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

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.

• Tavaborole 5% Topical Solution (Drug), also known as Kerydin: topical solution for application to toenails

Primary outcomes

• Number of Participants With Local Tolerability Reactions by Severity [Baseline up to Week 52]: 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).
• Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [Baseline up to 28 days after last dose of study drug (up to Week 52)]: 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.
• Number of Participants With Adverse Events (AEs) By Severity [Baseline up to 28 days after last dose of study drug (up to Week 52)]: 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.
• 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 [Baseline, 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.
• Change From Baseline in Vital Sign (Pulse Rate) at Week 52 [Baseline, 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.
• Change From Baseline in Vital Sign (Respiratory Rate) at Week 24 [Baseline, Week 24]: Respiratory rate was defined as the number of inspirations per minute.
• Change From Baseline in Vital Sign (Respiratory Rate) at Week 52 [Baseline, Week 52]: Respiratory rate was defined as the number of inspirations per minute.
• Percentage of Participants With Complete Cure of Target Great Toenail (TGT) at Week 52 [Week 52]: Complete cure was defined as completely clear nail, negative fungal culture and negative potassium hydroxide (KOH) wet mount.

Secondary outcomes

• 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 [Pre-dose, 4, 6, 8, 24 hours post-dose on Day 29]: 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.
• 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 [Pre-dose, 4, 6, 8, 24 hours post-dose on Day 29]: Elimination rate constant was defined as the rate at which a drug was removed from the body.
• Elimination Half-Life of Tavaborole [Pre-dose, 4, 6, 8, 24 hours post-dose on Day 29]: Elimination half-life (t1/2) was defined as the time required for the body to eliminate half of the drug than its original concentration.
• Percentage of Participants With Almost Complete Cure of Target Great Toenail (TGT) at Week 24 and 52 [Week 24, 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).
• Percentage of Participants With Clinical Efficacy of Target Great Toenail (TGT) at Week 24 and 52 [Week 24, 52]: Clinical efficacy target great toenail (TGT) was defined as completely clear nail or almost clear nail.
• Percentage of Participants With Mycological Cure of Target Great Toenail (TGT) at Week 24 and 52 [Week 24, 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.
• Percentage of Participants With Negative Fungal Culture of the Target Great Toenail (TGT) at Weeks 24 and 52 [Week 24, 52]

Sex: All, ages: 72 Months to 203 Months

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

Participant flow

Outcome results

• Number of Participants With Local Tolerability Reactions by Severity (Primary), Count of participants, Participants: Kerydin 54
• Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) (Primary), Count of participants, Participants: Kerydin 30
• Number of Participants With Adverse Events (AEs) By Severity (Primary), Count of participants, Participants: Kerydin 12
• Change From Baseline in Hematology Parameters (Leukocytes: Basophils, Eosinophils, Lymphocytes, Monocytes and Neutrophils) at Week 24 (Primary), Mean, percentage of leukocytes: Kerydin 0.6 +/- 0.53
• Change From Baseline in Hematology Parameters (Leukocytes: Basophils, Eosinophils, Lymphocytes, Monocytes and Neutrophils) at Week 52 (Primary), Mean, percentage of leukocytes: Kerydin 0.1 +/- 0.60
• Change From Baseline in Hematology Parameter (Hematocrit) at Week 24 (Primary), Mean, volume percentage of red blood cells: Kerydin 42.04 +/- 3.460
• Change From Baseline in Hematology Parameter (Hematocrit) at Week 52 (Primary), Mean, volume percentage of red blood cells: Kerydin -0.12 +/- 1.838
• Change From Baseline in Hematology Parameter (Erythrocytes) at Week 24 (Primary), Mean, 10^12 cells per liter: Kerydin 4.786 +/- 0.4323
• Change From Baseline in Hematology Parameter (Erythrocytes) at Week 52 (Primary), Mean, 10^12 cells per liter: Kerydin -0.009 +/- 0.2004
• Change From Baseline in Hematology Parameters (Hemoglobin) at Week 24 (Primary), Mean, gram per deciliter (g/dL): Kerydin 13.79 +/- 1.138
• Change From Baseline in Hematology Parameters (Hemoglobin) at Week 52 (Primary), Mean, gram per deciliter (g/dL): Kerydin 0.06 +/- 0.637
• Change From Baseline in Hematology Parameters (Leukocytes and Platelets) at Week 24 (Primary), Mean, 10^9 cells per liter: Kerydin 7.11 +/- 1.723
• Change From Baseline in Hematology Parameters (Leukocytes and Platelets) at Week 52 (Primary), Mean, 10^9 cells per liter: Kerydin -0.62 +/- 1.940
• Change From Baseline in Chemistry Parameters (Alanine Aminotransferase, Alkaline Phosphatase and Aspartate Aminotransferase) at Week 24 (Primary), Mean, International Unit per liter (IU/L): Kerydin 14.6 +/- 8.23
• Change From Baseline in Chemistry Parameters (Alanine Aminotransferase, Alkaline Phosphatase and Aspartate Aminotransferase) at Week 52 (Primary), Mean, International Unit per liter (IU/L): Kerydin -1.6 +/- 11.32
• Change From Baseline in Chemistry Parameters (Albumin and Protein) at Week 24 (Primary), Mean, gram per deciliter (g/dL): Kerydin 4.49 +/- 0.250
• Change From Baseline in Chemistry Parameters (Albumin and Protein) at Week 52 (Primary), Mean, gram per deciliter (g/dL): Kerydin -0.08 +/- 0.375
• Change From Baseline in Chemistry Parameters (Bilirubin, Creatinine, Glucose [Non-fasting] and Urea Nitrogen) at Week 24 (Primary), Mean, milligram per deciliter (mg/dL): Kerydin 0.46 +/- 0.279
• Change From Baseline in Chemistry Parameters (Bilirubin, Creatinine, Glucose [Non-fasting] and Urea Nitrogen) at Week 52 (Primary), Mean, milligram per deciliter (mg/dL): Kerydin -0.01 +/- 0.155
• Change From Baseline in Chemistry Parameters (Potassium and Sodium) at Week 24 (Primary), Mean, millimole per liter (mmol/L): Kerydin 4.25 +/- 0.404
• 18 more outcome measures not shown.

Adverse events

Time frame: Baseline up to Week 52

Serious adverse events by term

Other adverse events by term

• Results publication: 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. PMID 30811142

• Study Protocol (PDF, 2016-03-28)
• Statistical Analysis Plan (PDF, 2017-06-02)

• Pfizer CT.gov Call Center, Study director, Pfizer