Efficacy and Safety of Efinaconazole 10% Solution in the Treatment of Onychomycosis in Diabetic Patients
Phase: PHASE3
Conditions: Onychomycosis
Sponsor: Western University of Health Sciences

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Efficacy and Safety of Efinaconazole 10% Solution in the Treatment of 
Onychomycosis in Diabetic Patients
NCT03168841
5/23/17

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1. INTRODUCTION
                                   
           
1.1 Background 
            
1.2 Potential Pharmacotherapy 
            
1.3 Efinaconazole Description
1.4 Efinaconazole Safety and Adverse Effects
1.5 Efinaconazole Indications
2. STUDY DESIGN
2.1 Study Objective
2.2 Treatment Groups
2.3 Study Duration
2.4 Study Endpoints
   2.4.1 Primary Endpoints
   2.4.2 Secondary Endpoints
   2.4.3 Safety Endpoints
2.5 Measurement Methods
3. POTENTIAL ADVERSE EVENTS AND BENEFITS
3.1 Adverse effects of Efinaconazole
3.2 Benefits of Study
4. SUBJECT SELECTION
4.1 Informed Consent/Screening Visit
   4.1.1 Medical History Screening
   4.1.2 Physical Assessment Screening
      4.1.2.A Test for Acute Charcot Neuroarthropathy
      4.1.2.B Test for Peripheral Neuropathy
      4.1.2.C Preliminary Lab Tests
      4.1.2.D Dental Health Screening
4.2 Inclusion Criteria
4.3 Exclusion Criteria
4.4 Method of Subject Assignment to Treatment Groups
5. STUDY PROCEDURES
5.1 Initial Visit
   5.1.1 Enrollment
   5.1.2 Medical History
   5.1.3 Physical Examination
   5.1.4 Laboratory Procedures
   5.1.5 Radiographic Procedures
   5.1.6 Adverse Events Pre-screen
   5.1.7 Treatment
5.2 Follow-up Visits
   5.2.1 Medical History
   5.2.2 Physical Examination
   5.2.3 Laboratory Procedures 
   5.2.5 Adverse Events

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   5.2.6 Treatment 
5.3 Administration of Efinaconazole Methods  
   5.3.1 Storage and Handling of Efinaconazole 
   5.3.2 Subject Education
   5.3.3 Subject Compensation     
6. SUBJECT COMPLETION OR DISCONTINUATION
6.1 Subject Completion
6.2 Subject Discontinuation
6.3 Early Termination Appointment
7. SAFETY ASSESSMENT
7.1 Safety Evaluation
7.2 Adverse Events
   7.2.1 Adverse Events Causality 
7.3 Serious Adverse Events
7.4 Documentation and Reporting of Adverse Events 
8. SUBJECT PROTECTION REQUIREMENTS
9. REGULATORY REQUIREMENTS
10. RESPONSIBILITIES OF THE INVESTIGATORS
10.1 Obtaining Subject Informed Consent
10.2 Subject Confidentiality 
10.3 Access to Data/Documents
10.4 Product Delivery, Storage, and Returns 
10.5 Data Handling 
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INTRODUCTION

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1.1 Background 
Onychomycosis, a common pathology of the toenails, is even more prevalent among diabetic 
subjects. Nearly 26 million Americans suffer from diabetes, and approximately one-third of 
subjects with diabetes have toenail onychomycosis. Numerous studies have addressed the 
efficacy and safety of both topical and oral antifungal treatment options for onychomycosis in 
diabetic subjects. However, no study to date has specifically addressed the efficacy and safety 
of efinaconazole among diabetic subjects.
1.2 Potential Pharmacotherapy
Despite the existence of numerous topical antifungal agents for onychomycosis, data 
investigating the efficacy of topical antifungal agents among exclusively diabetic patient cohorts 
is limited. Ciclopirox 8% was evaluated in 2007 as a topical solution among a cohort 49 diabetic 
subjects. The study witnessed clinical improvement in 63.4% of subjects, with 54.3% attaining 
mycologic cure (Brenner et al., 2007). An earlier, 2001 study of ciclopirox 8% solution 
summarized the results of a 215-person diabetic subset of subjects. This study was 
observational, noncomparative, and uncontrolled, thereby limiting the usefulness of the data. 
The study reported that the mean affected nail area decreased from 64.3% to 25.7% after 6 
months of treatment (Seebacher, 2001). 
1.3 Efinaconazole 10% Solution Description
Efinaconazole 10% solution is a new triazole antifungal agent. The medication was developed 
specifically for the topical treatment of distal and lateral subungual onychomycosis (DLSO) (
Gupta, 2014). The medication was developed with consideration of the existing triazole 
antifungals itraconazole and fluconazole, with the formulation developed to more effectively 
penetrate the nail plate. The preparation was further enhanced with the development of nail 
lacquers to avoid product build-up and to reduce removal time. The solution is, specifically, an 
inhibitor of sterol 14alpha-demethylase (14-DM) (Tatsumi, 2013). In broth dilution tests in vitro, 
the solution was found to be more potent against reference strains than other common 
antifungals, including terbinafine, ciclopirox, itraconazole, and amorolfine, (Jo Siu, 2013).
1.4 Efinaconazole Safety and Adverse Effects
The safety of efinaconazole has been document in both Phase II and Phase III trials. Treatment 
associated adverse events have been relatively frequent by incidence, but of low morbidity and 
of frequency similar to vehicle alone. Two phase III studies noted rates for a single adverse 
event during treatment to be similar between efinaconazole to vehicle: in one study, 66% versus
61%, and in the second study, 64.5% versus 58.5% (Elewski, 2013). These adverse events 
included contact dermatitis (2.9% versus 1.9%, 1.4% versus 1.0%), eczema (3.4% versus 3.3%,
information not available in the second study), application site dermatitis (3.5% versus 0.0%, 
information not available in the second study), and application site vesicles (2.0% versus 0.0%, 
information not available in the second study). Discontinuation of the study as a result of 
adverse events was low, with 3.2% of treatment versus 0.5% of vehicle in the first study and 1.
9% versus 0.0% in the second.
An additional study investigated if efinaconazole had a relationship with contact sensitization (
Del Rosso, 2013). The study involved nine applications of efinaconazole 10% solution versus 

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vehicle over a three week period, with multiple follow-up applications three weeks later. The 
study concluded that the cumulative irritation scores were comparable between efinaconazole 
and vehicle alone.
1.5 Efinaconazole Indications
It is currently indicated for onychomycosis of the toenails (s) due to:
●
Trichophyton rubrum
●
Trichophyton mentagrophytes 
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STUDY DESIGN 
2.1 Study Objective

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The objective of this noncomparative, uncontrolled study is to determine the efficacy of topical 
efinaconazole 10% for toenail onychomycosis among subjects with diabetes mellitus. Specific 
indicators to measure efficacy of treatment will be the mycological cure rate, complete cure rate, 
and treatment success. Furthermore, an additional goal of the study is to gain knowledge of safety 
in the setting of a cohort of diabetic subjects. Safety will be determined by the incidence and nature 
of treatment associated adverse events. These will be recorded at each follow-up visit. 
2.2 Treatment Groups 
Adult subjects (18 years or older) with a medical history of controlled type 2 diabetes mellitus will be
considered for enrollment. Subjects will be eligible for enrollment if a clinical diagnosis of distal 
onychomycosis involving at least 20% of one great toenail (GT) has been made and confirmed by 
nail biopsy. There will be no restriction based on nail involvement; up to 100% of the nail may be 
involved. Furthermore, there will be no restriction based on toenail plate thickness. The enrollment 
period will be continued until 48 intention-to-treat subjects have been enrolled in the study.
2.3 Study Duration
The intended enrollment period will be six months, though this may be extended if necessary to  
achieve 48 intention-to-treat subjects. The treatment period, following enrollment, will be 50 weeks 
in duration. The intended total study duration, then, will be 76 weeks.
2.4 Efficacy Endpoints
Mycological cure will be defined as negative KOH examination and negative fungal culture of the 
target toenail sample.  
Clinical cure will be defined as 0% clinical involvement of the target toenail. Almost clinical cure 
will be defined as ≤10% clinical involvement of the target toenail.  
Complete cure will be defined as 0% clinical involvement and mycological cure. Treatment 
success will be defined as ≤10% clinical involvement of the target toenail and mycological cure. 
2.4.1 Primary Endpoints
1. The primary efficacy end point will be the proportion of subjects achieving complete cure at week 
50.
2.4.2 Secondary Endpoints
1. The secondary efficacy end points will include mycological cure rate, treatment success rate, 
clinical cure rate, and almost clinical cure rate.
2.4.3 Safety Endpoints
1. Type of Adverse Events
2. Frequency of Adverse Events
2.5 Measurement Methods
At each study visit, the treating podiatrist will visually and physically assess subjects.
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POTENTIAL RISKS AND BENEFITS
3.1 Adverse effects of Efinaconazole 

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The following are documented adverse effects of efinaconazole 10% solution, from a large two-armed 
study (Elewski, 2013):
Study 1
Study 2
N (%)
Efinaconazole (N =
 653)
Vehicle (N =
 213)
Efinaconazole (N =
 574)
Vehicle (N =
 200)
No. of subjects who reported at least 1 
TEAE
431 (66.0%)
130 (61.0%)
370 (64.5%)
117 (58.5%)
Individual TEAEs reported by >2% of subjects in at least 1 study
 Application site dermatitis
23 (3.5%)
0 (0.0%)
-
-
 Application site vesicles
13 (2.0%)
0 (0.0%)
7 (1.2%)
0 (0.0%)
 Arthralgia
13 (2.0%)
7 (3.3%)
18 (3.1%)
2 (1.0%)
 Back pain
16 (2.5%)
6 (2.8%)
19 (3.3%)
7 (3.5%)
 Blood creatinine phosphokinase 
increased
-
-
11 (1.9%)
5 (2.5%)
 Bronchitis
8 (1.2%)
4 (1.9%)
14 (2.4%)
3 (1.5%)
 Contact dermatitis
19 (2.9%)
4 (1.9%)
8 (1.4%)
2 (1.0%)
 Eczema
22 (3.4%)
7 (3.3%)
-
-
 Folliculitis
5 (0.8%)
5 (2.3%)
-
-
 Headache
15 (2.3%)
5 (2.3%)
25 (4.4%)
7 (3.5%)
 Hypertension
17 (2.6%)
10 (4.7%)
11 (1.9%)
5 (2.5%)
 Influenza
16 (2.5%)
8 (3.8%)
10 (1.7%)
1 (0.5%)
 Ingrowing nail
17 (2.6%)
1 (0.5%)
11 (1.9%)
2 (1.0%)
 Nasopharyngitis
78 (11.9%)
25 (11.7%)
63 (11.0%)
15 (7.5%)
 Procedural pain
10 (1.5%)
7 (3.3%)
6 (1.0%)
0 (0.0%)
 Sinusitis
30 (4.6%)
4 (1.9%)
17 (3.0%)
5 (2.5%)
 Tinea pedis
7 (1.1%)
6 (2.8%)
4 (0.7%)
6 (3.0%)
 Upper respiratory tract infection
38 (5.8%)
13 (6.1%)
35 (6.1%)
11 (5.5%)
 Urinary tract infection
12 (1.8%)
8 (3.8%)
12 (2.1%)
2 (1.0%)
TEAE, Treatment-emergent adverse event.
Subjects will be advised to contact study coordinators if they notice signs of any of the aforementioned 
adverse effects. 
3.2 Contraindications to Efinaconazole administration
●
Known hypersensitivity to efinaconazole
3.3 Benefits of Study 
The potential benefits of treating onychomycosis have been well-documented; these benefits are only 
heightened in the setting of diabetes mellitus.  A recent report investigated the impact of successful 
treatment with efinaconazole 10% solution among a group of subjects with onychomycosis. The study 
found a statistically greater improvement in all investigated aspects of quality of life compared to a 
controlled vehicle group (Tosti, 2014). Furthermore, the risk profile of the topical medication have been 
documented and represent qualitatively small levels of risk.
It is believed that the potential benefits of this study outweigh the potential risks.
4
SUBJECT SELECTION

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Prior to enrollment, an informed consent must be obtained. Eligibility will be determined by the 
established inclusion and exclusion criteria. Assuming a 50% screen rate, it is anticipated that a total
of 96 subjects will need to be screened to reach 48 intention-to-treat subjects. Using an estimate of 
55% for mycologic cure, 48 subjects will yield a 95% confidence interval of 0.281. 
4.1 Informed Consent/Screening Visit
Subjects will complete a written informed consent prior to enrollment. This will be administered by the 
investigators at the study site in the patient’s preferred language (English or Spanish). The informed 
consent must be signed and dated. Each subject will be assigned a number in ascending order 
beginning from 01. A screening log of all the subjects will be obtained for each written informed consent
. The screening log includes: screening number, first and last name, age, gender, eligibility status or 
reason for ineligibility. This information will be stored in a locked security box, and kept in a locked 
cabinet at the Arrowhead Regional Medical Center. This will be accessible only by specifically 
designated study personnel. 
4.1.1 Medical History Screening
Subject eligibility will be determined by the inclusion/exclusion criteria. Record if the subject does or 
does not meet the criteria.
1. Record date of visit, subject enrollment number, and subject initials
2. Verify subject eligibility based on inclusion and exclusion criteria. Adherence to criteria will be 
noted.
3. Record subject demographics, including date of birth, gender, race, and weight, and if there were
any treatments attempted prior to enrollment.
4.1.2 Physical Assessment Screening
Subject eligibility will be determined by the inclusion and exclusion criteria. Subject adherence to 
inclusion or exclusion criteria will be recorded. Screening will include reviewing and obtaining 
informed consent, reviewing inclusion/exclusion criteria, and the initial (complete) physical 
examination.
4.1.2.A Criteria for Diagnosis of Onychomycosis
To establish diagnosis, a positive potassium hydroxide (KOH) wet mount is required, along with a 
fungal culture positive for a dermatophyte species.
4.2 Inclusion Criteria
To be considered for inclusion, clinical diagnosis will need to be confirmed through positive KOH 
stain or positive mycologic culture findings. Involvement of at minimum 20% of the target great 
toenail will be required for inclusion. A negative pregnancy screen will be required among women 
of child-bearing age. These women will be required to be on oral contraceptive throughout the 
study duration. 
Subjects will be recruited from Arrowhead Regional Medical Center. 
4.3 Exclusion Criteria
Subjects will be excluded if any of the following exclusion criteria are met: 

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•
Diagnosis of a nondermatophyte fungus infection, diagnosis of proximal subungual 
onychomycosis, diagnosis of superficial white onychomycosis 
•
Diagnosis of peripheral arterial disease or anatomic abnormalities of the target toenail
•
Inability to follow through with all requisite office visits 
•
Routine use of a systemic corticosteroid, routine use of a systemic immunomodulator, or 
history of systemic antifungals within the prior five years.
•
Active interdigital tinea pedis refractory to topical antifungal treatments
•
Known hypersensitivity to efinaconazole
•
Use, within the month preceding screening, of: topical antifungal agents, topical anti-
inflammatory agents to the toes
•
Any history of oral systemic antifungal with known activity against dermatophytes
4.4 Method of Subject Assignment to Treatment Groups
Subjects will be enrolled into the study after verification of eligibility according to the inclusion and 
exclusion criteria. Written informed consent will also be obtained from subjects. 
 
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STUDY PROCEDURES 

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5.1 Initial Visit
5.1.1 Enrollment 
        Refer to section 4. 
5.1.2 Medical History
1. Record date of visit, subject enrollment number, and subject initials.
2. Verify subject eligibility based on inclusion and exclusion criteria. Adherence to criteria will be 
noted.
5.1.3 Physical Examination 
●
The complete history and physical will be performed at screening. At the first visit, the 
examination will be limited to a problem focused examination.
●
Digital assessment of the great toe/planimetry.
●
Vital signs.
●
Clinical assessment of the toenails.
5.1.4 Procedures
 
5.1.5 Adverse Events Pre-screen
Subjects’ health status will be studied for the purpose of recording adverse events in the future. 
5.1.6 Treatment
•
Eligible subjects will be given efinaconazole 10% solution, and instructed to apply the solution to
the great toenail (GT). If more toenails are affected, the solution may be applied in the same 
manner to all affected toenails as directed by the investigator and desired by the patient. 
5.2 Follow-up Visits 
Subjects will be assessed at the screening, at baseline, and at every 10 weeks until week 50 (at 
weeks 10, 20, 30, 40, and 50). The final assessment (week 50) will include a complete history and 
physical examination, replacing the lower extremity focused physical examination.
5.2.1 Medical History
1. Date of visit, subject enrollment number, and subject initials will be recorded at each follow-up 
visit.
2. Subject eligibility will be verified based on inclusion and exclusion criteria. Adherence to criteria 
will be noted.
5.2.2 Physical Examination 
●
Digital assessment of the great toe/planimetry
●
Lower extremity focused physical examination for visits at weeks 10, 20, 30, 40. A 
complete history and physical examination at week 50. 

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●
Vital signs
●
Clinical assessment of the toenails
5.2.3 Procedures
•
KOH wet mount and fungal culture at final office visit
•
Additional safety laboratory studies will be ordered as needed
•
Debridement of target toenail 
•
Debridement of other toenails as needed
5.2.4 Adverse Events
●
Each follow-up visit will include careful monitoring for adverse events 
5.3 Administration of Efinaconazole Methods
All subjects will be self-administering the medication. All related questions will be answered and 
concerns addressed.
5.3.1 Storage and Handling of Efinaconazole 
Efinaconazole will be stored by the subjects themselves, without requirement of freezing or refrigeration
. 
5.3.2 Subject Education
Subjects will be informed of all beneficial and adverse effects of efinaconazole during the written and 
oral consent process (refer to sections 3.1 and 4)
5.3.3 Subject Compensation
Subjects will be compensated a stipend for each attended office visit following screening. The amount 
of compensation will be of reasonable amount, and not excessively large as to inappropriately motivate 
subjects.
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SUBJECT COMPLETION OR DISCONTINUATION

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6.1 Subject Completion
The subject will be considered to have completed the study after completed the week 50 follow-up 
evaluation.
6.2 Subject Discontinuation
The subject will be discontinued from the study if the subject withdraws, is withdrawn due to an adverse
event, or is no longer able to be located. Any reason for discontinuation must be documented along 
with information about the health of the subject at the time of withdrawal. All attempts to contact subject
must be documented. After 3 documented attempts of contact, the subject will be considered 
discontinued.
6.3 Early Termination Appointment
If the subject elects to discontinue the study prior to completion, the subject will be asked to attend an 
early termination appointment. This early termination appointment will replace the final office visit. It will 
include the procedures of a follow-up office visit, with the addition of a complete history and physical. 
Subjects will be provided increased, but not excessive, financial compensation as motivation for 
attending this appointment. 
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SAFETY ASSESSMENTS
A safety evaluation will be conducted at every visit. 

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7.1 Safety Evaluation
Safety will be assessed by recording the nature, intensity, and duration of treatment related adverse 
events. Safety analyses will be performed on both an intention-to-treat and per-protocol analysis basis. 
The intention-to-treat population will include each patient receiving at least one dose of the medication, 
with at least one post-baseline assessment.
7.2 Adverse Events
An adverse event may be any unintended clinical, radiographic, or laboratory result associated with the 
use of treatment modality. An adverse event does not necessarily have causal relationship with the 
treatment intervention. 
 
Information collected during subject screening serves to determine if an adverse event started before or
during the course of study and to monitor its progression throughout the course of the study. Follow-up 
evaluation and treatment will continue until the adverse event has resolved. 
7.2.2 Adverse Events Causality 
Adverse events will be assessed for causality. The event is considered related to the treatment 
intervention if there is a reasonable possibility that the treatment could have contributed to the event. 
Evidence supporting the relation between treatment and adverse event can be derived from scientific 
and medical facts, observation, and professional opinion.
7.3 Serious Adverse Events
An adverse event is considered serious if:
●
it results in death
●
it is life threatening 
●
it requires hospitalization 
●
it results in disability or incapacity 
●
it jeopardizes the health of the subject
7.4 Documentation and Reporting of Adverse Events
Adverse events will be documented. Serious adverse events will be completely reported to the study 
grant sponsor, the institutional review board (IRB), and to the University Compliance Office, within 24 
hours of becoming aware of the serious adverse event. 
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SUBJECT PROTECTION REQUIREMENTS
The Principal Investigator is required to provide an Institutional Review Board (IRB)/Ethics Committee 
with necessary materials. The study cannot commence until the IRB/Ethics Committee provides written 

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approval of the proposed pilot study. Appropriate reports of progress of this study will be provided to 
the IRB/Ethics Committee in agreement with the policy established by the grant sponsor. 
Changes to an approved protocol may only be made by the grant sponsor with IRB authorization, 
except in instances deemed necessary to eliminate immediate harm to the subjects or when the 
change involves only administration or logistics.
Significant deviation from the protocol without appropriate approval will be regarded as a protocol 
violation.
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REGULATORY REQUIREMENTS
This study will be conducted in accordance with the principles consistent with Good Clinical Practice (
GCP).

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RESPONSIBILITIES OF THE INVESTIGATORS
10.1 Obtaining Subject Informed Consent
Information about the study in a language fully understandable by the eligible subject (English or 
Spanish) will be given in written and oral form by the investigator. It will be explained to subjects that 
they are free to refuse entry into the study and free to withdraw at any time. Written consent forms will 

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be approved by the grant sponsor. The original consent form is placed in the subject’s study records 
and a copy is provided to the subject.
10.2 Subject Confidentiality
The investigators will ensure that privacy of all subjects is maintained. Investigators will assure subjects
that their personal identity and all personal medical information will be safeguarded. In all documents 
submitted to the sponsor, subjects will be identified by a unique identification code. All personal medical
information will always be treated as confidential and in compliance with HIPAA regulations. 
10.3 Access to Data/Documents
The investigators will have access to data and documents obtained from subjects during the course of 
the study. Personal medical information may be studied for the purpose of verifying data recorded and 
subject eligibility and is only accessible to the investigators
10.4 Product Delivery, Storage, and Returns 
The investigator is responsible for ensuring that deliveries of all material involved with the study are 
correctly received and handled. Materials will be properly labeled and safely stored. All unopened 
materials will be returned to the study grant sponsor.
10.5 Data Handling 
All data collected will be included in a report to be submitted to the study grant sponsor. The data will 
be scanned and sent through secure electronic mail (e-mail). The report will be legible. Any errors will 
be corrected with a single line strike-through that does not obscure the original entry and annotated 
with the investigator’s initials and current date. No data will be withheld from the report and any missing
data will be noted with the reason for why it is missing. Frequency of case report submissions to the 
grant sponsor will be decided between the investigator and grant sponsor.
REFERENCES
1) Brenner MA1, Harkless LB, Mendicino RW, Page JC. Ciclopirox 8% nail lacquer topical solution for 
the treatment of onychomycosis in subjects with diabetes: a multicenter, open-label study. J Am Podiatr
Med Assoc. 2007 May-Jun;97(3):195-202. 
2) Seebacher C1, Nietsch KH, Ulbricht HM. A multicenter, open-label study of the efficacy and safety of
ciclopirox nail lacquer solution 8% for the treatment of onychomycosis in subjects with diabetes. Cutis. 

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2001 Aug;68(2 Suppl):17-22.
3) Gupta AK1, Simpson FC. Efinaconazole: a new topical treatment for onychomycosis. Skin Therapy 
Lett. 2014 Jan-Feb;19(1):1-4.
4) Tatsumi Y, Nagashima M, Shibanushi T, et al. Mechanism of action of efinaconazole, a novel 
triazole antifungal agent. Antimicrob Agents Chemother. 2013 May;57(5):2405-9.
5) Jo Siu WJ, Tatsumi Y, Senda H, et al. Comparison of in vitro antifungal activities of efinaconazole 
and currently available antifungal agents against a variety of pathogenic fungi associated with 
onychomycosis. Antimicrob Agents Chemother. 2013 Apr;57(4):1610-6. 
6) Elewski BE, Rich P, Pollak R, et al. Efinaconazole 10% solution in the treatment of toenail 
onychomycosis: Two phase III multicenter, randomized, doubleblind studies. J Am Acad Dermatol. 
2013 Apr;68(4):600-8.
7) Del Rosso JQ, Reece B, Smith K, et al. Efinaconazole 10% solution: a new topical treatment for 
onychomycosis: contact sensitization and skin irritation potential. J Clin Aesthet Dermatol. 2013 Mar;6(
3):20-4.
8) Tosti A, Elewski BE. Treatment of onychomycosis with efinaconazole 10% topical solution and 
quality of life. J Clin Aesthet Dermatol. 2014 Nov;7(11):25-30.