Conditions: Onychomycosis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 30
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the efficacy, safety and tolerability of HTS-519 Inserts in the treatment of mild to moderate toenail fungus disease of the big toenail.

Detailed description:
Open label, single-site

Arms:
arm 1: Active treatment

Interventions: intervention 1: HTS-519 Insert
Intervention descriptions: intervention 1: Maximum feasible dose of HTS-519 Insert per diseased nail

Protocol document:
Prot_SAP_001.pdf: 
CONFIDENTIAL 
Protocol No.: HTS-002B 
Hallux, Inc. 
Version 3.0 
12 September 2017 
 1 of 68 
CLINICAL STUDY PROTOCOL 
An Open-Label Phase 2 Study to Investigate the Efficacy, Tolerability, 
and Safety of the HTS-519 Insert in the Treatment of Subjects with Distal 
Lateral Subungual Onychomycosis of the Great Toenail
IND No. 
74,830 
Protocol No. 
HTS-002B 
Version No. 
3.0 (Amendment 2) 
Date of Protocol 
12 September 2017 
Authors 
 
Sponsor 
Hallux, Inc. 
23052 Alcalde Drive, Suite A 
Laguna Hills, CA 92653 
United States 
Confidentiality Statement: 
This protocol contains information that is the property of Hallux, Inc. (Hallux) and therefore is provided to you 
in confidence for review by you, your staff, an applicable ethics committee/institutional review board, and 
regulatory authorities. It is understood that this information will not be disclosed to others without the written 
approval from Hallux. 
This study will be conducted in compliance with Good Clinical Practice and the Declaration of 
Helsinki (with amendments), in accordance with local legal and regulatory requirements and in 
compliance with the applicable parts of the United States Code of Federal Regulations. 
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CONFIDENTIAL 
Protocol No.: HTS-002B 
Hallux, Inc. 
Version 3.0 
12 September 2017 
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1 
PROTOCOL SYNOPSIS 
PROTOCOL TITLE 
An Open-Label Phase 2 Study to Investigate the Efficacy, Tolerability, and 
Safety of the HTS-519 Insert in the Treatment of Subjects with Distal Lateral 
Subungual Onychomycosis of the Great Toenail 
PROTOCOL No. 
HTS-002B 
SPONSOR 
Hallux, Inc. 
INDICATION (PHASE) 
Distal lateral subungual onychomycosis (Phase 2) 
STUDY CENTERS 
One investigational site in the US 
INDICATION AND 
RATIONALE 
The purpose of this study is to evaluate the efficacy, clinical benefit, and safety 
of the HTS-519 Insert for the treatment of subjects with laboratory-confirmed 
distal lateral subungual onychomycosis (DLSO) of the great toenail. 
STUDY DESIGN 
This is a single-center open-label study to determine the efficacy of the maximal 
feasible dose (MFD) of the HTS-519 Insert 
INVESTIGATIONAL 
PRODUCT 
HTS-519 (Hallux Terbinafine Subungual) Insert, 
. 
ROUTE AND 
FREQUENCY OF 
ADMINISTRATION 
 Inserts will be administered subungually 3 times at intervals of 
4 weeks (at treatment visits Days 1, 29, and 57).  
STUDY OBJECTIVES 
The primary efficacy objective is to provide a preliminary estimate of the rate of 
complete cure of DLSO at Week 48 after treatment with the HTS-519 Insert. 
Secondary objectives will be to provide estimates of mycological and clinical 
cure rates, and other responder rates. 
Reports of physician and subject experiences with the procedure will also be 
elicited as an exploratory objective. Subjects will report their pain scores during 
and following HTS-519 Insert placement. Physicians will assess ease of 
insertion. Local tolerability and safety of administration of subungual inserts will 
be assessed. 
PLANNED SAMPLE SIZE 
AND STATISTICAL 
CONSIDERATIONS 
It is planned that at least 30 subjects will complete the 3 treatments specified.  
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Protocol No.: HTS-002B 
Hallux, Inc. 
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PATIENT POPULATION 
Inclusion Criteria 
1. Male or female between 18 and 74 years of age inclusive. 
2. Clinical diagnosis of DLSO in at least one great toenail. If both great toenails 
meet inclusion criteria, the toenail with the greater involvement will be 
designated the target toenail. 
3. Linear nail involvement of at least 4 mm, but without involvement of the 
proximal 3 mm of the nail, based on the investigator’s visual assessment. 
Overall nail involvement should be at least 25% but not more than 75% as 
per the investigator’s visual assessment (Grade 3). Nail thickness ≤ 2 mm or 
total thickness of the nail plus subungual debris measuring ≤ 3 mm. 
4. Subject’s nails are required to have a normal rate of growth (approximately 
1 mm / month or greater
 
. 
5. Laboratory confirmation of DLSO with direct microscopy of subungual debris 
positive for hyphal elements (KOH test) and fungal culture positive for 
dermatophytes. 
6. Generally of good health. 
7. Willing to comply with protocol requirements and sign a statement of 
informed consent. 
8. Willing to refrain from using any lotions, creams, liquids, or polish on the 
large toenail or on the skin immediately adjacent to the large toenail during 
the treatment period unless directed to do so by the investigator. 
9. Willing to refrain from using on the toenails topical products to which the 
subject has a high risk of developing an allergic reaction and/or dermatitis; 
10. Willing to refrain from receiving pedicures for the duration of the study. 
11. Willing to refrain from using topical steroids or topical antifungals on the 
great toenail or the skin immediately adjacent to the great toenail, or 
systemic antifungals for the duration of the study. 
PATIENT POPULATION 
Exclusion Criteria 
1. History of severe or chronic immunosuppression, an immunocompromised 
condition, known or suspected HIV, extensive dermatomycoses, extensive 
recurrent herpes zoster or severe dermatitis affecting the feet that would 
interfere with safety and tolerability assessments. 
2. Any systemic or dermatologic disorder, such as uncontrolled psoriasis, 
severe eczema, or severe atopic dermatitis which, in the opinion of the 
investigator, will interfere with the study results or increase the risk of 
adverse events (subjects with mild, controlled psoriasis, eczema, or 
dermatitis may be included if the condition would not interfere with safety 
and tolerability assessments). 
3. Any severe and/or chronic disease that would affect a subject’s nail growth 
or interfere with the subject’s ability to complete the trial, such as severe 
renal failure, peripheral vascular disease, severe chronic obstructive 
pulmonary disease, severe heart disease, uncontrolled diabetes mellitus or 
other endocrine disease, or uncontrolled malignancy. 
4. History of toenail surgery or any significant injury to the target toenail matrix. 
5. Treatment with any investigational drug within 1 month prior to Screening. 
6. Topical antifungal treatment applied to the feet within 1 month prior to the 
start of study treatment. 
7. Use of oral terbinafine within 6 months, or use of any other oral antifungal 
drug within 3 months, prior to the start of study treatment. 
8. Hypersensitivity to terbinafine or to any other ingredients of the formulation. 
9. Active onychomycosis of the fingernail. 
10. Symptomatic tinea pedis requiring treatment at Day 1 of the study. 
11. Superficial white, proximal subungual onychomycosis, lichen planus, 
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CONFIDENTIAL 
Protocol No.: HTS-002B 
Hallux, Inc. 
Version 3.0 
12 September 2017 
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psoriasis, or any condition that interfere with the treatment procedure or 
assessment of clear nail. 
12. Structural deformities of the target toenail or foot (eg, genetic or pigment 
disorders, chemical damage, tumors) that would interfere with treatment 
procedures or with assessments of efficacy, safety, or tolerability. 
13. Suspected subungual dermatophytoma.  
14. Any other condition that in the opinion of the investigator renders the subject 
unsuitable for participation in this study. 
EFFICACY 
ASSESSMENTS 
Efficacy is determined in the target great toenail by  
x 
evaluation of clinical cure (complete clearance of signs and symptoms) 
using the Investigator Global Assessment Scale, further documented by 
digital photography analysis, and  
x 
laboratory confirmation of mycological cure (negative culture for 
dermatophytes and negative KOH microscopy). 
From these assessments the efficacy outcomes of complete cure (mycological 
cure and clinical cure), mycological cure, clinical cure and effective treatment 
(no more than 10% affected nail) will be determined.
 
 
 
SAFETY ASSESSMENTS 
Safety assessments include monitoring AEs and local tolerability at the 
administration site using a 4-point scale.  Pain assessments at time of treatment 
and 7-days post procedure.  Results of physical examination and vital signs 
measurements will be assessed. 
STATISTICAL METHODS 
Cure rates will be estimated along with 95% confidence intervals.  Interval 
parameters such as length and ratios will be characterized using descriptive 
statistics. The primary analysis population will be the intent-to-treat population. 
The analysis of safety is conducted in the population of all treated subjects.  
Rates of AEs and local tolerance assessments will be presented descriptively.  
Events of clinical significance will be identified individually and described without 
inferential statistics.   
 
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CONFIDENTIAL 
Protocol No.: HTS-002B 
Hallux, Inc 
Version 3.0 
12 September 2017 
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Table 1-1  
Schedule of Study Procedures 
 
Screening 
Allocation and Treatment 
Post-Treatment 
Procedure 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Screening 
 
Baseline 
Day 
1 
Week 4 
Day  
29 ±3 
Week 8 
Day 
57 ±3 
Week 12 
Day 
85 ±7 
Week 16 
Day 
113 ±7 
Week 20 
Day  
141 ±7 
Week 24 
Day  
169 ±7 
Week 36 
Day  
253 ±7 
Week 48 
Day  
337 ±7 
ENROLLMENT AND SCREENING 
 
 
 
 
 
 
 
 
 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
Demographic, medical/medication history 
X 
Xa 
 
 
 
 
 
 
 
 
Inclusion / exclusion criteria 
X 
Xa 
 
 
 
 
 
 
 
 
Target toenail measurements 
X 
X 
 
 
 
 
 
 
 
 
INTERVENTIONS 
 
 
 
 
 
 
 
 
 
 
Notch target great toenailb 
 
 
 
 
 
 
Administration site assessment 
 
X 
X 
X 
 
 
 
 
 
 
Pain assessment 
 
X 
X 
X 
 
 
 
 
 
 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
Physical examination and vital signs 
X 
 
 
 
 
 
 
 
 
X 
Subungual sample for KOH microscopy and 
fungal culture  
Xc 
 
 
 
 
 
 
X 
X 
X 
Investigator Global Assessment of clear naild  
X 
 
 
 
X 
X 
X 
X 
X 
X 
Digital photographyd  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense subject diary 
 
Xe 
Xe 
Xe 
 
 
 
 
 
 
Review and record adverse events 
 
X 
Xf 
Xf 
Xf 
X 
X 
X 
X 
X 
Monitor concomitant medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a Record any change from baseline   
b When the notch is approaching the area of the distal groove due to outgrowth of the nail, re-notch the superficial nail plate and continue measurements   
c Subungual sampling may be repeated to confirm diagnosis of DLSO by fungal culture 
d Nails should be clipped prior to assessments  
e Next day follow-up call to check for adverse events, changes in medication 
f Includes review of subject diary 
 
 
1 
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Post-Treatment-Extension 
Procedure 
Visit 11 
Visit 12 
Week 60 
Day  
420 ±7 
Week 72  
Day  
504 ±7 
ENROLLMENT AND SCREENING 
 
 
Informed consent  
 
 
Demographic, medical/medication history 
 
 
Inclusion / exclusion criteria 
 
 
Target toenail measurements 
 
 
INTERVENTIONS 
 
 
Notch target great toenailb 
 
 
Administer study treatment 
 
 
Administration site assessment 
 
 
Pain assessment 
 
 
ASSESSMENTS 
 
 
Physical examination and vital signs 
 
 
Subungual sample for KOH microscopy and 
fungal culture  
X 
X 
Investigator Global Assessment of clear naild  
X 
X 
Digital photographyd  
X 
X 
Dispense subject diary 
 
 
Review and record adverse events 
 
 
Monitor concomitant medications 
 
 
a Record any change from baseline   
b When the notch is approaching the area of the distal groove due to outgrowth of the nail, re-notch the superficial nail plate and continue measurements   
c Subungual sampling may be repeated to confirm diagnosis of DLSO by fungal culture 
d Nails should be clipped prior to assessments  
e Next day follow-up call to check for adverse events, changes in medication 
f Includes review of subject diary 
 
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Protocol No.: HTS-002B 
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Version 3.0 
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TABLE OF CONTENTS 
 
1 
PROTOCOL SYNOPSIS ................................................................................. 2 
TABLE OF CONTENTS .................................................................................................. 7 
LIST OF ABBREVIATIONS ........................................................................................... 11 
2 
KEY ROLES AND CONTACT INFORMATION ............................................. 12 
3 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE .................................................................................................. 13 
3.1 
Background Information ........................................................................... 13 
3.2 
Rationale .................................................................................................. 14 
3.3 
Potential Risks and Benefits .................................................................... 16 
3.3.1 
Potential Risks .............................................................................................. 16 
3.3.2 
Potential Benefits .......................................................................................... 17 
4 
STUDY OBJECTIVES ................................................................................... 18 
4.1 
Study Objectives ...................................................................................... 18 
4.2 
Study Outcome Measures ....................................................................... 18 
4.2.1 
Primary .......................................................................................................... 18 
4.2.2 
Secondary ..................................................................................................... 19 
4.2.3 
Exploratory .................................................................................................... 19 
5 
SELECTION AND WITHDRAWAL OF PATIENTS ....................................... 21 
5.1 
Subject Inclusion Criteria ......................................................................... 21 
5.2 
Subject Exclusion Criteria ........................................................................ 22 
5.3 
Subject Recruitment and Retention ......................................................... 23 
5.4 
Subject Withdrawal and Stopping Criteria ................................................ 23 
5.5 
Handling of Subject Withdrawals or Discontinuation of Study 
Intervention .............................................................................................. 24 
5.6 
Study Discontinuation .............................................................................. 24 
6 
STUDY DESIGN ........................................................................................... 25 
6.1 
Study Design ........................................................................................... 25 
6.2 
Procedures and Assessments Flow ......................................................... 26 
7 
STUDY INTERVENTION .............................................................................. 27 
7.1 
Investigational Product Description .......................................................... 27 
7.1.1 
Acquisition ..................................................................................................... 27 
7.1.2 
Formulation, Packaging and Labelling .......................................................... 27 
7.1.3 
Product Storage and Stability ........................................................................ 27 
7.2 
Dosage, Preparation and Administration of Study Product ...................... 27 
7.3 
Modification of Study Product Administration ........................................... 29 
7.4 
Treatment Accountability and Compliance Checks .................................. 30 
7.5 
Procedures for Training of Clinicians on Procedural Intervention ............ 30 
7.6 
Assessment of Clinician and/or Subject Compliance with Study 
Procedural Intervention ............................................................................ 31 
7.7 
Prior and Concomitant Medications/Treatments ...................................... 31 
7.8 
Allocation to Treatment ............................................................................ 31 
7.9 
Treatment Blinding Code ......................................................................... 31 
8 
STUDY VISIT SCHEDULE AND CONTACTS .............................................. 32 
8.1 
Screening (Visit 1) ................................................................................... 32 
8.2 
Allocation and Treatment Visits ............................................................... 32 
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8.2.1 
Enrolment / Baseline, Day 1, (Visit 2) ............................................................ 32 
8.2.2 
Day 29 ±3 days, (Visit 3), and Day 57 ±3 days, (Visit 4) ............................... 33 
8.3 
Post-Treatment Visits............................................................................... 33 
8.3.1 
Intermediate Visits: Day 85 ±7 days, (Visit 5 – Week 12), 113 ±7 days, 
(Visit 6 – Week 16), and 141 ±7 days, (Visit 7 – Week 20) ........................... 33 
8.3.2 
Intermediate Visits: Day 169 ±7 days (Visit 8 – Week 24) and Day 253 
±7 days (Visit 9 – Week 36) .......................................................................... 34 
8.3.3 
End of Study, Day 337 ±7 days (Visit 10 – Week 48) .................................... 34 
8.4 
Post-Treatment Extension Visits .............................................................. 34 
8.4.1 
Study Extension Visit, Day 420 ±7 days (Visit 11 – Week 60) ....................... 34 
8.4.2 
Study Extension Visit, Day 504 ±7 days (Visit 12 – Week 72) ....................... 35 
8.5 
Withdrawal Visit ....................................................................................... 35 
8.6 
Unscheduled Visit .................................................................................... 35 
9 
EFFICACY ASSESSMENTS ......................................................................... 36 
9.1 
Evaluation of the Target Toenail .............................................................. 36 
9.1.1 
Investigator Global Assessment of Clear Nail ............................................... 36 
9.1.2 
Digital Photography ....................................................................................... 36 
9.1.3 
Subungual Sampling for Mycology ................................................................ 37 
9.2 
Evaluations Associated with the Insertion Procedure .............................. 37 
9.2.3 
Investigator Insertion Rating .......................................................................... 37 
10 
SAFETY ASSESSMENTS ............................................................................ 38 
10.1 
Local Tolerability ...................................................................................... 38 
10.2 
Patient Assessment of Pain ..................................................................... 38 
10.3 
Physical Examination and Vital Signs Measurements ............................. 38 
10.4 
Adverse Events ........................................................................................ 39 
10.4.1 
Adverse Event Definition and Documentation ............................................... 39 
10.4.2 
Serious Adverse Events ................................................................................ 40 
10.5 
Time Period and Frequency for Event Assessment and Follow-up ......... 40 
10.6 
Adverse Event Characteristics ................................................................. 40 
10.6.1 
Adverse Event Severity ................................................................................. 41 
10.6.2 
Adverse Event Relationship to Study Treatment ........................................... 41 
10.6.3 
Expectedness of Adverse Events .................................................................. 42 
10.7 
Reporting Procedures .............................................................................. 42 
10.7.1 
Investigator Reporting Requirements - SAE.................................................. 42 
10.7.2 
Sponsor Reporting Requirements ................................................................. 43 
11 
STATISTICAL CONSIDERATIONS .............................................................. 45 
11.1 
Statistical Hypotheses.............................................................................. 45 
11.2 
Sample Size Determination ..................................................................... 45 
11.3 
Final Analysis Plan .................................................................................. 45 
11.3.1 
Analysis Populations ..................................................................................... 45 
11.3.2 
Demographics and Baseline Characteristics ................................................. 45 
11.3.3 
Prior and Concomitant Medications .............................................................. 45 
11.3.4 
Statistical Methods for Efficacy Parameters .................................................. 46 
11.3.5 
Safety Analysis .............................................................................................. 46 
12 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS .................................................................................... 47 
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13 
QUALITY CONTROL AND QUALITY ASSURANCE .................................... 48 
13.1 
Monitoring Procedures ............................................................................. 48 
13.2 
Quality Assurance .................................................................................... 48 
14 
ETHICS COMMITTEE REVIEW/INFORMED CONSENT ............................. 49 
14.1 
Ethical Conduct of the Study .................................................................... 49 
14.2 
Institutional Review Board ....................................................................... 49 
14.3 
Informed Consent .................................................................................... 49 
14.4 
Exclusion of Women, Minorities, and Children (Special Populations) ...... 50 
14.5 
Disclosure and Confidentiality .................................................................. 50 
14.6 
Future Use of Stored Specimens and Other Identifiable Data ................. 50 
15 
DATA HANDLING AND RECORD KEEPING ............................................... 51 
15.1 
Data Management Responsibilities ......................................................... 51 
15.2 
Data Capture Methods ............................................................................. 52 
15.3 
Types of Data .......................................................................................... 52 
15.4 
Schedule and Content of Reports ............................................................ 52 
15.5 
Study Records Retention ......................................................................... 53 
15.6 
Publication and Data Sharing Policy ........................................................ 53 
15.7 
Protocol Deviations .................................................................................. 53 
16 
LITERATURE REFERENCES ...................................................................... 54 
SIGNATURES AND AGREEMENT WITH THE PROTOCOL ....................................... 56 
APPENDIX 1: GENERAL PROCEDURE AND ASSESSMENT CONDITIONS ............. 57 
APPENDIX 2: QUANTITATIVE ASSESSMENT OF NAIL GROWTH, 
SUBUNGUAL HYPERKERATOSIS AND NAIL WIDTH ................................ 58 
APPENDIX 3: DISTAL DIGITAL BLOCK ....................................................................... 59 
APPENDIX 4: MYCOLOGY SPECIMEN SAMPLING AND HANDLING ....................... 60 
APPENDIX 5: PRECANNULATION PROCEDURE ...................................................... 63 
APPENDIX 6: HTS-519 ADMINISTRATION PROCEDURE ......................................... 64 
APPENDIX 7: ADMINISTRATION SITE ASSESSMENT SCALE ................................. 68 
 
 
 
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Table 1-1  
Schedule of Study Procedures .................................................................. 5 
Table 4-1  
Investigator Global Assessment Scale..................................................... 18 
Table 4-2  
Secondary Efficacy Outcomes ................................................................. 19 
Table 4-3  
Exploratory Efficacy Outcomes ................................................................ 19 
Table 5-1  
Reason and Description of Subject Withdrawal or Discontinuation ......... 24 
Table 6-1  
Study Design ........................................................................................... 25 
Table 6-2  
Procedure and Assessment Flow ............................................................ 26 
Table 9-1  
Investigator Global Assessment Scale..................................................... 36 
Table 10-1  Adverse Event Severity ............................................................................ 41 
Table 10-2  Terms for Defining Relationship of Adverse Events to Study 
Product .................................................................................................... 41 
 
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LIST OF ABBREVIATIONS 
ADL 
Activities of daily living 
AE 
Adverse event 
AR 
Adverse reaction 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
 
 
CFR 
Code of Federal Regulations 
 
 
CRF 
Case report form 
DLSO 
Distal lateral subungual onychomycosis 
EDC 
Electronic data capture 
EOS 
End of Study 
FDA 
U.S. Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HTS 
Hallux Terbinafine Subungual 
ICH 
International Conference on Harmonization 
IGA 
investigator Global Assessment 
IRB 
Institutional Review Board 
KOH 
Potassium hydroxide 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFD 
Maximum feasible dose 
NRS 
Numerical rating scale 
OTC 
Over-the-Counter (non-prescription) 
PEG 
Polyethylene Glycol 
PK 
Pharmacokinetic 
 
 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAR 
Suspected adverse reaction 
SOP 
Standard operating procedure 
SQL 
Sonora Quest Laboratories 
TBF 
Terbinafine 
WMA 
World Medical Association 
 
 
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2 
KEY ROLES AND CONTACT INFORMATION 
 
Name / Role 
Address 
Sponsor 
Hallux, Inc. (Hallux) 
23052 Alcalde Drive, Suite A 
Laguna Hills, CA 92653 
Telephone: (800) 380 9130 
Fax: (949) 315 7373 
Sponsor Medical Monitor 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE  
3.1 Background Information 
Onychomycosis or tinea unguium is a chronic fungal infection of the nail unit affecting 
2-18% of the population worldwide.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
.  
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3.2 Rationale 
Hallux is developing an investigational treatment for DLSO that utilizes areas of reduced 
adherence between nail bed and nail plate to deliver a biodegradable insert containing 
the potent fungicidal terbinafine to the subungual space, targeting areas with high fungal 
viability, 
 
 
The HTS-519 Insert contains
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3.3 Potential Risks and Benefits 
Terbinafine has been approved for use as a topical agent for skin infections since 1993 
and orally for the treatment of onychomycosis since 1996.  Both the topical and oral 
formulations are generally regarded as safe and effective. 
 
HTS-002B is the first clinical study that uses the HTS-519 Insert.  
 
 
 
.  
 
3.3.1 Potential Risks 
 
 
Figure 3-2  
Sample Location and Percentage Viable Organisms by Fungal Culture 
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The expected adverse events (AEs) are application site reactions, including pain, 
swelling, irritation, and hematoma; although many patients show none of these 
reactions.  The implantation procedure in all 6 clinical trials conducted to date has been 
preceded by local anesthesia, either topical ethyl chloride or a lidocaine digital block.  
Those patients who reported post-procedural pain usually experienced discomfort within 
2 days following the procedure.  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
3.3.2 Potential Benefits 
Subungual administration of the HTS-519 Insert has the potential benefit of delivering 
the effective antifungal terbinafine in high concentrations directly to the site of infection, 
without systemic exposure. 
 
 
  The clinical effect of subungual 
administration of the HTS-519 Insert may deliver a complete cure rate that is at least 
comparable to the current gold standard.  
 
 
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4 
STUDY OBJECTIVES 
4.1 Study Objectives 
The primary efficacy objective of this study is to provide a preliminary estimate of the 
rate of complete cure of DLSO at Week 48 after treatment with the HTS-519 Insert. 
Secondary objectives will be to provide estimates of mycological and clinical cure rates, 
and other responder rates. 
 
Reports of physician and subject experiences with the procedure will also be elicited as 
an exploratory objective. Subjects will report their pain scores during and following 
HTS-519 Insert placement. Physicians will assess ease of insertion. Local tolerability 
and safety of administration of subungual inserts will be assessed. 
 
 
 
 
 
4.2 Study Outcome Measures 
 
4.2.1 Primary 
The primary outcome measure, complete cure at Visit 10 (Week 48), is based on clinical 
evaluation of “clear nail” using the Investigator’s Global Assessment (IGA) Scale 
(Section 9.1.1) and laboratory confirmation of mycological cure of the target toenail 
(Section 9.1.2). 
 
The investigator will evaluate the extent of clear nail or absence of signs of residual 
onychomycosis using the IGA Scale (Table 4-1), with a Grade 0 representative of a 
clinical cure.  The investigator’s assessment will be documented by digital photography 
planimetric analysis by Canfield Scientific, Inc.  
Subungual samples will be assessed for KOH visualization by microscopy and fungal 
culture for dermatophytes by a laboratory.  Since subjects enroll with both a positive 
KOH (fungal elements present at microscopy) and positive culture for dermatophytes, a 
mycological cure is declared when both laboratory assessments are negative. 
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4.2.2 Secondary 
The four secondary outcome measures are combinations of the same parameters used 
for evaluating the primary efficacy outcome of complete cure (Table 4-2). 
Table 4-2  
Secondary Efficacy Outcomes 
Efficacy Outcome 
Efficacy Criteria 
 
investigator Assessment / Planimetry 
Laboratory Outcome 
Complete Cure other 
than at Week 48 (EOS) 
Grade 0 - Completely clear nail, with nail 
area clear of signs of residual disease  
Negative KOH microscopy 
and  
Negative culture for 
dermatophytes 
Effective Treatment 
Grade 1 - Almost clear nail with ≤ 10% 
affected nail 
Mycological Cure 
Not a determinant in outcome 
Clinical Cure 
Grade 0 - Completely clear nail, with nail 
area clear of signs of residual disease  
Not a determinant in the 
outcome 
 
4.2.3 Exploratory 
Exploratory efficacy outcomes are summarized in Table 4-3. 
Table 4-3  
Exploratory Efficacy Outcomes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.2.3.1 
 
 
 
  
 
 
 
 
  
 
 
 
 
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5 
SELECTION AND WITHDRAWAL OF PATIENTS 
Subjects with a clinical diagnosis of DLSO of the large toenails caused by 
dermatophytes, laboratory confirmed by KOH visualization and positive culture for 
dermatophytes, will be enrolled until 30 subjects have completed the 3 treatments 
specified by the protocol. 
 
Approximately 60 subjects will be screened for entrance to the study. Based on 
previous studies in this indication, it is expected that the majority of subjects will be 
male. Subjects will be recruited from a single podiatric practice, the 
 
. The practice operates from 
additional locations 
 that may serve as 
referral (not treatment) centers. 
 
Subjects must meet all of the following inclusion criteria (Section 5.1) to be eligible for 
enrollment into the study and must not meet any of the exclusion criteria listed in 
Section 5.2 in order to be eligible. 
5.1 Subject Inclusion Criteria 
1. Male or female between 18 and 74 years of age inclusive. 
2. Clinical diagnosis of DLSO in at least one great toenail. If both great toenails meet 
inclusion criteria, the toenail with the greater involvement will be designated the 
target toenail. 
3. Linear nail involvement of at least 4 mm, but without involvement of the proximal 3 
mm of the nail, based on the investigator’s visual assessment. Overall nail 
involvement should be at least 25% but not more than 75% as per the investigator’s 
visual assessment (Grade 3). Nail thickness ≤ 2 mm or total thickness of the nail 
plus subungual debris measuring ≤ 3 mm. 
4. Subject’s nails are required to have a normal rate of growth (approximately 1 mm / 
month or greater)
 
. 
5. Laboratory confirmation of DLSO with direct microscopy of subungual debris 
positive for hyphal elements (KOH test) and fungal culture positive for 
dermatophytes. 
6. Generally of good health. 
7. Willing to comply with protocol requirements and sign a statement of informed 
consent. 
8. Willing to refrain from using any lotions, creams, liquids, or polish on the large 
toenail or on the skin immediately adjacent to the large toenail during the treatment 
period unless directed to do so by the investigator. 
9. Willing to refrain from using on the toenails topical products to which the subject has 
a high risk of developing an allergic reaction and/or dermatitis; 
10. Willing to refrain from receiving pedicures for the duration of the study. 
11. Willing to refrain from using topical steroids or topical antifungals on the great 
toenail or the skin immediately adjacent to the great toenail, or systemic antifungals 
for the duration of the study. 
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5.2 Subject Exclusion Criteria 
1. History of severe or chronic immunosuppression, an immunocompromised condition, 
known or suspected HIV, extensive dermatomycoses, extensive recurrent herpes 
zoster or severe dermatitis affecting the feet that would interfere with safety and 
tolerability assessments. 
2. Any systemic or dermatologic disorder, such as uncontrolled psoriasis, severe 
eczema, or severe atopic dermatitis which, in the opinion of the investigator, will 
interfere with the study results or increase the risk of adverse events (subjects with 
mild, controlled psoriasis, eczema, or dermatitis may be included if the condition 
would not interfere with safety and tolerability assessments). 
3. Any severe and/or chronic disease that would affect a subject’s nail growth or 
interfere with the subject’s ability to complete the trial, such as severe renal failure, 
peripheral vascular disease, severe chronic obstructive pulmonary disease, severe 
heart disease, uncontrolled diabetes mellitus or other endocrine disease, or 
uncontrolled malignancy. 
4. History of toenail surgery or any significant injury to the target toenail matrix. 
5. Treatment with any investigational drug within 1 month prior to Screening. 
6. Topical antifungal treatment applied to the feet within 1 month prior to the start of 
study treatment. 
7. Use of oral terbinafine within 6 months, or use of any other oral antifungal drug 
within 3 months, prior to the start of study treatment. 
8. Hypersensitivity to terbinafine or to any other ingredients of the formulation. 
9. Active onychomycosis of the fingernail. 
10. Symptomatic tinea pedis requiring treatment at Day 1 of the study. 
11. Superficial white, proximal subungual onychomycosis, lichen planus, psoriasis, or 
any condition that interfere with the treatment procedure or assessment of clear nail. 
12. Structural deformities of the target toenail or foot (eg, genetic or pigment disorders, 
chemical damage, tumors) that would interfere with treatment procedures or with 
assessments of efficacy, safety, or tolerability. 
13. Suspected subungual dermatophytoma.  
14. Any other condition that in the opinion of the investigator renders the subject 
unsuitable for participation in this study. 
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5.3 Subject Recruitment and Retention 
Subjects will be primarily recruited from a single podiatric practice and 3 (non-treatment) 
locations that are part of the practice.  
 
 
 
 
 
 
 
 
 
5.4 Subject Withdrawal and Stopping Criteria 
In accordance with legal requirements and ICH GCP, subjects may withdraw from the 
study at any time without stating a reason and without prejudice to further treatment.  A 
subject’s participation is to be terminated immediately upon his/her request.  If, at the 
time of refusal, HTS-519 has already been administered, the subject will be advised on 
follow-up safety procedures.  
 
The investigator may withdraw a subject from the study and discontinue study treatment 
and assessments at any time. 
 
The subject and the investigator are advised to be alert to any adverse effects that may 
be attributable to the study medication or procedures, and not to continue study 
treatments when there is any perceived risk of harm to the subject.  
 
A subject’s discontinuation from the study will be considered if a subject experiences a 
serious adverse event (SAE) or develops conditions which would have prevented 
his/her entry into the study according to the safety-related medical exclusion criteria. 
 
The investigator must discontinue a subject from the study if the following criteria are 
met: 
x Any subject who develops intolerable adverse effects attributable to the study 
procedures - an “intolerable adverse effect” is one that is regarded by either the 
subject or the investigator or both as necessitating the discontinuation of study 
treatment. 
x Biochemical or clinical evidence of liver injury with total bilirubin levels greater 
than 3 times the upper limit of normal is detected. 
 
If a subject is discontinued because of an AE, the event will be followed until it is 
resolved or it is considered to have stabilized and does not require further follow-up. 
 
If a subject is discontinued at any time after entering the study, the subject will stop 
receiving further treatment.  The investigator will make every effort to see the subject 
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and complete a final evaluation, following the end of study assessments (Section 8.3.3). 
This is not required if a subject is withdrawn prior to dosing. 
 
Early discontinuation of each subject who has given informed consent to participate will 
be recorded in the case report form (CRF) including the primary reason for 
discontinuation, other than study completion, as described in Table 5-1: 
 
Table 5-1  
Reason and Description of Subject Withdrawal or Discontinuation 
Reason 
Description 
Failure to meet eligibility criteria 
Failure to meet inclusion and / or exclusion criteria 
Adverse Events (AE) 
Clinical events occurred or laboratory results are reported that in the 
medical judgment of the investigator are grounds for discontinuation in 
the best interests of the subject. 
Lost to Follow-Up 
The subject stopped coming for visits and study personnel were unable 
to contact the subject. 
Withdrawal of Consent 
The subject desired to withdraw from further participation in the study. 
The subject is not obliged to provide any reason for withdrawal of 
consent, but where a reason is given this will be recorded in the CRF. 
Study Terminated by Sponsor 
An indication that a clinical study was stopped by its sponsor. 
Physician Decision 
A position, opinion or judgment to withdraw or discontinue the subject 
from the study reached after consideration by a physician. 
Protocol Deviation 
The subject failed to adhere to the protocol requirements, and, in the 
investigator’s opinion, the best interest of the subject or study 
assessment of safety of the subject would be affected by continued 
involvement. 
Lost to Follow-Up 
The subject stopped coming for visits and study personnel were unable 
to contact the subject. 
Death 
Outcome was death 
Other 
The subject was terminated for a reason, other than one previously 
listed, that could potentially impact data or subject safety. 
 
5.5 Handling of Subject Withdrawals or Discontinuation of Study Intervention 
All enrolled subjects will be included in the study analysis whether or not they withdraw 
from the study or discontinue the study procedures after enrollment.
 
 
5.6 Study Discontinuation 
This study may be suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to the investigator 
and regulatory authorities.  If the study is prematurely terminated or suspended, the 
principal investigator will promptly inform the IRB and will provide the reasons for the 
termination or suspension.  
 
 
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6 
STUDY DESIGN 
6.1 Study Design 
This is a single-center, open-label study intended to establish preliminary point 
estimates of efficacy and assess the clinical benefits and safety of HTS-519 Insert, 
administered in the subungual space, in subjects with clinically and laboratory-
confirmed DLSO of the great toenail. 
 
All subjects will be screened for DLSO and will meet specific inclusion and exclusion 
criteria. 
 
If both great toenails have clinical and laboratory evidence of onychomycosis and fulfill 
the inclusion / exclusion criteria, the one with the greater involvement will be designated 
as the target nail for efficacy evaluation, but both of the great toenails may be treated 
and evaluated for safety if the subject and the investigator consent.  
 
Treatment will be administered to all subjects 
  Each subject will 
receive a dose 
 based on 
 
 nail involved by 
disease (Section 7.2).  Each treatment visit will be followed up with a phone contact the 
next day to enquire about adverse events. 
 
After the last treatment on Day 57, subjects will return for follow-up observations 4 
weeks apart, until Visit 8 (Week 24). Thereafter, subjects are followed-up every 12 
weeks until End of Study Visit 10 (Week 48).  Study design is summarized in Table 6-1. 
At Week 48, subjects that in the opinion of the investigator have a reasonable chance to 
reach a complete cure in the 24 weeks following the End of Study Visit or have reached 
a complete cure at Visit 10, will be invited to complete additional visits. Subjects that 
meet the extension criterion at Visit 10 will be evaluated again at Visit 11 (Week 60) to 
determine their eligibility to remain in the study until Visit 12 (Week 72). 
 
Treatment efficacy will be evaluated on the basis of mycology (KOH test results and 
culture for dermatophytes) and clinical signs (investigator assessment of clear nail and 
length of unaffected nail as determined by planimetric photographic measurements).  
Persistence of treatment effect will be assessed during the post-treatment phase 
(Section 9). 
 
Safety measurements will include local clinical signs and symptoms, including 
erythema, edema, hematoma, bruising, itching, and pain; and reports of adverse events 
(Section 10). 
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6.2 Procedures and Assessments Flow 
The major procedure and assessments performed by the investigator or delegated staff 
on the (target) great toenail during the study are summarized and sequenced in Table 
6-2 for all visits categorized as either screening, treatment and post-treatment visits. 
 
Table 6-2  
Procedure and Assessment Flow 
Procedure 
Visits and Order of Procedure 
 
Aim 
Procedure / Tool 
Subjects 
Screen 
Treatment 
Post- 
Treatment 
 
Target toenail assessment, nail clipping and notching 
 
 
 
Standardized assessment 
of clear nail (growth) & 
treatment 
Clipping and measurements of the 
nail with caliper / ruler; notching of 
the nail 
All 
1 
1 
1 
Digital photography (Canfield Manual) 
 
 
 
 
Visual evidence of disease 
and emergence of clear 
nail  
Digital image capture of the target 
great toenail per Canfield Manual 
All 
2 
2 
2 
Distal Digital Block (
 
 
 
 
 
Local anesthesia of nail 
unit 
Infiltration anesthesia (liocaine 2%) 
All 
 
3 
 
Subungual Sampling for Mycology (
 
 
 
 
 
Laboratory confirmation 
DLSO 
Subungual material sampling by 
curettage 
All 
3 
 
3 
Precannulation Procedure (
 
 
HTS-519 Insert Administration Procedure (
 
 
End of Assessment of Procedure(s) – Site Administration Reaction 
(
 
 
 
Local tolerability 
assessment of procedural 
site 
Site Administration Assessment 
Scale 
All 
6 
End of Assessment of Procedure(s) – Digital Photography (Canfield Manual) 
 
 
 
 
Documentation of areas of 
diseased nail, emergence 
of clear nail and status pre- 
and post procedure 
Outline diseased nail and obtain 
digital image of the dorsal surface 
of the great toenail per Canfield 
Manual 
All 
4 
7 
4 
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7 
STUDY INTERVENTION 
7.1 Investigational Product Description 
The HTS-519 (Hallux Terbinafine Subungual) Insert is a
 
 
 
 
 
 
7.1.1 Acquisition 
The HTS-519 Insert will be supplied by the sponsor, Hallux, Inc.  
 
 
 
  
7.1.2 Formulation, Packaging and Labelling 
The HTS-519 Insert is supplied 
. Each 
applicator is packaged in a sealed pouch for single use.  A label with the following 
information will be affixed to each unit package: 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
7.1.3 Product Storage and Stability 
The HTS-519 Insert should be stored at room temperature 59-860F / 15-300C.  
7.2 Dosage, Preparation and Administration of Study Product 
Placement of HTS-519 Inserts 
 
 
 
 
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Dose determination therefore starts with measuring the 
 involved 
nail 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.3 Modification of Study Product Administration 
Small deviations
 
 is anticipated and referred to as opportunistic placement.  
 
Anatomical nail and disease characteristics necessitating a different insertion point 
(opportunistic placement) than determined from Table 7-2 could includ
 
 
 
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The investigator may decide to administer fewer HTS-519 Inserts than determined by 
 
 
 
 
With clearing of the nail 
 the number of 
HTS-519 Inserts should be adjusted accordingly. 
 
 
 
 
Any modification to the optimal 
 administration as described 
above must be documented in the CRF. 
7.4 Treatment Accountability and Compliance Checks 
It is the investigator/Institution’s responsibility to establish a system for handling study 
treatments and products. This includes: 
x Maintaining accurate records of receipt of all test articles by a responsible 
person, including dates of receipt. 
x Providing treatment to subjects only as directed in the protocol.  Reasons for 
departure from the expected dispensing regimen must be recorded.  
x Storing all study treatments and supplies at site in a secure, restricted access 
area (eg, a locked room) under room temperature conditions and protected from 
light, moisture, and freezing as stated on the label. 
x Reconciling delivery records with records of usage and destroyed/returned stock.  
Records of usage should include the identification of the person to whom the 
study treatment was dispensed and the quantity and date of dispensing.  This 
record is in addition to any drug accountability information recorded in the CRF.  
Any discrepancies must be accounted for on the appropriate forms.  Certificates 
of delivery and return must be signed, preferably by the investigator or a 
pharmacist, and copies retained in the investigator Site File. 
 
 
 
 
 
 
 
 
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7.6 Assessment of Clinician and/or Subject Compliance with Study Procedural 
Intervention 
Study treatments are administered by the treating investigator at Day 1, Day 29, and 
Day 57.  
 
 
 
The presence of HTS-519 Inserts after placement will be confirmed visually if not 
obscured 
  
 
 
 
 
 
7.7 Prior and Concomitant Medications/Treatments 
Any concomitant medication deemed necessary for the welfare of the subject during the 
study may be given at the discretion of the investigator.  It is the responsibility of the 
investigator to ensure that details regarding the medication are recorded in full in the 
CRF. 
 
Prohibited medications include: 
x Concomitant use of systemic antimycotics during the study.  Topical antifungal 
medicines will be permitted for subjects who develop symptomatic tinea pedis 
during the course of the study but contact with the large target toe must be 
avoided. 
x Use of lotions, creams, liquids, or polish on the target great toenail or the skin 
immediately adjacent to the target great toenail during the study is prohibited. 
7.8 Allocation to Treatment 
Each subject who satisfies the criteria to participate in the study will be assigned a 
unique subject number.  The subject numbers will be assigned sequentially in the order 
in which subjects are enrolled.  The investigator will administer the required number of 
HTS-519 Inserts 
  
7.9 Treatment Blinding Code 
This is an open label study in which investigator and subject are not blinded to 
treatment. 
 
 
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8 
STUDY VISIT SCHEDULE AND CONTACTS 
Study visits are based on the number of days from the date of the study visit at Baseline 
(Day 1) and summarized in Table 1-1.  During the treatment phase a window of ±3 days 
is allowed for the study visit based on the date of Baseline. For all other study visits, a 
window of ±7 days is allowed for each study visit based on the date of Baseline. 
8.1 Screening (Visit 1) 
The screening visit will occur within approximately 6 weeks of the Baseline visit.  At 
Screening, the following procedures will be completed for each subject: 
x Explain the particulars of the study to potential subjects. 
x Obtain and document informed consent from potential subjects before performing 
any study-related procedures. 
x Obtain demographic, medical history and concomitant medication information. 
x Review inclusion/exclusion criteria for eligibility. 
x Perform a physical examination and obtain vital signs needed to determine 
eligibility. 
x Evaluate the involved great toenail(s) for anatomical (nail width) and disease 
characteristics as per 
 and complete the Investigator Global 
Assessment Scale (
 to confirm eligibility. 
x Collect subungual samples by curettage from each great toenail for which there 
is clinical suspicion of the presence of onychomycosis.  Examine subungual 
samples using KOH microscopy. Confirm the presence of hyphae and ship 
unused subungual material to the central mycology laboratory for confirmatory 
fungal culture for dermatophytes (
 and enroll the subject into the 
study. The tissue sample for screening mycology may be collected up to 8 weeks 
before the start of study therapy. 
x Outline affected area of the great toenail(s) and obtain a digital photograph of the 
dorsal surface of the toenail(s) for analysis by Canfield Scientific as described in 
the Canfield manual. 
8.2 Allocation and Treatment Visits 
 
8.2.1 Enrolment / Baseline, Day 1, (Visit 2) 
Results of fungal cultures, clinical laboratory assessments, and digital photography 
analysis will be reviewed by the Principal investigator in order to notify subjects of their 
eligibility to continue in the study.  Subjects meeting eligibility criteria will return for their 
Baseline visit within approximately 6 weeks of Screening.  At Baseline, the following 
procedures are to be completed:  
x Review inclusion/exclusion criteria for eligibility. 
x Document any changes to medical history, physical condition, concomitant 
medications according to the subject’s response since the Screening visit. 
x Evaluate the involved great toenail(s) for anatomical (nail width) and disease 
characteristics as per 
 and complete the Investigator Global 
Assessment Scale (
 to confirm eligibility.  
x Determine the location of the great toenail designated as the target toenail for the 
duration the study. If both great toenails have clinical and laboratory evidence of 
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onychomycosis, the one with the greater involvement will be designated as the 
target nail for the primary efficacy evaluation. Both great toenails may be treated. 
x Notch the target toenail 3 mm from the lunula as a baseline for nail growth 
measurement (
 
x Obtain subject evaluation of pain before, during and after the infiltration 
anesthetic and cannulation procedure (
 
x Administer study treatment as described in 
 and record site 
administration reactions 
 if any.  
x Obtain a digital photograph of the dorsal surface of the toenail(s) for analysis by 
Canfield Scientific as described in the Canfield manual. 
x Dispense subject 7-day diary. 
x Schedule the next day follow-up phone contact and Day 29 visit. 
 
8.2.2 Day 29 ±3 days, (Visit 3), and Day 57 ±3 days, (Visit 4) 
At study visit 3, and visit 4, the following procedures will be performed:  
x Document any changes to concomitant medications and occurrence of adverse 
events according to the subject’s response since the last visit. 
x Retrieve the subject 7-day diary and review for completeness. 
x Administer study treatment as described in 
 and record site 
administration reactions (
 if any.  
x Obtain subject evaluation of pain before, during and after the infiltration 
anesthetic and cannulation procedure (
 
x Obtain a digital photograph of the dorsal surface of the toenail(s) for analysis by 
Canfield Scientific as described in the Canfield manual. 
x Dispense subject 7-day diary. 
x Schedule the next day follow-up phone contact and the Day 57 and Day 85 Visit 
as appropriate for the visit. 
8.3 Post-Treatment Visits 
 
8.3.1 Intermediate Visits: Day 85 ±7 days, (Visit 5 – Week 12), 113 ±7 days, (Visit 6 
– Week 16), and 141 ±7 days, (Visit 7 – Week 20) 
At study Visits 5, 6, and 7, the following procedures will be completed:  
x Document any changes to concomitant medications and occurrence of adverse 
events according to the subject’s response since the last visit. 
x Retrieve the subject 7-day diary and review for completeness (Visit 5 only). 
x Evaluate the (target) great toenail for clear nail and extent of clear nail using the 
Investigator Global Assessment Scale as described in
 
x Obtain a digital photograph of the dorsal surface of the toenail(s) for analysis by 
Canfield Scientific as described in the Canfield manual. 
x Schedule the Day 113 and 141 Visits respectively. 
 
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8.3.2 Intermediate Visits: Day 169 ±7 days (Visit 8 – Week 24) and Day 253 ±7 
days (Visit 9 – Week 36) 
At the study visit 8 and 9, the following procedures will be conducted:  
x Document any changes to concomitant medications and occurrence of adverse 
events according to the subject’s response since the last visit. 
x Evaluate the (target) great toenail for clear nail and extent of clear nail using the 
investigator Global Assessment Scale as described in 
 
x Collect subungual samples by curettage from each treated great toenail and ship 
to the central mycology laboratory for confirmatory fungal culture for 
dermatophytes and KOH microscopy as described in 
. 
x Obtain a digital photograph of the surface area of the target great toenail for 
analysis by Canfield Scientific as per the Canfield Manual. 
x Schedule the Day 253 and 337 Visits respectively. 
 
8.3.3 End of Study, Day 337 ±7 days (Visit 10 – Week 48) 
When the subject returns for the End of Follow-up Visit, the following procedures will be 
completed:  
x Document any changes to concomitant medications and occurrence of adverse 
events according to the subject’s response since the last visit. 
x Perform a physical examination, including vital signs. Collect subungual samples 
by curettage from each treated great toenail and ship to the central mycology 
laboratory for confirmatory fungal culture for dermatophytes and KOH 
microscopy as described in 
 
x Evaluate the (target) great toenail for clear nail and extent of clear nail using the 
investigator Global Assessment Scale as described in 
 
x Obtain a digital photograph of the surface area of the target great toenail for 
analysis by Canfield Scientific as per the Canfield Manual. 
x Schedule the Day 420 Visit for those subjects that in the opinion of the 
investigator have the ability to reach a complete cure over the next 24 weeks 
based on clinical improvement observed during the entire study duration and 
mycological status, or have reached a complete cure at this Visit. 
8.4 Post-Treatment Extension Visits 
 
8.4.1 Study Extension Visit, Day 420 ±7 days (Visit 11 – Week 60) 
For those subjects returning for the Study Extension Visit, the following procedures will 
be completed:  
x Evaluate the (target) great toenail for clear nail and extent of clear nail using the 
investigator Global Assessment Scale as described in 
  
x Collect subungual samples by curettage from each treated great toenail and ship 
to the central mycology laboratory for fungal culture for dermatophytes and KOH 
microscopy as described in 
 
x Obtain a digital photograph of the surface area of the (target) great toenail for 
analysis by Canfield Scientific as per the Canfield Manual. 
x Schedule the Day 504 Visit for subjects with a complete cure at this visit and for 
those subjects that in the opinion of the investigator have the ability to achieve a 
complete cure by Visit 12. 
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8.4.2 Study Extension Visit, Day 504 ±7 days (Visit 12 – Week 72) 
For those subjects returning for the Study Extension Visit, the following procedures will 
be completed:  
x Evaluate the (target) great toenail for clear nail and extent of clear nail using the 
investigator Global Assessment Scale as described in 
 
x Collect subungual samples by curettage from each treated great toenail and ship 
to the central mycology laboratory for confirmatory fungal culture for 
dermatophytes and KOH microscopy as described in 
 
x Obtain a digital photograph of the surface area of the (target) great toenail for 
analysis by Canfield Scientific as per the Canfield Manual. 
 
8.5 Withdrawal Visit 
For any subject who withdraws from the study prior to Week 48, the End of Study (Visit 
10) assessments should be performed and recorded to the extent possible and 
appropriate. 
8.6 Unscheduled Visit 
Although every effort will be made to see subjects at the per protocol visits unplanned 
visits may occur.  These unscheduled visits may occur to perform additional 
assessments or procedures outside of the protocol specific visit calendar.  These 
assessments could be related to the emergence of new clinical signs and symptoms or 
adverse events, lab results or questions the subject may have about the study or for any 
other clinical reason.   
 
Unscheduled visits will be assigned the designation Visit “0”.  The date of the visit and 
observations relevant to the study will be recorded in the CRF (eg, adverse events, 
change in medication) under “unscheduled visit”.  If there are no specific observations to 
be captured the reason of the visit is recorded in the medical records only. 
 
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9 
EFFICACY ASSESSMENTS 
9.1 Evaluation of the Target Toenail 
The investigator will clinically establish the presence of DLSO of the great toenail as 
well as any clinical involvement of other toenails.  Thickness of subungual 
hyperkeratosis will be measured in millimeters (one decimal point) from the top of the 
nail plate to the nail bed, using a caliper.  Nail width will be recorded in millimeters 
 
 
  
 
The affected area of the nail 
 may be outlined by the 
investigator prior to target toenail evaluation and digital image collection to facilitate 
central image review.  
 
The assessments listed in 
 
 determine subject eligibility 
and treatment efficacy and are conducted after clipping the nail to the distal groove (the 
transverse demarcation extending across the distal digit that divides the hyponychium 
from the volar epidermis).  Subjects are therefore allowed to cut their toenails, but not 
beyond the target nail’s distal groove so as not to interfere with the assessment of clear 
nail.  
 
9.1.1 Investigator Global Assessment of Clear Nail 
Evaluation of clear nail will be based upon that portion of surface area of the nail that is 
clear of signs of disease (ie, nail dystrophy, onycholysis or subungual hyperkeratosis) 
attributable to onychomycosis and active infection.  The investigator will assess the 
involved great toenail for the extent of clear nail using the investigator Global 
Assessment (IGA) Scale.  Missing nail is considered diseased nail. 
Table 9-1  
Investigator Global Assessment Scale 
Note that a completely clear nail is not necessarily a “perfect nail” as the appearance of 
the nail may be affected by comorbid and pre-existing conditions unrelated to DLSO, 
such as longitudinal ridging, lamellar nail splitting, trachyonychia, brittle nails, and 
trauma, that will not respond to antifungal treatment. 
 
9.1.2 Digital Photography 
A high resolution digital photograph of the target nail is taken with specialized 
photographic equipment and computer hardware standardized for distance and lighting 
provided by Canfield Scientific (central imaging lab) to document visual evidence of nail 
disease, nail clearance or status post subungual sampling or HTS-519 Insert 
administration. 
 
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Each subject will place the target foot in the toe stop that also functions as an internal 
scale included in all images to allow objective measurements of clear nail.  The digital 
image will be captured before and after treatment administration as per the Canfield 
manual provided as a separate document.  The image will be electronically uploaded 
instantaneously to Canfield Scientific for immediate assessment of quality. 
 
9.1.3 Subungual Sampling for Mycology 
As described in
 the investigator collects subungual samples by curettage 
from each great toenail for which there is clinical suspicion of the presence of 
onychomycosis.   
 
At Screening samples will be examined by the investigator using KOH microscopy to 
confirm the presence of septate hyphae, and remaining subungual material will be sent 
to the mycology laboratory for KOH visualization and confirmatory fungal culture for 
dermatophytes.  After the Screening visits, the samples may be sent to the laboratory 
without the on-site KOH microscopy. 
 
If at Screening the KOH microscopy exhibits septate hyphae, but the culture fails to 
grow dermatophytes the culture may be repeated. If 2 sequential cultures are negative, 
it is recommended that the nail not be included in the study and no further cultures are 
attempted. 
 
Cultures grown from samples taken during the study will be stored at the central 
mycology laboratory for future susceptibility testing at the end of the study.  Results will 
be reported separately from the final study report. 
9.2 Evaluations Associated with the Insertion Procedure 
 
9.2.1 Insertion Point 
 
 
 
 
 
 
 
9.2.2 Insertion Depth 
 
 
 
. 
 
9.2.3 Investigator Insertion Rating 
A 5-point Likert scale will be used for the investigator’s assessment of ease of insertion. 
The scoring ranges from 1-5 with (1) = very easy, (2) = easy, (3) = difficult, (4) = very 
difficult and (5) = impossible to administer the HTS-519 Insert.  
 
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10 SAFETY ASSESSMENTS 
The safety of HTS-519, administered subungually, will be assessed by monitoring local 
tolerability at the administration site, adverse events, and evaluating data from physical 
examinations and vital signs measurements. 
10.1 Local Tolerability 
Before and after placement of HTS-519 Insert(s) and at each visit the investigator will 
examine the nail unit and surrounding tissue for adverse signs and symptoms.  
Immediately following the administration of an insert the event of bleeding will be 
evaluated specifically by the investigator using the following scale:
 
 
  
 
Within 1 hour of treatment the subject will record the level of 
 
.  The signs and symptoms will be rated as 0 = 
none, 1 = mild, 2 = moderate, or 3 = severe as defined in
 
 
After each treatment the subject will be provided a 7-day diary to record the same 
assessments every evening using the rating scale described in detail in 
  
The day after treatment a phone contact will take place to ensure that the diary is 
completed and to collect any changes in medication and health status. 
 
The presence or absence of a subungual hematoma will be documented by the 
investigator at every visit.  In addition, over the course of the study, the investigator will 
observe the nail unit for signs of nail dystrophy, foreign body reactions, and infectious 
processes such as paronychia and osteomyelitis.  
10.2 Patient Assessment of Pain 
The numerical rating scale (NRS) is a one-dimensional pain intensity scale with a 
number 0 (no pain) located on the left and a number 10 (worst pain imaginable) 
displayed on the right of the horizontal scale.27  The subject will be instructed to select a 
number that best represents their perception of the degree of pain.  The magnitude of 
the pain associated with anesthesia, access to the subungual space and placement of a 
HTS-519 Insert is collected on paper by the subject and subsequently recorded in the 
CRF. 
 
The subject will be provided a subject diary for seven days following each insertion 
procedure to record pain levels using the same numerical rating scale every evening. 
10.3 Physical Examination and Vital Signs Measurements 
An abbreviated physical examination will be performed at Screening and Week 48. The 
examination will focus on the essential aspects of the subjects’ illness and general 
physical condition, including examination of the foot for the presence of tinea pedis and 
adequacy of circulation etc.. 
 
Vital signs assessed include heart rate and blood pressure using a blood pressure 
recording device with an appropriate cuff size. Measurements will be made after the 
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subject has been resting supine for a minimum of 5 minutes.  Weight will be measured 
as well. 
10.4 Adverse Events 
 
10.4.1 Adverse Event Definition and Documentation 
An adverse event (AE) is any untoward medical occurrence in a subject, administered 
an investigational product and which does not necessarily have to have a causal 
relationship with this treatment (21 CFR 312.32).  An AE (also referred to as an adverse 
experience) can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated 
with the use of an investigational product, whether or not considered related to the 
investigational product. 
 
Adverse events may be volunteered spontaneously by the subject or discovered as a 
result of general, non-leading questioning, through physical examination, laboratory 
test, or other means. 
 
Adverse events resulting from concurrent illnesses, reactions to concurrent illnesses, 
reactions to concurrent medications, or progression of disease states must be recorded.  
Any medical condition that is present at the time that the subject is screened but does 
not deteriorate should not be reported as an AE.  However, if the signs or symptoms 
associated with the medical condition deteriorate at any time during the study, it should 
be recorded as an AE. 
 
Abnormal laboratory values or test results will be recorded as AEs only if (1) they induce 
clinical signs or symptoms, (2) require therapy, or (3) are considered by the investigator 
to be of clinical significance.  Prior medical conditions/diseases are considered AEs only 
if they worsen after the start of protocol-specified study procedures.  
 
All AEs reported or observed from the time a subject signs informed consent until exit 
from the study must be recorded in detail on the appropriate page of the CRF and 
followed until the event is resolved, the event reaches a clinically stable outcome, or the 
subject is lost to follow-up.  For each AE, the AE record will include type of event, start 
and stop dates, severity (mild, moderate, or severe), seriousness, relationship to the 
study treatment (definite, probably, possibly, unlikely, or not related), actions taken 
(required treatment or observations), and outcome. 
 
Adverse events that are prospectively collected as outcomes or observations include 
procedure related pain, post-treatment symptoms collected in a subject diary and an 
investigator assessment of the nail before and after treatment.  For the purpose of this 
study this prospectively collected information will not be again reported as AEs unless:  
x 
Considered clinically significant by the Investigator, 
x 
Requiring treatment or study treatment modification, or 
x 
Meeting the criteria for a Serious Adverse Event (SAE) 
A temporary change in nail appearance reasonably associated with healing or clearing 
of disease is not considered an adverse event, unless any of the 3 criteria above apply. 
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10.4.2 Serious Adverse Events 
An AE or SAR is considered “serious” (see 21 CFR 312.32) if, in the view of either the 
investigator or sponsor, the adverse event: 
x Results in death. 
x Is life threatening (i.e., the subject was at risk of death at the time of the event; it 
does not refer to an event that hypothetically might have caused death if it was 
more severe). 
x Requires insubject hospitalization or prolongation of existing hospitalization 
x Results in persistent or significant incapacity or substantial disruption of the 
ability to conduct activities of normal life. 
x Is a congenital anomaly / birth defect. 
x Is considered to be an important medical event. 
 
Based upon medical and scientific judgment, important medical events that may not be 
immediately life threatening, or result in death or hospitalization, but may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the 
definition above may be considered a serious adverse event (SAE). 
 
Hospitalizations are defined as official admission, not necessarily an overnight stay for 
observation or for an out-subject procedure.  If, however, the investigator feels that the 
cause of the out-subject procedure or overnight stay is medically significant, then the 
event will be considered an SAE with the serious criteria of Important Medical Event.  A 
hospitalization for social reasons in the absence of an AE is not an SAE.  Additionally, if 
a subject is hospitalized for a procedure that was planned prior to the study, this will not 
be considered an SAE.  If a hospitalization is prolonged, such as for a fever, then that 
fever will be considered an SAE. 
10.5 Time Period and Frequency for Event Assessment and Follow-up 
The investigator will record all reportable events with start dates occurring any time after 
informed consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after 
the last day of study participation in the CRF.  At each study visit, the investigator will 
inquire about the occurrence of AE/SAEs since the last visit.  Events will be followed for 
outcome information until resolution or stabilization. 
10.6 Adverse Event Characteristics 
Each AE has three attributes as described in 
.  
Severity and relationship to study treatment are recorded in the CRF by the investigator.  
The Medical Monitor and the Study PI will be responsible for determining whether an 
SAE is expected or unexpected.  An adverse event will be considered unexpected if the 
nature, severity, or frequency of the event is not consistent with the risk information 
previously described for the intervention.   
 
 
 
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10.6.1 Adverse Event Severity 
The investigator will classify the severity (intensity) of each AE according to the 
following definitions summarized in Table 10-1: 
 
Table 10-1  
Adverse Event Severity 
Classification 
Definition 
Mild 
Moderate 
Severe 
 
It should be pointed out that the term “severe” is a measure of intensity and that a 
severe AE is not necessarily serious. 
 
10.6.2 Adverse Event Relationship to Study Treatment 
All events considered to be noxious and unintended responses to an investigational 
product related to any dose should be considered an Adverse Reaction (AR).  The 
phrase “responses to a medicinal product” means that a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility. 
 
A suspected adverse reaction (SAR) therefore indicates any AE for which there is a 
reasonable possibility that the drug caused the adverse event, ie, there is evidence to 
suggest a causal relationship between the drug and the adverse event. 
 
The determination of the causal relationship between the drug and the adverse event 
will be based in part on the investigator’s assessment of the relationship of the AE to the 
investigational treatment.  An AE considered by the investigator to be probably or 
definitely related to the study treatment is to be considered an AR, and an AE 
considered by the investigator to be possibly related to the study treatment is a SAR, 
but not an AR.  An AE considered by the investigator unlikely to be related, or to be 
unrelated, to the study treatment, is not a SAR, unless the sponsor determines 
otherwise based on other evidence. 
 
The investigator will assess the likely relationship of each AE to the investigational 
product according to the definitions outlined in Table 10-2. 
 
Table 10-2  
Terms for Defining Relationship of Adverse Events to Study Product 
Association 
Definition 
Interpretation 
Not Related 
Adverse Event (AE) 
- Unrelated 
Unlikely 
Related 
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Association 
Definition 
Interpretation 
Possibly 
Related  
Suspected Adverse 
Reaction (SAR) - 
Related 
Probably 
Related  
Adverse Reaction 
(AR) - Related 
Definitely 
Related 
 
 
10.6.3 Expectedness of Adverse Events 
An AE or SAR is considered “unexpected” if it is not listed in the Investigator’s Brochure 
or is not listed at the specificity or severity that has been observed; or, if an 
Investigator’s Brochure is not required or available, is not consistent with the risk 
information described in the general investigational plan or elsewhere in the current 
application, as amended. 
 
“Unexpected” as used in this definition, also refers to AEs or SARs that are mentioned 
in the Investigator’s Brochure as occurring with a class of drugs or as anticipated from 
the pharmacological properties of the drug, but are not specifically mentioned as 
occurring with the particular drug under investigation. 
10.7 Reporting Procedures 
Clinical safety personnel will be available for SAE reporting on a 24-hour basis.  Reports 
will be reviewed during normal business hours.  Investigator instructions and sponsor 
requirements for safety reporting are outlined in 
 
respectively. 
 
The Medical Monitor for this study is
 
 
 
10.7.1 Investigator Reporting Requirements - SAE 
Site personnel must report any AE that meets SAE criteria or unusual frequency of AEs 
within 24 hours from the time staff is aware of the event to the medical monitor (or 
designee for this study), even if the event(s) appear to be unrelated to study treatment. 
 
Follow-up information about a previously reported SAE must also be reported to the 
medical monitor (or designee) within 24 hours of receiving it.  Follow-up reports 
regarding the status of the SAE and the subject’s subsequent course should be 
submitted until the SAE has subsided, the condition stabilized (in the case of persistent 
impairment), the subject receives alternative therapy, or the subject dies. 
 
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Electronic submission of initial and follow-up information and automatic e-mail 
notification of the Medical Monitor will occur when the investigator completes the SAE 
report form in the CRF.  Once submitted, the medical monitor or designee will send a 
confirmation email to the investigator within 1 business day.  In the event a confirmation 
email is not received, contact the Medical Monitor directly by phone, email or fax.  A 
confirmation of receipt will be sent within 1 business day. 
 
If the SAE has not been previously documented (ie, is a new occurrence) and it is 
thought to be related to the investigational product (or therapy), the medical monitor 
may contact the investigator to obtain further information.  If warranted, an investigator 
alert may be issued, to inform all investigators involved in any study with the same 
product (or therapy) that this SAE has been reported.  
 
The IRB should also be notified of SAEs and of any follow-up information in writing 
according to their reporting requirements. 
 
10.7.2 Sponsor Reporting Requirements 
Hallux must notify the FDA and all participating investigators of any potential serious 
risks associated with use of the study product as they are identified during this clinical 
trial.  This notification must be made as soon as possible but in no case later than 15 
calendar days (7 calendar days for fatal or life-threatening SARs) after determining that 
the information qualifies for reporting based on the following criteria: 
 
10.7.2.1 
Serious and unexpected suspected adverse reactions.   
The sponsor must report any suspected adverse reaction that is both serious and 
unexpected to all concerned Investigators/Institutions, to the Institutional Review Boards 
(IRBs), where required, and to the regulatory authority(ies).  A single or small number of 
events of a specific AE must be reported as a SAR only if there is a reasonable 
possibility that study product caused the event (ie, there is evidence to suggest a causal 
relationship between the study product and the AE).  For example: 
x A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure (eg, angioedema, hepatic injury, Stevens-Johnson 
Syndrome and acute liver failure); 
x One or more occurrences of an event that is not commonly associated with drug 
exposure, but is otherwise uncommon in the population exposed to the drug (eg, 
tendon rupture); 
x An aggregate analysis of specific events observed in a clinical trial (such as known 
consequences of the underlying disease or condition under investigation or other 
events that commonly occur in the study population independent of drug therapy) 
that indicates those events occur more frequently in the drug treatment group than a 
concurrent or historical control group. 
 
10.7.2.2 
Increased rate of serious suspected adverse reactions 
The sponsor must also report any clinically important increase in the frequency of a 
serious SAR over that which is listed in the protocol or Investigator’s Brochure. 
 
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10.7.2.3 
Unexpected fatal or life-threatening suspected adverse reactions 
The sponsor must notify the FDA of any unexpected fatal or life-threatening suspected 
adverse reactions as soon as possible but in no case later than 7 calendar days after 
the sponsor’s initial receipt of the information.   
 
Expedited reports should comply with the applicable regulatory requirement(s) and with 
the International Conference on Harmonisation (ICH) Guideline for Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting (E2A).  The Sponsor 
should submit to the regulatory authority(ies) all safety updates and periodic reports, as 
required by applicable regulatory requirement(s). 
 
 
 
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11 STATISTICAL CONSIDERATIONS 
A detailed and comprehensive Statistical Analysis Plan (SAP), describing all statistical 
analyses will be prepared and approved prior to database lock.  The statistical analysis 
and report will conform to relevant ICH guidance.  Any changes to the statistical 
methods need not be reported as a protocol amendment but must be documented in the 
clinical study report.  
11.1 Statistical Hypotheses 
 
11.2 Sample Size Determination 
 
 
 
11.3 Final Analysis Plan 
The standard summary statistics for analysis of the categorical baseline and outcome 
variables (
) will be count and 
proportion (expressed as percentage).  The following standard summary statistics will 
be used for analysis of continuous baseline and outcome variables: N, mean, standard 
deviation, median, quartiles, and maximum and minimum.  
 
11.3.1  Analysis Populations 
 
 
 
 
 
 
 
 
11.3.2 Demographics and Baseline Characteristics 
Subject demography and baseline characteristics will be presented in by-subject listings 
and summarized by descriptive statistics.  A separate summary and listing will be 
provided for subjects discontinued before randomization (Screen Failures). 
 
11.3.3 Prior and Concomitant Medications 
Prior and concomitant medication information for all randomized subjects will be 
presented in a by-subject listing. 
 
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11.3.4 Statistical Methods for Efficacy Parameters 
The appropriate standard summary statistics will be used for all efficacy variables. 
 
 
 
 
11.3.5 Safety Analysis 
Extent of exposure to study treatments will be summarized according to the number of 
subjects exposed and the total dose administered.  
 
Incidence, relatedness, and severity of AEs and SAEs will be tabulated by preferred 
term and system organ class using the most recent version of MedDRA.  Adverse 
events will be summarized by presenting the number and percentage of subjects having 
any AE, having an AE in each body system and having each individual AE. 
 
Of particular interest are the AEs involving administration site reactions (ie erythema, 
burning/stinging, itching, scaling, swelling/edema) and self-reported pain.  These will be 
listed separately and summarized by frequency counts at each visit and at each time 
point of the subject diary.  In addition, the incidence of SAEs, drug related AEs, serious 
and drug-related AEs, and any AEs resulting in discontinuation from the study will be 
listed. 
 
Vital signs measurements and physical examination findings, together with changes 
from baseline assessments, will be described using standard summary statistics. 
 
Baseline for all physical examination evaluations and vital signs measurements will be 
defined as the last evaluation just prior to the first administration of study treatment. 
 
 
 
 
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12 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
 
Source data are all information, original records of clinical findings, observations, or 
other activities in a clinical trial necessary for the reconstruction and evaluation of the 
trial.  Source data may be written or typed by authorized and qualified study personnel 
directly from clinical observation, or they may be generated, on paper or electronically, 
by an automated measurement device or system of devices. 
 
Source documents may include, for example, subject medical records, screening or 
enrollment logs, laboratory reports, electrocardiograms, subject diaries, drug dispensing 
and collection records, drug accounting logs, study notes, and study-related 
correspondence. 
 
In order to ensure the integrity of the study data, procedures must be in place to allow 
every element of the study data to be traced to its source.  It is the responsibility of the 
study monitor to verify that data recorded on the CRF are an accurate transcription of 
the source data.  The source documents are typically the property of the study site itself, 
and may include data that are not relevant to the study database and are therefore not 
subject to study-related quality control procedures.   
 
The study site must maintain a list of originators (persons, devices, and instruments) of 
all source data.  The list for persons should include signatures, initials, and user 
identification (user ID) tags that will permit a reviewer to trace the source data records to 
their originator. 
 
In order to facilitate source data verification of the CRF, all source documents must be 
maintained at the study site in individual subject folders.  While not strictly a source 
document, the original signed Informed Consent document is to be kept in the same 
folder for ease of review.  Source documents must be maintained in the same way for 
all enrolled study subjects and for screen failures (individuals who are screened for the 
study but who do not meet the entrance criteria). 
 
The investigator must assure that the subject’s anonymity will be maintained.  On all 
study documentation, with the exception of the consent form and subject identification 
logs, subjects will only be identified by their unique identification code and initials and 
will not be referred to by name. 
 
All records will be kept in a secure storage area with limited access.  Clinical information 
will not be released without the written permission of the subject (or the subject’s legal 
guardian), except as necessary for monitoring and auditing by the Sponsor, its 
designee, U.S. Food and Drug Administration (FDA) or other regulatory agencies, or the 
IRB. 
 
 
 
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13 QUALITY CONTROL AND QUALITY ASSURANCE 
As specified in the investigator’s agreement, the investigator agrees to allow the 
sponsor’s (or designated CRO’s) study monitor, quality assurance auditor, health 
authority inspector, and/or IRBs inspector direct access to all relevant source 
documents, and to allocate his/her time and the time of his/her staff to the 
auditor/inspector to discuss findings and any issues. 
13.1 Monitoring Procedures 
During the study, the study monitor will review the progress of the study on a regular 
basis to ensure adequate and accurate data collections.  Specific data verification 
procedures will be described in a study-specific monitoring plan that includes aspects of 
ongoing remote and periodical on-site monitoring activities.   
 
Monitoring site visits to review CRFs, subject case notes, administrative documentation 
including the investigator Site File, and telephone communications with site staff, will be 
performed throughout the study. 
 
At each study monitoring visit, the investigator will make available all records pertaining 
to the study.  To allow sufficient time to assemble documentation for the study monitor, 
monitoring visits will be confirmed in advance of planned visits. 
 
Significant or relevant communications with the Sponsor or sponsor’s designated study 
representative should be documented by the site and retained for the study file. 
13.2 Quality Assurance 
In addition to the routine monitoring procedures and to ensure compliance with GCP 
and all applicable regulatory requirements, the investigator(s)/Institution(s) will permit 
study-related audits, IRB review, and regulatory inspection(s), providing direct access to 
all source documents, drug records, and original CRFs at some or all of the study sites 
used in the study. 
 
The sponsor or sponsor’s representative, will provide prior notice of such a planned 
GCP audit, during or after completion of the study.  The investigator should promptly 
notify the sponsor or CRO of any audits scheduled by any regulatory authorities or IRB 
and promptly forward copies of any audit reports received to the sponsor. 
 
 
 
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14 ETHICS COMMITTEE REVIEW/INFORMED CONSENT 
14.1 Ethical Conduct of the Study 
The study will be conducted in accordance with ethical principles expressed in ICH 
E6(R1): Good Clinical Practice (GCP) guidelines, the WMA Declaration of Helsinki,28 
IRBs, and in accordance with the United States Title 21 Code of Federal Regulations 
(CFR) Part 50 Protection of Human Subjects. 
 
This study must be carried out in compliance with the protocol, applicable laws and US 
regulatory requirements. 
14.2 Institutional Review Board 
The final study protocol, subject informed consent form and other documentation or 
information provided subjects will be reviewed and approved by the IRB in compliance 
with local regulations.  Approval will be received in writing before initiation of the study. 
 
Any changes to the study design will be formally documented in protocol amendments 
and approved by the IRB prior to implementation, except in the case of changes made 
to protect subject safety, which will be implemented immediately. 
14.3 Informed Consent 
The investigator is responsible for obtaining informed consent from the subject after 
adequate explanation of the aims, methods, anticipated benefits, and potential hazards 
of the study and before any protocol-specific screening procedures or any study 
medications are administered.  The investigator or designee will answer any questions 
that may arise.  Subjects will be given the opportunity to discuss the study with their 
surrogates or think about it prior to agreeing to participate. 
 
This informed consent should be given by means of a standard written statement, 
provided in non-technical language.  The subject is required to read and review the 
document or have the document read to him or her before signing and dating it.  If 
written consent is not possible, oral consent can be obtained, if witnessed by a signed 
statement from one or more persons not involved in the study, mentioning why the 
subject was unable to sign the form.  No subject can enter the study before informed 
consent has been obtained from him/her, or his/her legally authorized representative. 
 
Subjects will also be asked to consent to allow the sponsor, sponsor representative, or 
external regulatory auditor to review their medical records to confirm compliance with 
GCP. 
 
The acquisition of informed consent should be documented in the subject’s clinical or 
research record and the informed consent form should be signed and personally dated 
by the subject and by the person who conducted the informed consent discussion.  The 
original signed informed consent form should be retained in the investigator Site File 
and a copy of the signed consent should be provided to the subject prior to participation 
in the trial. 
 
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The subjects will be informed that they may withdraw from the study at any time without 
prejudice to further treatment. They will receive all information that is required by local 
regulations and ICH guidelines. 
14.4 Exclusion of Women, Minorities, and Children (Special Populations) 
Individuals of any gender or racial/ethnic group may participate in this study as long as 
their age is between 18-74 inclusive. 
14.5 Disclosure and Confidentiality 
 
14.5.1 Confidentiality of Study Documentation 
By signing the protocol, the investigator agrees to keep all information provided by the 
sponsor in strict confidence and to request similar confidentiality from his/her staff and 
the IRB.  Study documents provided by the study sponsor (ie, protocols, investigators' 
brochures, CRFs and other material) will be stored appropriately to ensure their 
confidentiality.  The information provided by the sponsor to the investigator may not be 
disclosed to others without direct written authorization from the sponsor, except to the 
extent necessary to obtain informed consent from subjects who wish to participate in the 
trial. 
 
14.5.2 Privacy of Individual Health Information 
Subject confidentiality is strictly held in trust by the investigators, study staff, and the 
sponsor(s) and their agents.  This confidentiality is extended to cover testing of 
biological samples in addition to any study information relating to subjects. 
While all data records will be identified by the corresponding subject number, the 
identity of the subject will be held in confidential source documents at the study site.  No 
information concerning the study or the data will be released to any unauthorized third 
party except as specifically authorized by each individual subject in the written informed 
consent. 
 
The study monitor or other authorized representatives of the sponsor may inspect all 
study documents and records required to be maintained by the investigator, including 
but not limited to, medical records (office, clinic, or hospital) for the study subjects.  The 
clinical study site will permit access to such records.  All study personnel with access to 
this information are legally bound not to disclose it. 
14.6 Future Use of Stored Specimens and Other Identifiable Data 
De-identified digital images of the subject’s toenail(s) will be stored during the duration 
of the study at Canfield Scientific, before being archived at the sponsor after study 
completion. 
 
No biological samples will be stored for future use and no genetic testing will be 
performed.  
 
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15 DATA HANDLING AND RECORD KEEPING 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported.  All source documents should be completed in a neat, 
legible manner to ensure accurate interpretation of data.  The investigators will maintain 
adequate case histories of study subjects, including accurate case report forms (CRFs), 
and source documentation. 
15.1 Data Management Responsibilities 
Data collection and accurate documentation are the responsibility of the study staff 
under the supervision of the investigator.  All source documents and laboratory reports 
must be reviewed by the study team and data entry staff, who will ensure that they are 
accurate and complete.  Unanticipated problems and adverse events must be reviewed 
by the investigator or designee. 
 
Once recorded, the study data must be protected from unauthorized modification or 
deletion, and all authorized modifications and deletions must be securely linked in the 
permanent record with their author, time of change, and reason for change (ie, the audit 
trail must be maintained).  There must be a procedure whereby the PI certifies the data 
to be accurate and complete and releases the data for transmittal to the sponsor or 
CRO.  
 
Procedures and specifications for management of the study data once released to 
sponsor or CRO will be described in detail in a separate Data Management Plan to be 
approved by the sponsor.  This document will include definitions of the data sets and 
variables, references to prevailing SOPs, and descriptions of the following procedures: 
x Procedures for data management review and query processing; 
x Procedures for assignment and medical review of standard preferred-term coding of 
adverse events, concomitant medications, or other terminology collected in the study 
data; 
x Procedures for electronic data transfer of study data elements from external non-
CRF data sources, such as analytical, imaging, or other specialized laboratory 
services; 
x Procedures for certification and closure of the database prior to unblinding. 
 
Procedures for data collection and data management will be designed to ensure that 
each data element may be traced with a high level of confidence from its originator or 
recorder to its representation in the study database and then to its place in the analysis 
and integrated clinical study report according to GCP.  
 
At each stage in the data collection and management process, the data must be 
accessible for review by authorized parties, such as the study monitor, a designated 
auditor, and an FDA inspector. 
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15.2 Data Capture Methods 
The primary data collection tool for the study is an electronic data capture (EDC) or 
CRF system designed to record all the data required by the protocol in designated 
labeled fields.  A computer generated password and specific roles to access and use 
the EDC will be provided to study staff prior to study start.   
 
Each page of the CRF is headed by identifying information including the study number, 
subject number, and study visit number or time point. Entries to the CRF are made by 
authorized site staff according to written CRF Completion Guidelines for the study or as 
instructed by a qualified trainer at study initiation. 
 
Case report form entries may be written directly from clinical observation or they may be 
transcribed from source data recorded at an earlier time.  The originator of the data (ie, 
the individual making the observation or evaluation) date and time of the recorded event 
are captured electronically.  
 
Each CRF must be completed within 5 days of a visit, reviewed, and subsequently 
signed, and dated by the investigator as outlined in the project timeline.  The completed 
CRF will be reviewed by data management after monitoring is complete. A copy of the 
completed CRF will be provided to the investigator. The copy will remain at the site in 
the investigator’s files. 
 
Computer systems and devices which are used to produce electronic source documents 
must conform to the principles described in relevant regulatory guidances (eg, the 
FDA’s Draft Guidance [December 2010] on Electronic Source Documentation in Clinical 
Investigations, and references therein), which are designed to ensure the security and 
integrity of those data sources. 
15.3 Types of Data 
During the conduct of this study, safety and efficacy data will be collected in the CRF. 
Safety data consist of standard adverse event data as well as specific site 
administration reaction data.  Efficacy data consist of investigator assessments of clear 
nail and laboratory data from the Center of Medical Mycology and emergence of clear 
nail.  Outcome data include assessments of pain and ease of insertion. 
15.4 Schedule and Content of Reports 
The following reports will be generated during the conduct of this open label study to 
monitor study progress and quality.  
 
A screening log will be kept to monitor and analyze reasons for screen failure.  
 
The quality of subungual sampling will be assessed for the ability of the investigator to 
visualize septate hyphae.  In addition, results from the Center of Medical Mycology will 
be reviewed for evidence of bacterial contamination of the sample and the ability of a 
clinical diagnosis of DLSO to be confirmed by laboratory means. The review may lead 
to modifications to the subungual sampling technique at the site. 
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 digital image result reports issued for each subject at each visit, will be 
reviewed for photo quality, correct trimming of the nail, subungual sampling technique 
and congruence with sequential IGA results. 
 
Early terminations will be tracked in order to ensure that subjects return for their final 
visit.  Protocol deviations will be monitored and the determination of protocol deviations 
will be determined prior to unlocking the database. 
15.5 Study Records Retention 
The investigator is required to maintain all study documentation, including regulatory 
documents, copies of CRFs, signed informed consent forms, and records for the receipt 
and disposition of study medications, for a period of at least 2 years following the last 
approval date of a marketing application in an ICH region or until at least 2 years after 
the formal discontinuation of clinical development of the investigational product, 
whichever comes later. 
15.6 Publication and Data Sharing Policy 
Following completion of the study, the data may be considered for a formal presentation 
at a scientific meeting or for publication in a scientific journal.  In these cases, the 
Sponsor will be responsible for these activities and will work with the investigator(s) to 
determine how the manuscript is written and edited, the number and order of authors, 
the publication to which it will be submitted, and other related issues.  Data are the 
property of the Sponsor and cannot be published without prior authorization from the 
Sponsor, but data and publication thereof will not be unduly withheld. 
 
The publication or presentation of any study results shall comply with all applicable 
privacy laws, including, but not limited to, the Health Insurance Portability and 
Accountability Act (HIPAA) of 1996. 
15.7 Protocol Deviations 
The investigator or designee must document and explain in the subject’s source 
documentation any deviation, intentional or unintentional, from the approved protocol 
that may affect the subject’s rights, safety, or well being and/or the completeness, 
accuracy, and reliability of the study data.  
 
Protocol deviations will be documented by the clinical monitor throughout the course of 
monitoring visits.  Investigators will be notified of deviations in writing by the monitor and 
corrective action and preventative action plan will be instituted in accordance with 
sponsor’s SOPs.  The IRB will be notified of all protocol violations in a timely manner as 
per its guidelines. 
 
 
 
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16 LITERATURE REFERENCES 
 
 
 
 
 
 
 
 
 
 
 
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