytes) at Week 52		Baseline, Week 52
Change From Baseline in Hematology Parameters (Hemoglobin) at Week 24		Baseline, Week 24
Change From Baseline in Hematology Parameters (Hemoglobin) at Week 52		Baseline, Week 52
Change From Baseline in Hematology Parameters (Leukocytes and Platelets) at Week 24		Baseline, Week 24
Change From Baseline in Hematology Parameters (Leukocytes and Platelets) at Week 52		Baseline, Week 52
Change From Baseline in Chemistry Parameters (Alanine Aminotransferase, Alkaline Phosphatase and Aspartate Aminotransferase) at Week 24		Baseline, Week 24
Change From Baseline in Chemistry Parameters (Alanine Aminotransferase, Alkaline Phosphatase and Aspartate Aminotransferase) at Week 52		Baseline, Week 52
Change From Baseline in Chemistry Parameters (Albumin and Protein) at Week 24		Baseline, Week 24
Change From Baseline in Chemistry Parameters (Albumin and Protein) at Week 52		Baseline, Week 52
Change From Baseline in Chemistry Parameters (Bilirubin, Creatinine, Glucose [Non-fasting] and Urea Nitrogen) at Week 24		Baseline, Week 24
Change From Baseline in Chemistry Parameters (Bilirubin, Creatinine, Glucose [Non-fasting] and Urea Nitrogen) at Week 52		Baseline, Week 52
Change From Baseline in Chemistry Parameters (Potassium and Sodium) at Week 24		Baseline, Week 24
Change From Baseline in Chemistry Parameters (Potassium and Sodium) at Week 52		Baseline, Week 52
Change From Baseline in Vital Sign (Blood Pressure) at Week 24		Baseline, Week 24
Change From Baseline in Vital Sign (Blood Pressure) at Week 52		Baseline, Week 52
Change From Baseline in Vital Sign (Pulse Rate) at Week 24	Pulse rate was defined as the number of pulsations noted in a peripheral artery per minute after participant rested supine for 5 minutes.	Baseline, Week 24
Change From Baseline in Vital Sign (Pulse Rate) at Week 52	Pulse rate was defined as the number of pulsations noted in a peripheral artery per minute after participant rested supine for 5 minutes.	Baseline, Week 52
Change From Baseline in Vital Sign (Respiratory Rate) at Week 24	Respiratory rate was defined as the number of inspirations per minute.	Baseline, Week 24
Change From Baseline in Vital Sign (Respiratory Rate) at Week 52	Respiratory rate was defined as the number of inspirations per minute.	Baseline, Week 52
Percentage of Participants With Complete Cure of Target Great Toenail (TGT) at Week 52	Complete cure was defined as completely clear nail, negative fungal culture and negative potassium hydroxide (KOH) wet mount.	Week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Observed Plasma Concentration (Cmax) of Tavaborole		Pre-dose, 4, 6, 8, 24 hours post-dose on Day 29
Time to Maximum Observed Plasma Concentration (Tmax) of Tavaborole		Pre-dose, 4, 6, 8, 24 hours post-dose on Day 29
Area Under the Plasma Concentration-Time Curve From Hour Zero to Hour 24 (AUC24) of Tavaborole	AUC24 was defined as the area under the plasma concentration-time curve from hour 0 to hour 24. AUC24 was calculated using the linear trapezoidal rule.	Pre-dose, 4, 6, 8, 24 hours post-dose on Day 29
Area Under the Plasma Concentration-Time Curve Extrapolated to Infinity (AUCinf) of Tavaborole		Pre-dose, 4, 6, 8, 24 hours post-dose on Day 29
Elimination Rate Constant of Tavaborole	Elimination rate constant was defined as the rate at which a drug was removed from the body.	Pre-dose, 4, 6, 8, 24 hours post-dose on Day 29
Elimination Half-Life of Tavaborole	Elimination half-life (t1/2) was defined as the time required for the body to eliminate half of the drug than its original concentration.	Pre-dose, 4, 6, 8, 24 hours post-dose on Day 29
Percentage of Participants With Almost Complete Cure of Target Great Toenail (TGT) at Week 24 and 52	Almost complete cure was defined as almost clear nail and negative mycology (negative mycology was defined as negative fungal culture and negative KOH wet mount).	Week 24, 52
Percentage of Participants With Clinical Efficacy of Target Great Toenail (TGT) at Week 24 and 52	Clinical efficacy target great toenail (TGT) was defined as completely clear nail or almost clear nail.	Week 24, 52
Percentage of Participants With Mycological Cure of Target Great Toenail (TGT) at Week 24 and 52	Mycological cure was defined as negative mycology of the TGT. Negative mycology was defined as negative fungal culture and negative potassium hydroxide (KOH) wet mount. Participants with only one result for either fungal culture or KOH were excluded from this analysis.	Week 24, 52
Percentage of Participants With Negative Fungal Culture of the Target Great Toenail (TGT) at Weeks 24 and 52		Week 24, 52

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

General Publications

• Rich P, Spellman M, Purohit V, Zang C, Crook TJ. Tavaborole 5% Topical Solution for the Treatment of Toenail Onychomycosis in Pediatric Patients: Results from a Phase 4 Open-Label Study. J Drugs Dermatol. 2019 Feb 1;18(2):190-195.

Study record dates

Study Major Dates

• Study Start (Actual): October 22, 2015
• Primary Completion (Actual): July 27, 2017
• Study Completion (Actual): July 27, 2017

Study Registration Dates

• First Submitted: January 3, 2018
• First Submitted That Met QC Criteria: January 12, 2018
• First Posted (Actual): January 23, 2018

Study Record Updates

• Last Update Posted (Actual): April 17, 2018
• Last Update Submitted That Met QC Criteria: March 19, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: Fungal infection of the nail
• Additional Relevant MeSH Terms: Skin Diseases; Infections; Bacterial Infections and Mycoses; Skin Diseases, Infectious; Mycoses; Tinea; Dermatomycoses; Nail Diseases; Onychomycosis; Anti-Infective Agents; Antifungal Agents; Tavaborole
• Other Study ID Numbers: TAV-ONYC-401; C3371003 (Other Identifier: Alias Study Number)