Conditions: Onychomycosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 184
Healthy volunteers: yes

Brief summary:
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi- Site Phase 2b Clinical Study to Assess the Efficacy, Safety and Tolerability of 8-Week Regimens of NVXT topical product in Patients with Mild to Moderate Onychomycosis

Detailed description:
Evaluate safety and tolerability of the two regimens of NVXT (Treatment Groups A and B) in patients with mild to moderate distal subungual onychomycosis of the target toenail.

Arms:
arm 1: daily dosing for one 8-week treatment period (Treatment Group A) and two 8-week treatment periods separated by a 32-week rest period (Treatment Group B), arm 2: two 8-week treatment periods separated by a 32-week rest period (Treatment Group C),

Interventions: intervention 1: NVXT topical intervention 2: Placebo (Vehicle) Topical
Intervention descriptions: intervention 1: topical treatment intervention 2: Placebo (Vehicle) Topical

Protocol document:
Prot_001.pdf: 
CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens of N ovexatin ®' 1 0% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
1.0 
TITLE PAGE 
Drug Products 
Design 
Population 
Sponsor 
Protocol Number 
Novum Study Number 
IND# 
Protocol Date 
Novexatin 10% topical solution 
Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site 
Phase 2b Clinical study 
Male or female patients, age 18 or over, with mild to moderate fungal 
infection of the toenail 
Taro Pharmaceuticals USA, Inc 
NVXT 1404 
71442603 
111292 
July 08, 20 I 6 
This document is a confidential communication of Novum Pharmaceutical Research Services. Receipt of 
this document constitutes an agreement by the recipient that no unpublished information contained herein 
will be disclosed without Novum's written approval. 
71442603 Rev. 2 • July 08, 2016 • Novum Pharmaceutical Research Services • Page I of 62 
NIIRB 
July 19, 2016 
APPROVED 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
2.0 
KEY STUDY PERSONNEL AND FACILITIES 
Sponsor: 
CRO: 
Sponsor's Representatives: 
CRO representative: 
Medical Monitor: 
Biostatistician: 
Taro Pharmaceuticals U.S.A., Inc. 
3 Skyline Drive 
Hawthorne, NY 10532 
Novum Pharmaceutical Research Services (Novum) 
225 W. Station Square Drive, Suite 200 
Pittsburgh, P A 15219 
Natalie Y antovskiy 
Senior Director, Clinical Research 
Taro Pharmaceuticals U.S.A., Inc. 
Phone: 914-345-9001 Ext.6849 
Email: Natalie.Yantovskiy@Taro.com 
Deborah O'Neil PhD 
Chief Scientific Officer 
NovaBiotics Ltd. 
Email: deborah@novabiotics.co.uk 
Gail Gongas 
Vice President, Clinical Trials 
Novum Pharmaceutical Research Services 
Tel: 412-363-3300 x 522 
Fax: 412-291-3171 
Email: gdgongas@novumprs.com 
Paolo Maria Fanzio, MD 
Medical Monitor 
Novum Pharmaceutical Research Services 
Tel: 412-363-3300 x 597 
Fax: 412-924-0522 
Email: pmfanzio@novumprs.com 
Jianhua Liu, M.Sc. 
Senior Biostatistician 
Novum Pharmaceutical Research Services 
Tel: 647-779-6883 
Email: jliu@novumprs.com 
71442603 Rev. 2 • July 08, 2016 • Novum Pharmaceutical Research Services • Page 2 of 62 


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CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, I 0% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
PRINCIPAL INVESTIGATOR'S SIGNATURE 
I _________________ , agree to conduct the study (protocol # NVXT 1404, 
Rev 2) in accordance with FDA regulations, ICH guidelines and Good Clinical Practice. I understand that 
no deviations from the protocol may be made without the prior permission of the Sponsor (Taro 
Pharmaceuticals, USA, Inc.) or Novum Pharmaceutical Research Services, the company managing the 
study. 
Principal Investigator 
Date 
71442603 Rev. 2 • July 08, 20 I 6 • Novum Pharmaceutical Research Services • Page 4 of 62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
3.0 
TABLE OF CONTENTS 
1.0 
TITLE PAGE .................................................................................................................................... 1 
2.0 
KEY STUDY PERSONNEL AND FACILITIES ............................................................................ 2 
SIGNATURE PAGE ..................................................................................................................................... 3 
3.0 
TABLE OF CONTENTS .................................................................................................................. 5 
4.0 SYNOPSIS .............................................................................................................................................. 9 
5.0 
SCHEMATIC .................................................................................................................................. 17 
6.0 
LIST OF ABBREVIATIONS AND TERMS ................................................................................. 18 
7.0 
BACKGROUND INFORMATION ................................................................................................ l9 
7. 1 
Investigational product ............................................................................................................ 19 
7.2 
Background ............................................................................................................................... 19 
7.3 
Summary ofNovexatin Non-Clinical Studies ..................................................................... 20 
7.4 
Summary ofNovexatin Clinical Studies .............................................................................. 22 
8.0 
STUDY OBJECTIVES ................................................................................................................... 22 
9.0 
INVESTIGATIONAL PLAN ......................................................................................................... 23 
9.1 
Study Design and Plan Description ............................................................................................. 23 
9.2 
Selection of Study Design ........................................................................................................... 24 
9.3 
Selection of Study Population ..................................................................................................... 24 
9.3.1 
Inclusion Criteria ................................................................................................................. 25 
9.3 .2 
Exclusion Criteria ................................................................................................................ 26 
9.3.3 
Restrictions during the Study .............................................................................................. 27 
9.3.4 
Removal of Patients from the Study .................................................................................... 28 
9.3.5 
Early Terminations and Protocol Deviations ...................................................................... 29 
9.3.6 
Clinical Study Termination ................................................................................................. 30 
9.4 
Treatn1ents ................................................................................................................................... 30 
9.4.1 
Treatments Administration .................................................................................................. 30 
9.4.2 
Identity of Investigational Product ...................................................................................... 31 
9.4.3 
Method of Assigning Patients to Treatment Groups ........................................................... 32 
9.4.4 
Study Blind .......................................................................................................................... 33 
9.4.5 
Compliance ......................................................................................................................... 33 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 5 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
9.5 
Study Conduct ............................................................................................................................. 34 
9.5.1 
Visit 1: Day -35 to -1 (Screening) ....................................................................................... 34 
9.5.2 
Visit 2: Day 1 (Baseline and Randomization I 1st Treatment start) ..................................... 35 
9.5.3 
Visit 3: Day 57± 4 (1st Treatment completion; the last dose will be on Day 56) ............... 36 
9.5.4 
Visit 4: Day 141 ± 7 (lnterim) ............................................................................................. 36 
9.5.5 
Visit 5: Day 281 ± 14 (2nd Treatment start) ......................................................................... 37 
9.5.6 
Visit 6: Day 337 ± 14 (2nd Treatment completion; the last dose should be applied the day 
before Visit 6) ..................................................................................................................................... 38 
9.5.7 
Visit 7: Day 365 ± 14 (4 weeks post-treatment or Early Termination) ............................... 39 
9.6 
Study Procedures ......................................................................................................................... 40 
9.6.1 
Infonned Consent ................................................................................................................ 40 
9.6.2 
De1nographics ..................................................................................................................... 40 
9.6.3 
Medical History ................................................................................................................... 40 
9.6.4 
Vital Signs ........................................................................................................................... 40 
9.6.5 
Physical Exam ..................................................................................................................... 40 
9.6.6 
Concomitant Medication Use .............................................................................................. 41 
9.6.7 
Pregnancy Test .................................................................................................................... 41 
9.6.8 
Dispensing StudyProduct ................................................................................................... 41 
9.6.9 
Collecting Study Product .................................................................................................... 41 
9.6.1 0 
Dosing Instructions and Diary ............................................................................................. 41 
9.6.11 
Dosing Coinpliance ............................................................................................................. 41 
9.6.12 
Target Nail Trin11ning ......................................................................................................... 42 
9.6.13 
Visual Assessment and Planimetry .................................................................................... .42 
9.6.16 
KOH Stain ........................................................................................................................... 43 
9 .6.17 
Sample for Mycological Culture ......................................................................................... 43 
9.6.18 
Application Site Reactions: ................................................................................................ .43 
9.6.19 
Health Status/Adverse Events ............................................................................................. 44 
9.7 
Adverse Events ............................................................................................................................ 44 
9.7.1 
Definitions ........................................................................................................................... 44 
9. 7.2 
Severity of Adverse Event.. ................................................................................................ .45 
9.7.3 
Relationship of Adverse Event ............................................................................................ 45 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 6 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens of N ovexatin ®' 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
9.8 
Serious Adverse Events ............................................................................................................... 46 
9.8.1 
Definition ............................................................................................................................ 46 
9.8.2 
Repoiiing ............................................................................................................................. 46 
10.0 
STATISTICAL METHODS ........................................................................................................... 47 
10.I 
Statistical Plan ............................................................................................................................. 47 
10.2 
Determination of Sample Size ..................................................................................................... 47 
10.3 
Study Populations ........................................................................................................................ 48 
1 0.3.1 
Intent-to-Treat Population (ITT) ......................................................................................... 48 
I0.3.2 
Safety Population ................................................................................................................ 48 
10.4 
Baseline Co1nparability ............................................................................................................... 48 
I 0.5 
Efficacy Endpoints ...................................................................................................................... 48 
10.6 
Efficacy Analyses ........................................................................................................................ 49 
10.6 
Safety Analysis ............................................................................................................................ 50 
11.0 
REGULATORY OBLIGATIONS .................................................................................................. 52 
11.1 
Institutional Review Board .......................................................................................................... 52 
II.2 
Study Docu1nentation .................................................................................................................. 52 
II.2.I 
Protocol ............................................................................................................................... 52 
1I.2.2 
Infonned Consent ................................................................................................................ 52 
1I.2.3 
Protocol and Informed Consent Changes ............................................................................ 52 
Il.2.4 
Source Documents and Case Report Forms ........................................................................ 53 
I1.2.5 
Drug Accountability ............................................................................................................ 53 
II.2.6 
Drug Storage ....................................................................................................................... 53 
II.2.7 
Pregnancies ......................................................................................................................... 53 
II.2.8 
Withdrawals due to Adverse Events ................................................................................... 53 
Il.2.9 
Reporting Safety Information to the IRB ............................................................................ 54 
II.2 .I 0 
Record Retention ............................................................................................................. 54 
11.2.11 
Study Monitoring and Auditing ...................................................................................... 54 
I1.2.12 
End of the Trial ............................................................................................................... 54 
I1.2.13 
Clinical Study Report ...................................................................................................... 54 
13.0 APPENDICES ..................................................................................................................................... 55 
APPENDIX A ......................................................................................................................................... 55 
71442603 Rev. 2 • July 08, 2016 • Novum Pharmaceutical Research Services • Page 7 of 62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
APPENDIX B ......................................................................................................................................... 56 
APPENDIX C ......................................................................................................................................... 5? 
APPENDIX D ......................................................................................................................................... 58 
APPENDIX E .......................................................................................................................................... 59 
APPENDIX F .......................................................................................................................................... 60 
14.0 
REFERENCES ................................................................................................................................ 62 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 8 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
4.0 SYNOPSIS 
Protocol Number 
NVXT 1404 (Novum study# 71442603) 
Title 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-
Site Phase 2b Clinical Study to Assess the Efficacy, Safety and Tolerability 
of 8-Week 
Regimens 
of Novexatin®l 0% 
Topical 
Solution 
(Taro 
Pharmaceuticals, 
USA, 
Inc.) 
111 
Patients 
with 
Mild 
to 
Moderate 
Onychomycosis 
Objectives 
1. Determine the rates of therapeutic cure of Novexatin® 10% topical 
solution (Taro Pharmaceuticals, USA) after daily dosing for one 8-week 
treatment period (Treatment Group A) and two 8-week treatment 
periods separated by a 32-week rest period (Treatment Group B), and 
Placebo (vehicle) topical solution (Taro Pharmaceuticals, USA) after 
two 8-week treatment periods separated by a 32-week rest period 
(Treatment Group C), at three test-of-cure visits (Day 141, Day 281 and 
Day 365) 
111 patients with mild to moderate distal subungual 
onychomycosis of the target toenail. 
2. 
Compare rates of therapeutic cure between Treatment Groups according 
to a hierarchical evaluation scheme detailed in the statistical sections. 
3. 
Evaluate safety and tolerability of the two regimens ofNovexatin® 10% 
topical solution (Treatment Groups A and B) in patients with mild to 
moderate distal subungual onychomycosis ofthe target toenail. 
Sponsor 
Taro Pharmaceuticals, USA, Inc. 
Study Products 
Test: Novexatin®10% Topical Solution 
Placebo: Placebo (Vehicle) Topical Solution 
Study Design 
Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site 
Phase 2b 
Study Population 
Up to 180 male or female patients, age 18 or over, with mild to moderate 
fungal infection ofthe toenail. 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 9 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, I 0% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
Study Conduct 
Inclusion Criteria 
Patients will be randomly assigned to the following treatment groups, with up 
to 60 patients per group 
Treatment Group A: Test treatment for Days 1 - 56 and Placebo treatment 
for Days 281-336 
Treatment Group B: Test treatment for Days 1- 56 and Days 281-336 
Treatment Group C: Placebo treatment for Days 1 -56 and Days 281 - 336 
Patients will be scheduled for a total of 7 clinic visits: 
• 
Visit 1: Days -3 5 to -1 (Screening) 
• 
Visit 2: Day 1 (Baseline and Randomization I 1st Treatment start) 
• 
Visit 3: Day 57± 4 (1st Treatment completion) 
• 
Visit 4: Day 141 ± 7 (Interim) 
• 
Visit 5: Day 281 ± 14 (2nd Treatment start) 
• 
Visit 6: Day 337 ± 14 (2nd Treatment completion) 
• 
Visit 7: Day 365 ± 14 (4 weeks post-treatment) 
Unscheduled visits will be allowed as deemed necessary by Investigator. 
I. 
Male and female patients aged 18 or over. 
2. 
Clinical diagnosis of onychomycosis of the target toenail (defined as 
one of the infected great toenails). 
3. 
Onset of clinical signs of onychomycosis of the target toenail < 2 
years of the screening. 
4. 
Clinical signs and symptoms of onychomycosis, confirmed by 
positive KOH microscopy of the target toenail. 
5. Before randomization, a confirmed positive fungal culture, of the 
target toenail. 
6. 
Mild to moderate severity at Visit 1 as defined by Investigator's 
estimation of approximately 10% to 35% toenail involvement. 
7. 
At least 5 mm of clear nail on the target toenail between the lunular 
proximal nail fold and the deepest extend of the onychomycosis. 
8. The deepest extend of onychomycosis should not contact the lunula. 
9. 
Besides onychomycosis, patients are in overall good health, or have a 
condition under stable treatment and are willing to comply with 
adequate foot care for the duration of the study. 
10. Females of childbearing potential must not be pregnant or lactating at 
baseline (as confirmed by a negative urine pregnancy test with a 
sensitivity of less than 25 mlU/mL or equivalent units of human 
chorionic gonadotropin). Women of childbearing potential must 
agree to the use of a reliable method of contraception (e.g., total 
abstinence, IUD, a double-barrier method [such as condom plus 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 10 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
Exclusion Criteria 
diaphragm with spermicide], oral, transdermal, injected or implanted 
non- or hormonal contraceptive), throughout the study. If the female 
is using a hormonal contraceptive, the same product must be taken 
for 1 month before baseline and must agree not to replace with some 
other hormonal contraceptives during the study. A sterile sexual 
partner is not considered an adequate form of birth control. 
All females will be considered to be of childbearing potential unless they: 
• 
Are post-menopausal, defined as women who have been 
amenorrheic for at least 12 consecutive months, without other 
known or suspected primary cause. 
• 
Have been sterilized surgically or who are otherwise proven 
sterile (i.e., total hysterectomy or bilateral oophorectomy) with 
surgery at least 4 weeks before baseline. Tubal ligation will not 
be considered a surgically sterile method. 
Female patients of childbearing potential are defined as: 
• 
Women without prior hysterectomy of at least 4 weeks, or who 
have had any evidence of menses in the past 12 months. 
• 
Females who have been amenorrheic for ~ 12 months, but the 
amenorrhea ts possibly from other causes, including pnor 
chemotherapy, anti-estrogens or ovarian suppression. 
11. Signed informed consent form which meets all current ICH/FDA 
regulations. 
1. Patients under 18 years of age. 
2. Females who are pregnant, lactating or likely to become pregnant 
during the study. 
3. Patients with proximal onychomycosis, dermatophytomas, fungal 
spikes, 
limited 
lateral 
onychomycosis, 
white 
superficial 
onychomycosis or significant dystrophy of the target toenail that in 
the Investigator's opinion 
would 
unpmr the 
evaluation 
of 
onychomycosis. 
4. Patient has total dystrophic or proximal subungal onychomycosis of 
the target toenail. 
5. 
History or current diabetes and/or peripheral vascular disease. 
6. 
Presence of mycotic spikes or patient has exclusively lateral groove 
involvement of the target toenail. 
7. Patients with distal nail plate thickness of the target toenail greater 
than 3 mm. 
8. 
Patient had no new nail growth requiring nail trimming in the target 
toenail over the previous 2 months. 
9. 
Previous treatment for onychomycosis of the toenail within the last 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 11 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofN ovexatin ®' 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
12 months that was unresponsive to treatment. 
10. Onychomycosis not caused by a dermatophyte (e.g., mold infection, 
Candida spp or bacterial infection). 
11. Patients with a history of a trauma involving nail bed of the target 
toenail before onset of clinical signs of onychomycosis. 
12. Patients with any significant active or past medical condition or 
abnormal laboratory value or who are required to start a medical 
therapy that in the opinion of the Investigator would make them 
unsuitable for study participation or compromise patient safety. 
13. Patients who are unable to reach their infected toenails and 
administer the study product to affected toes. 
14. Patients who are likely to apply toenail polish, cosmetic products or 
undergo professional pedicures during the study. 
15. Current or history of psoriasis or Lichen planus within the previous 
12 months. 
16. Immunocompromised either because of concomitant disease (e.g., 
HIV), or ongoing treatment (e.g., chemotherapy), including patients 
with a history of organ transplant and patients on long-term 
corticosteroid therapy (refer to paragraph 9.3.3 for use of 
concomitant corticosteroid therapy). 
17. Receipt of any drug as part of a research study within 30 days prior to 
dosing. 
18. Use within 4 weeks before baseline of 1) topical antifungal therapies 
on the feet, 2) immunomodulators or 3) systemic corticosteroids. 
19. Use of topical corticosteroids on the feet within 2 weeks before 
baseline. 
20. Use 
of systemic 
antifungal 
agents 
for 
the 
treatment 
of 
onychomycosis or any antifungal with known activity against 
dermatophytes within the previous 24 weeks. 
21. Current evidence of drug abuse or history of drug abuse within 1 year 
before the first dose, including, in the opinion of the Investigator, 
history of alcohol abuse or active alcoholism. 
22. Inability to understand the protocol requirements, instructions, and 
study-related 
restrictions, 
the 
nature, 
scope, 
and 
possible 
consequences ofthe clinical study. 
23. Unlikely to comply with the protocol requirements, instructions, and 
study-related restrictions, such as uncooperative attitude, inability to 
return for follow-up visits, and improbability of completing the 
clinical study. 
24. Patient is the Investigator or his/her deputies, research assistant, 
pharmacist, clinical study coordinator, other staff or relative thereof 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 12 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
Route of 
Administration 
Treatment 
Efficacy 
Endpoints 
directly involved in the conduct of the clinical study or employed by 
the clinical site, or a first-degree relative of a site employee. 
25. Patients with previous exposure to the study drug, or with known 
allergy to the drug or any of its components. 
Topical 
Thin coat of study product will be applied to all toenails on feet with affected 
toenails once daily for either one or two 8-week intervals over an 
approximate 11-month intermittent treatment period (at Days 1 - 56 and 
Days 281 
336) and 12-month study duration. 
The product should be applied at approximately the same time every day, 
preferably in the morning, after the patient has washed all toes with a non-
medicated cleanser, rinsed with warm water, and patted dry with soft towel. 
The nails should be completely dry before applying the study treatment. 
The primary endpoint is the propmiion of patients in each treatment group 
with a complete therapeutic cure of onychomycosis of the target toenail 
assessed at each of the two test-of-cure visits (Day 141 and Day 365). 
The secondary endpoint-1 is the proportion of patients in each treatment 
group with a complete or almost complete therapeutic cure of onychomycosis 
of the target toenail assessed at each of the two test-of-cure visits (Day 141 
and Day 365). 
The secondary endpoint-2 is the proportion of patients in each treatment 
group with a mycological cure of the target toenail assessed at each of the 
two test-of-cure visits (Day 141 and Day 365). 
The secondary endpoint-3 is the proportion of patients in each treatment 
group with a complete clinical cure of the target toenail assessed at each of 
three test-of-cure visits (Day 141, Day 281 and Day 365). 
The secondary endpoint-4 is the proportion of patients in each treatment 
group with a satisfactory clinical cure of the target toenail assessed at each of 
three test-of-cure visits (Day 141, Day 281 and Day 365). 
Complete therapeutic cure IS defined as both complete clinical and 
mycological cure of the target toenail 
Almost complete therapeutic cure is defined as both mycological and 
satisfactory clinical cure of the target toenail 
Mycological cure is defined as a negative KOH test and a negative fungal 
culture. 
Complete clinical cure is defined as 0% nail involvement. 
Satisfactory clinical cure IS defined as :'S 5% of the target toenail 
involvement. 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 13 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
Safety Endpoints 
Sample Size 
Determination 
Statistical 
Analyses 
Adverse events will be classified using standard MedDRA terminology 
Version 19 or higher and summarized by treatment group. Adverse events 
reported during the study will be tabulated in a summary table listing the 
type, date of onset, date of resolution, incidence, severity, outcome, action 
taken, and Investigator's opinion of relationship to the study product. Signs 
and symptoms of onychomycosis will not be considered adverse events, 
unless in the Investigator's opinion, they have increased in frequency and/or 
severity to such an extent that the Investigator/patient considers that it is in 
the patient's best interest to be dropped from continued participation in the 
study and given alternative therapy for their onychomycosis. 
If sufficient data exist, adverse event frequencies will be compared between 
treatments using Fisher's exact test or a similar test. 
Concomitant medication use during the study will be tabulated by patient. 
The primary statistical analysis of interest is a comparison of the rates 
(propmiion of patients) of Complete Therapeutic Cure of N ovexatin ® 1 0% 
topical solution to the rate of Complete Therapeutic Cure of placebo in the 
Intent-to-Treat Population (ITT). The rates of Complete Therapeutic Cure for 
the Novexatin® 10% topical solution 8-week treatment regimens are expected 
to be approximately 49%. The rate of Complete Therapeutic Cure for placebo 
is expected to be approximately 21%. Approximately 46 patients in each 
treatment group in the ITT population will provide at least 80% power to 
show a difference at p < 0.05 (two-sided Z test and a pooled response rate for 
the standard error of the difference in proportions) between each of the active 
treatment groups and the placebo group. To allow for a 23% drop-out rate, a 
total of 180 patients will be enrolled in the study, with up to 60 patients in 
each ofthe treatment groups. 
Safety: All safety parameters will be listed and summarized descriptively. 
Changes from baseline will be calculated, if appropriate. 
Efficacy: In order to preserve an overall type-1 error (alpha) of 5%, a 
hierarchical evaluation scheme for evaluation of complete and almost 
complete therapeutic cure, complete and satisfactory clinical cure and 
mycologic cure will be employed for the primary and secondary endpoints. 
The four comparisons of interest for the primary endpoint and the secondary 
endpoints -1 and -2 are: 
1. 
Group B versus Group C 
at the test-of-cure visit at Day 365 
2. 
Group A versus Group C 
at the test-of-cure visit at Day 365 
3. 
Group B versus Group A- at the test-of-cure visit at Day 365 
4. 
(Group A + Group B) versus Group C - at the test-of-cure visit at 
Day 141 
71442603 Rev. 2 • July 08, 2016 • Novum Pharmaceutical Research Services • Page 14 of 62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
The five comparisons of interest for the secondary endpoints -3 and -4 are: 
1. 
Group B versus Group C-at the test-of-cure visit at Day 365 
2. 
Group A versus Group C-at the test-of-cure visit at Day 365 
3. 
Group B versus Group A- at the test-of-cure visit at Day 365 
4. 
(Group A+ Group B) versus Group C-at the test-of-cure visit at 
Day 281 
5. 
(Group A+ Group B) versus Group C-at the test-of-cure visit at 
Day 141 
Statistical testing will begin with comparison 1. If statistical significance is 
attained with comparison 1 (p < 0.05), then a claim of superiority for 
comparison 1 can be made and the next comparison in the hierarchical 
evaluation scheme can be tested for statistical significance. If statistical 
significance is not attained for comparison 1 (p 2: 0.05), then testing of all 
subsequent comparisons is stopped. The hierarchical, conditional-stepwise 
evaluation scheme allows for each comparison to be evaluated at the 5% 
level, while preserving an overall type I error rate of no more than 5%. For 
the proportion of patients in each treatment group with a therapeutic, clinical 
or mycological cure of onychomycosis in the treatment area, the statistical 
analysis for superiority will be conducted using two-sided Z-Tests and a 
pooled response rate for the standard error of the difference in proportions for 
each comparison of interest. The primary and secondary analyses will be 
performed using an observed case (OC) analysis in the Intent-to-Treat (ITT) 
population. Patients discontinued because of lack of treatment effect will be 
included in the primary analysis as treatment failures. 
The following two sensitivity analyses will also be performed on the primary 
efficacy endpoints in the hierarchical, conditional-stepwise evaluation 
scheme: 
1. Analysis will be performed also including patients without an assessment 
at Day 365 ± 14. Patients with missing data at Day 365 ± 14 will be 
considered therapeutic failures. 
2. 
Analysis will be performed also including patients without an assessment 
at Day 365 ± 14. Patients in Group C with missing data at Day 365 ± 14 
will be treated as therapeutic successes and patients from the Groups A 
and B with missing data at Day 365 ± 14 will be treated as therapeutic 
failures. 
Similar sensitivity analyses on the primary endpoint will be conducted 
including patients without an assessment at Day 141 ± 7 for the 4th 
comparison in the hierarchical, conditional-stepwise evaluation scheme. 
Efficacy results will be used to calculate the sample size for the Phase 3 
studies. 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 15 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens of N ovexatin ®' 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 16 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
5.0 
SCHEMATIC 
Visit I 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
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Day 
-35 to -I 
I 
(Week 
(Week 
8) 
(Week 20) 
40) 
Informed Consent 
X 
Inclusion/ Exclusion Criteria Review 
X 
X 
Demographics 
X 
Medical History 
X 
Physical Examination 
X 
Vital Signs 
X 
X 
X 
KOH test 
X 
X 
Fungal Culture collection 
X 
X 
Clinical Lab Tests 
X 
X 
Target Nail trimming (if needed) 
before nail involvement/appearance 
X 
X 
X 
X 
assessments 
Target toenail involvement (assessed 
X 
X 
X 
X 
X 
by visual assessment)* 
Planimetry Assessment 
X 
X 
X 
X 
Evaluation oftoenail 
condition/appearance (by patient and 
X 
X 
X 
X 
investigator) 
Investigator Clinical Assessment 
X 
X 
X 
X 
X 
Urine Pregnancy Test** 
X 
X 
X 
X 
X 
Dispense study product, supplies 
X 
X 
Dispense Diary/Instructions 
X 
X 
X 
X 
Application site reactions 
X 
X 
X 
Collect unused/empty bottle 
X 
Collect and Review Patient Diary 
X 
X 
X 
Adverse Event Assessments 
X 
X 
X 
X 
Concomitant Medication Review 
X 
X 
X 
X 
X 
Schedule next visit 
X 
X 
X 
X 
X 
.. 
~At VIsit I, both toenails will be assessed If a bilateral mfectwn ofthe big toenails are present. 
* * All women of childbearing potential 
Visit 6 
Visit 7 
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X 
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X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 17 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, I 0% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
6.0 
LIST OF ABBREVIATIONS AND TERMS 
Abbreviation 
Term 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
c 
Celsius 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
CTCAE 
Common toxicity criteria for Adverse Events 
eCTD 
electronic Common Technical Document 
ELISA 
Enzyme-Linked Immunosorbent Assay 
FDA 
Food and Drug Administration 
FU 
Follow Up 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IUD 
Intrauterine Device 
kg 
kilograms 
KOH 
Potassium hydroxide 
LLOQ 
Lower Limit of Quantitation 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
ml 
milliliter 
!-11 
microliter 
NOAEL 
No Observed Adverse Effect Level 
NDA 
New Drug Application 
OHRP 
Office of Human Rights Protection 
OTC 
Over-the-Counter 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
USA 
United States of America 
USP 
United States Pharmacopeia 
w/v 
Weight per volume 
71442603 Rev. 2 • July 08, 2016 • Novum Pharmaceutical Research Services • Page 18 of 62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
7.0 BACKGROUND INFORMATION 
7.1 
Investigational product 
10% Novexatin 
Chemical name: Cyclo[ arginyl-arginyl-arginyl-arginyl- arginyl-arginyl-arginyl], acetate 
Chemical formula: C42Hs4N2s07 
7.2 
Background 
Onychomycosis (tinea unguium) is a fungal infection of the toenails that is predominantly 
caused by dermatophytic fungi. The most common clinical pattern of onychomycosis is 
distal subungual onychomycosis (DSO), in which the distal edges of the nail plate are the 
initial site of invasion by the causative fungi beginning at the hyponychium. The infecting 
organism migrates proximally through the underlying nail matrix. Mild inflammation 
develops resulting in focal parakeratosis and subungual hyperkeratosis. 1•2 The nail 
becomes thick and opaque in color. Additionally, the nail can also become rough and 
crumbly. Almost all species of dermatophytes have been associated with onychomycosis, 
but the major dermatophytes associated with this condition (worldwide) are Trichophyton 
rub rum, 
and 
T mentagrophytes. 
Other 
dermatophytes less 
commonly linked to 
onychomycosis are T tonsurans, T violaceum, Epidermophyton jloccosum, T schoenleinii, 
T. concentricum, 
and, rarely, Microsporum gypseum, M 
canis, M 
audouinii, T 
soudanense, and T. gourvilii. 
Population surveys have confirmed that such fungal infections of the nail affect more than 
I 0% of the population in developed countries, 1- 3 and more than 50% in some sub-
populations.4 The incidence of onychomycosis has been increasing, owing to such factors 
as diabetes, immunosuppression and increasing age. 1 
In the Amazon region, the 
dermatophytoses have the highest incidence among the superficial mycotic infections. This is 
attributable to environmental factors characteristic of this region, such as the high temperature 
and relative humidity, which provide conditions favorable to fungal dispersion and development. 5 
Onychomycosis can cause pain, discomfort and disfigurement and may produce serious 
physical and occupational limitations, as well as reducing quality of life. 
Treatment of fungal toenail infection requires an understanding of the ultrastructure of the 
nail. Keratinocytes exist within the nail plate and are strongly linked by numerous 
desmosomes and phospholipid layers. The nail plate consists of 3 different layers: a thin 
ventral plate, a thick intermediate plate, and a thin dorsal plate (Figure 1). The cells of the 
dorsal plate are very flat and lack nuclei. The cells of the intermediate plate are less flat 
and have cytoplasmic portions. The ventral plate consists of 1-2 cell layers with nuclear 
residues. As a result of their composition and structure, the 3 nail plate layers can have 
different penetration characteristics for a medicinal product. 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 19 of62 


CONFIDENTIAL. PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
Figure 1: Anatomy of the Nail 
Nail plat<? 
Lunula -il-il-ilc+ 
Proximal 
nail fold -$-"-c--:-:-=---'-'--'--:':--~. 
Cuticle or 
<?ponychium 
Lateral -----" 
nail fold 
Nail plate 
Dorsal !a}'E't' ----, 
Hyponychium 
Nail bed 
Nail matrix 
At present, the currently approved, marketed medicinal products available for the treatment of 
fungal nail infection have a number of shOJicomings in regard to both safety and efficacy?·6-8 The 
topical therapies ( ciclopirox and amorolfine) have poor levels of efficacy.9 The systemic 
treatment options (terbinafine and itraconazole especially) have associated adverse effects and 
toxicity profiles of concern. 10•11 Several authors reported liver toxicity and therefore monitoring 
of liver function during itraconazole therapy is imp01iant. 11 This unmet clinical need and a 
detailed understanding of host-pathogen interactions and the microbiology of fungal toenail 
infection have led to the development of Novexatin® by NovaBiotics. Novexatin is a backbone 
cyclized peptide of 7 L-isomer arginine residues; the chemical name is cyclo[arginyl- arginyl -
arginyl - arginyl - arginyl - arginyl - arginyl - arginyl ], acetate. The L-isomer component 
comprises 93% of the Cyclo[7xArg] material with 7% as a single amino acid in the D-
configuration.12 This third-generation, cationic antimicrobial peptide (cAMP) provides the active 
component of a treatment for topical administration for fungal infection of the nail. Novexatin has 
the potential to address the significant efficacy and safety shortcomings of the limited number of 
current and emerging treatment options of onychomycosis. 
7.3 
Summary of Novexatin Non-Clinical Studies 
From in vitro antifungal susceptibility studies novexatin exhibited dose-dependent fungicidal 
activity (median MIC90 of 1 mM) and killed Trichopyton spp. via membranolysis within 3 
hours of exposure in infected nail fragments. 13 Treatment with Novexatin I 0% for 28 days 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 20 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
cleared quantifiable fungi in infected nail fragments and eradicated fungal growth in an ex vivo 
full thickness human toenailmodel. 13 
Single and repeated-dose toxicology studies by the intravenous, oral and dermal routes of 
administration have been performed with novexatin. 14 No signs of local or systemic toxicity 
were seen in minipigs during repeated-dose dermal toxicology studies with up to 50 mg/kg/day 
of novexatin (> lOX proposed clinical dose) topically applied in the proposed clinical 
formulation. The dermal no-observed-adverse-effect level (NOAEL) was 50 mg/kg/day. 14 
Acute toxicity studies with intravenous doses of novexatin in rats and dogs identified the 
maximum tolerated dose (MTD) to be 2 mg/kg/day with the no observed adverse effect level 
(NOAEL) of 0.5 mg/kg/day in male rats and 1.25 mg/kg/day in female rats. 14 In rats, 
toxicological signs seen at higher doses included transient signs such as abnormal respiration, 
subdued behavior, hunched posture, body held low, and rolling gait. 
Histopathology 
examination identified signs of kidney tubule regeneration in some animals dosed above the 
NOAEL. In a mouse study to investigate the potential oral toxicity mediated by a single dose 
of novexatin in the proposed clinical formulation an MTD of approximately 260 mg/kg was 
identified. 14 The toxicological profile of the D- and L-enantiomers is equivalent and their 
bioactivity is identical. 12 
Toxicokinetic evaluations in the repeat studies showed no quantifiable plasma concentrations 
of novexatin in the minipig dermal administration study.12'14 Plasma data from the intravenous 
rat repeated-dose study showed a terminal plasma half-life (tv,) of approximately 3-6 
hours.J2,14 
An ex vivo study showed an average 3.53% of the radiolabelled novexatin applied to the 
surface of the nail was able to penetrate deep into the nail plate of uncompromised (i.e., by 
infection) intact full- thickness human nail. 
In a human skin penetration study, novexatin absorption was minimal, accounting for 0.01% of 
the applied dose. 12 This low systemic exposure was also observed in dermal sensitization 
studies where the systemic exposure was below the lower limit of quantification (LLOQ) of 
the bioanalytical assay employed to monitor serum levels. Owing to the minimal systemic 
exposure seen from in vitro and in vivo dermal studies, major organ systems are not expected to 
be exposed to measureable levels ofnovexatin. 
Details of the results of the 
non-clinical studies are provided 
111 the Novexatin 
Investigator's Brochure. 12 
In a 60-Day Dermal (Semi-Occluded) Toxicity Study in the Minipig with a 14-Day Treatment-
Free Period novexatin in a new formulation, administered by dermal application daily to the back 
for at least 60 consecutive days to the minipig, at concentrations of 5 % and 10 % was well 
tolerated. There was no evidence of either local or systemic target organ toxicity after the 
treatment period. 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 21 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens of N ovexatin ®' 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
7.4 
Summary of Novexatin Clinical Studies 
In Phase I/IIa studies with topical administration of Novexatin (referred to as a 9.3% 
solution representing 93 mg/mL of the L-configuration, equivalent to the current 10% 
solution) in 40 otherwise healthy patients with mild-moderate fungal infection of the 
toenail(s) on no current topical or systemic antifungal therapy showed a low incidence of 
adverse events (AEs ). 12 AEs judged possibly related to study product were limited to 
application site reaction and headache. For AEs overall and for the events judged 
possibly related, the incidences among Novexatin- and placebo-treated patients were 
similar. Plasma concentrations of novexatin were below the lower limit of quantitation 
of the enzyme-linked immunosorbent assay (ELISA). 12 
In a Phase I study the systemic exposure and pharmacokinetics of novexatin in a new 
formulation was determined after repeated once-daily topical application of Novexatin 
solution, 10% in a maximal-use setting in adult patients with distal subungual onychomycosis 
of the toenails and in healthy adult subjects without onychomycosis. Safety was assessed 
through the evaluation of changes from pre-dose in physical examination findings, vital signs, 
clinical laboratory findings, 12-lead ECGs and by the occurrence of adverse events (type, 
frequency, severity) and premature discontinuations from study. 
The results of this An Open-Label, Multiple-Dose, Safety and Pharmacokinetic Study of 
Novexatin® Solution, 10% in Healthy Adult Volunteers and in Patients with Severe Distal 
Subungual Onychomycosis study demonstrate that Novexatin solution 10% is safe and plasma 
concentrations of novexatin were below the lower limit of quantitation of the enzyme-linked 
immunosorbent assay (ELISA) following 28-day maximum-use once-daily topical doses in 
healthy subjects and patients with severe DSO. 
No serious AEs were reported during the conduct of this study. The study product was well 
tolerated by all subjects. There were no screening or post-study laboratory results outside of 
normal range that were deemed Clinically Significant by the Investigator. All vital signs 
measurements were within normal range, returned to normal after repeated measurements, or 
were deemed Not Clinically Significant by the Investigator, except for subject 072, who had 
unrelated hypertension and began therapy after following up with primary care physician. 
There were no episodes of application site reactions. There were no AEs possible or probable 
related to the study product. 
The Phase Ila pilot multiple-dose study determined the safety, tolerability and efficacy of 
Novexatin in a new formulation in patients with mild-to-moderate fungal infection of the 
toenail. 
8.0 
STUDY OBJECTIVES 
1. Determine the rates of complete therapeutic cure of Novexatin® 10% topical solution (Taro 
Pharmaceuticals, USA) after daily dosing for one 8-week treatment period (Treatment Group 
A) and two 8-week treatment periods separated by a 32-week rest period (Treatment Group 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 22 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
B), and Placebo (vehicle) topical solution (Taro Pharmaceuticals, USA) after two 8-week 
treatment periods separated by a 32-week rest period (Treatment Group C), at three test-of-
cure visits conducted at Day 141, Day 281 and Day 365 in patients with mild to moderate 
distal subungual onychomycosis of the target toenail. 
2. Compare rates of complete therapeutic cure between Treatment Groups according to a 
hierarchical evaluation scheme detailed in the statistical sections. 
3. Evaluate safety and tolerability of the two regimens ofNovexatin® 10% topical solution 
(Treatment Groups A and B) in patients with mild to moderate distal subungual 
onychomycosis of the target toenail. 
9.0 
INVESTIGATIONAL PLAN 
9.1 
Study Design and Plan Description 
This randomized, placebo-controlled, double-blind, parallel-group, multi-site study is designed to 
evaluate and compare the efficacy and safety oftwo dosing regimens ofNovexatin® 10% topical 
solution (Taro Pharmaceuticals USA) for the treatment of mild to moderate distal subungual 
onychomycosis of the target toenail. Additionally the active formulation in these regimens will be 
assessed for superiority to a placebo topical solution. 
Up to 180 eligible patients with distal subungual onychomycosis who meet all the inclusion 
criteria and none of the exclusion criteria will be enrolled into the study at Visit 1. Patients must 
be at least 18 years of age, in overall good health. They should have a current diagnosis of distal 
subungual onychomycosis of mild-moderate severity. Before any study-specific procedures are 
performed all patients will read and sign the IRE-approved informed consent form. 
At least 60 qualified patients in each treatment group will receive randomized and blinded study 
product. The randomization scheme will be 1:1:1 (Active Treatment A: Active Treatment B: 
Placebo C). The study products are: 
Test: Novexatin® 10% Topical Solution (Taro Pharmaceuticals, USA) 
Placebo: Placebo (Vehicle) Topical Solution (Taro Pharmaceuticals, USA) 
Patients will be assigned to one of the three treatment groups as outlined below and described in 
Section 9.4 ofthis protocol. 
Treatment Group A: Test treatment for Days 1 -
56 and Placebo treatment for 
Days 281 -336 
Treatment Group B: Test treatment for Days 1 -56 and Days 281 - 336 
Treatment Group C: Placebo treatment for Days 1 56 and Days 281-336 
Treatment and study durations will be as follows: 
Study Duration: 365 days (52 weeks) 
71442603 Rev. 2 • July 08, 2016 • Novum Pharmaceutical Research Services • Page 23 of 62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofN ovexatin ®' 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
Patients will undergo evaluation for clinical and mycological cure of onychomycosis at each of 
the 7 clinic visits. Randomized patients who withdraw from the study will not be replaced. The 
study will be conducted according to the following schedule: 
Visit Schedule: 
• 
Visit 1: Days -35 to -1 (Screening) 
• 
Visit 2: Day 1 (Baseline and Randomization I 1st Treatment start) 
• 
Visit 3: Day 57± 4 (1st Treatment completion) 
• 
Visit 4: Day 141 ± 7 (Interim) 
• 
Visit 5: Day 281 ± 14 (2"d Treatment start) 
• 
Visit 6: Day 337 ± 14 (2"d Treatnient completion) 
• 
Visit 7: Day 3 65 ± 14 ( 4 weeks post - treatment) 
The primary efficacy endpoint is the proportion of patients 111 each treatment group with a 
complete therapeutic cure of onychomycosis of the target toenail assessed at Day 141 and at the 
last test-of-cure visit at Day 365 following either one 8-week treatment period or two 8-week 
treatment periods. The safety profile of each treatment group will be evaluated by comparing 
adverse events, application site reactions, monitoring vital signs and changes in clinical 
laboratory results obtained throughout the study. 
The definitions of efficacy variables are stated below: 
• 
Complete Therapeutic cure: Complete Clinical Cure and Mycological Cure 
• 
Complete Clinical Cure: A patient with 0% nail involvement 
• 
Mycological Cure: Negative KOH and negative culture for dermatophytes associated with 
onychomycosis 
• 
Satisfactory Clinical Cure:~ 5% of the target toenail involvement 
9.2 
Selection of Study Design 
Study product dosing is based on previous clinical studies with Novexatin and doses 
recommended in Investigator's Brochure. As the product composition (cationic peptide) is not 
comparable to currently marketed products, the study will be conducted in accordance with FDA 
advice and fmiher communication regarding this class of drugs, specific recommendations for 
IND 111292, and input from Taro Pharmaceuticals, USA. 
9.3 
Selection of Study Population 
The study will include patients who are diagnosed with onychomycosis by clinical and also 
microbiological analysis of samples taken from the toenail. In order to participate in this study, 
patients must have positive cultures. 
The stage of 'mild-moderate' will describe the degree of fungal infection of the toenail, and this 
will be determined by examination of the appearance of the affected toenail(s). Patients with 
involvement of more than a single toenail will have evaluation based on both big toenails if a 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 24 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
bilateral infection is present at screening. At Visit 2, a target toenail will be identified by the 
investigator and all fmther evaluations will be based on the target toenail. See Appendix A for 
target toenail identification. 
Patients with concurrent disorders that would increase the risk of study participation or confound 
the interpretation of results, in the judgment of the Investigator, will not be included in the 
clinical study. 
9.3.1 
Inclusion Criteria 
1. Male and female patients aged 18 or over. 
2. 
Clinical diagnosis of onychomycosis of the target toenail (defined as one of the infected great 
toenails). 
3. Onset of clinical signs of onychomycosis of the target toenail < 2 years of the screening. 
4. Clinical signs and symptoms of onychomycosis, confirmed by positive KOH microscopy of 
the target toenail. 
5. 
Prior to randomization, a confirmed positive fungal culture, of the target toenail. 
6. 
Mild to moderate severity at Visit 1 as defined by Investigator's estimation of approximately 
10% to 35% toenail involvement. 
7. At least 5 mm of clear nail on the target toenail between the lunular proximal nail fold and 
the deepest extend of the onychomycosis. 
8. 
The deepest extend of onychomycosis should not contact the lunula. 
9. 
Besides onychomycosis, patients are in overall good health, or have a condition under stable 
treatment and are willing to comply with adequate foot care for the duration of the study. 
10. Females of childbearing potential must not be pregnant or lactating at baseline (as confirmed 
by a negative urine pregnancy test with a sensitivity of less than 25 mlU/mL or equivalent 
units of human chorionic gonadotropin). Women of childbearing potential must agree to the 
use of a reliable method of contraception (e.g., total abstinence, IUD, a double-barrier method 
[such as condom plus diaphragm with spermicide], oral, transdermal, injected or implanted 
non- or hormonal contraceptive), throughout the study. If the female is using a hormonal 
contraceptive, the same product must be taken for 1 month before baseline and must agree 
not to replace with some other hormonal contraceptives during the study. A sterile sexual 
partner is not considered an adequate form of birth control. 
All females will be considered to be of childbearing potential unless they: 
• 
Are post-menopausal, defined as women who have been amenorrheic for at least 12 
consecutive months, without other known or suspected primary cause. 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 25 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
• 
Have been sterilized surgically or who are otherwise proven sterile (i.e., total 
hysterectomy or bilateral oophorectomy) with surgery at least 4 weeks before 
baseline. Tubal ligation will not be considered a surgically sterile method. 
Female patients of childbearing potential are defined as: 
• 
Women without prior hysterectomy of at least 4 weeks, or who have had any 
evidence of menses in the past 1 2 months. 
• 
Females who have been amenorrheic for 2'. 12 months, but the amenorrhea is possibly 
from other causes, including prior chemotherapy, anti-estrogens or ovarian 
suppression. 
1 1. Signed informed consent form which meets all current ICH/FDA regulations 
9.3.2 
Exclusion Criteria 
1. 
Patients under 18 years of age. 
2. 
Females who are pregnant, lactating or likely to become pregnant during the study. 
3. Patients with proximal onychomycosis, dermatophytomas, fungal spikes, limited 
lateral onychomycosis, white superficial onychomycosis or significant dystrophy of 
the target toenail that in the Investigator's opinion would impair the evaluation of 
onychomycosis. 
4. 
Patient has total dystrophic or proximal subungal onychomycosis of the target 
toenail. 
5. 
History or current diabetes and/or peripheral vascular disease. 
6. 
Presence of mycotic spikes or patient has exclusively lateral groove involvement of 
the target toenail. 
7. 
Patients with distal nail plate thickness of the target toenail greater than 3 mm. 
8. 
Patient had no new nail growth requiring nail trimming in the target toenail over the 
previous 2 months. 
9. 
Previous treatment for onychomycosis of the toenail within the last 12 months that 
was unresponsive to treatment. 
10. Onychomycosis not caused by a dermatophyte (e.g., mold infection, Candida spp or 
bacterial infection). 
1 1. Patients with a history of a trauma involving nail bed of the target toenail before 
onset of clinical signs of onychomycosis. 
12. Patients with any significant active or past medical condition or abnormal laboratory 
value or who are required to start a medical therapy that in the opinion of the 
Investigator would make them unsuitable for study participation or compromise 
patient safety. 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 26 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens of N ovexatin ®' 1 0% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
13. Patients who are unable to reach their infected toenails and administer the study 
product to affected toes. 
14. Patients who are likely to apply toenail polish, cosmetic products or undergo 
professional pedicures during the study. 
15. Current or history of psoriasis or Lichen planus within the previous 12 months. 
16. Immunocompromised either because of concomitant disease (e.g., HIV), or ongoing 
treatment (e.g., chemotherapy), including patients with a history of organ transplant 
and patients on long-term corticosteroid therapy (refer to paragraph 9.3.3 for use of 
concomitant corticosteroid therapy). 
17. Receipt of any drug as part of a research study within 3 0 days prior to dosing. 
18. Use within 4 weeks before baseline of 1) topical antifungal therapies on the feet, 
2) immunomodulators or 3) systemic corticosteroids. 
19. Use of topical corticosteroids on the feet within 2 weeks before baseline. 
20. Use of systemic antifungal agents for the treatment of onychomycosis or any 
antifungal with known activity against dermatophytes within the previous 24 weeks. 
21. Current evidence of drug abuse or history of drug abuse within 1 year before the first 
dose, including, in the opinion of the Investigator, history of alcohol abuse or active 
alcoholism. 
22. Inability to understand the protocol requirements, instructions, and study-related 
restrictions, the nature, scope, and possible consequences of the clinical study. 
23. Unlikely to comply with the protocol requirements, instructions, and study-related 
restrictions, such as uncooperative attitude, inability to return for follow-up visits, 
and improbability of completing the clinical study. 
24. Patient is the Investigator or his/her deputies, research assistant, pharmacist, clinical 
study coordinator, other staff or relative thereof directly involved in the conduct of 
the clinical study or employed by the clinical site, or a first-degree relative of a site 
employee. 
25. Patients with previous exposure to the study drug, or with known allergy to the drug 
or any of its components. 
9.3.3 
Restrictions during the Study 
The following concomitant medications will not be allowed during the study and during the 
specified washout periods before Visit 1: 
Restricted 
Examples (not 
Washout 
medication 
comprehensive) 
Systemic antifungals 
Sporanox®, 
24 weeks 
71442603 Rev. 2 • July 08, 2016 • Novum Pharmaceutical Research Services • Page 27 of 62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
terbinafine, 
Topical antifungals on 
Lotrimin([l)' tea tree oil, 
4 weeks 
feet 
crystal violet 
Systemic 
prednisone, 
4 weeks 
corticosteroids 
prednisolone 
Topical 
2 weeks 
corticosteroids 
Immunomodulators 
chemotherapy, 
4 weeks 
rheumatoid arthritis 
drugs 
Note: Treatment for tinea pedis or tinea cruris will be allowed during the study, and a topical 
antifungal medication will be provided to patients as deemed necessary by Investigator. 
Occasional short term use of systemic and topical corticosteroids other than the feet is allowed to 
the extent that, in the opinion of the investigator, does not compromise the study results. 
The use of topical corticosteroids on the feet is restricted for the entire study. 
The use of intranasal, inhaled or ophthalmic corticosteroids is allowed up to 1 mg/day. 
9.3.4 
Removal of Patients from the Study 
Patients will be advised that they are free to withdraw from the study at any time for any reason 
or, if necessary, the Investigator may withdraw a patient from the study to protect the health of 
that patient. A patient may also be withdrawn for not complying with study procedures. The 
clinical report will include all reasons for early withdrawals. 
All patients who are randomized will be included in the safety analysis comparing the test and 
placebo products. If a patient terminates from the study early, all efforts will be made to complete 
the patient's end of study visit procedures. For early termination the Investigator shall fully 
document the reason for early termination. Reasons for early termination may include the 
following: 
• 
Patient withdrew consent 
• 
Significant adverse event that led the Investigator or patient to withdraw for safety 
reasons 
• 
Non-compliance with protocol requirements/protocol deviation (e.g., use of restricted 
medication, not following dosing procedures, failure to make scheduled study visits in a 
timely fashion). A patient may also be withdrawn by the Investigator if: 
o 
A protocol deviation or intercurrent illness occurs during the conduct of the clinical 
study, which, in the clinical judgment of the Investigator or after discussion with the 
Sponsor, may invalidate the clinical study 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 28 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
o 
It is discovered that the patient was included in the clinical study in contradiction to 
the inclusion and exclusion criteria 
• 
Pregnancy 
• 
Significant worsening of onychomycosis such that the Investigator and/or patient believes 
it is in the best interest of the patient to withdraw from the study and be provided 
alternative treatment 
• 
Adverse event: if a patient reports symptoms, which are considered unacceptable by the 
patient or the Investigator, he/she will be withdrawn from the clinical study. The 
appropriate AE form in the Case Report Form (CRF) will be completed. 
• 
Participant enrolls in another clinical trial, or is found to have previously enrolled in this 
clinical trial 
All reason(s) for premature withdrawal will be recorded. All patients who withdraw or are 
withdrawn from the clinical study because of an AE, or clinical laboratory abnormality will be 
followed up at suitable intervals in order to evaluate the course of the AE or laboratory 
abnormality and to ensure reversibility or stabilization. The subsequent outcomes of these AEs 
will be recorded in the patient's source file. 
Patients who withdraw or are withdrawn after exposure to study product will not be replaced. 
9.3.5 
Early Terminations and Protocol Deviations 
The following rules and conventions will be used for patients who terminate from the study early 
or are dropped from the study because of protocol deviations. 
If a patient terminates from the study early, all efforts will be made to complete Visit 7 study 
procedures. 
Any patient who either requests to be dropped from the study because of lack of therapeutic 
efficacy or is dropped by the Investigator for lack of therapeutic efficacy will automatically be 
considered a "clinical failure" irrelevant of their target toenail assessment score at the termination 
visit. 
Any patient who uses any protocol restricted medication specifically for the treatment of their 
infection will be discontinued from further participation in the study and automatically be 
considered a "clinical failure" irrelevant of their target toenail assessment score at the last visit. 
Any patient who uses any protocol restricted medication NOT specifically for the treatment of 
their onychomycosis will be discontinued from further participation in the study. The patient will 
be considered a "clinical cure" or "clinical failure" based on the target toenail assessments at the 
termination visit. 
Any patient who is dropped for any other reason, other than those covered above, had a positive 
baseline culture and makes at least one post-baseline visit where clinical assessments for target 
toenail are performed and/or a KOH and/or mycological culture result is obtained, will be 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 29 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofN ovexatin ®' 1 0% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
included in the ITT. Examples would include: failure to use the study products as required by the 
protocol (see section 9.4.5), patient withdraws consent for continued pmiicipation, patient fails to 
make study visits on a timely basis. 
9.3.6 
Clinical Study Termination 
The clinical study may be terminated if: 
• 
The Sponsor considers the applied dose of the study product to be no longer relevant 
• 
The Sponsor decides to terminate the clinical study, in particular because data not 
known before become available and raise concern about the safety of the patients so 
that continuation of the clinical study would pose potential risks to the patients 
Termination of the clinical study, for any reason, must be mutually agreed upon by the Principal 
Investigator and the Sponsor, and must be documented. However, clinical study results will be 
reported according to the requirements outlined in this protocol as far as applicable. 
9.4 
Treatments 
9.4.1 
Treatments Administration 
Patients will be provided with verbal and written instructions on how to dose. Patients are to 
begin dosing on Day 1 in the office with a clinic staff member observing. 
The following treatments will be assessed in this study: 
• 
Treatment Group A: Test treatment for Days 1 - 56 and Placebo treatment for Days 
281-336 
• 
Treatment Group B: Test treatment for Days 1-56 and Days 281-336 
• 
Treatment Group C: Placebo treatment for Days 1-56 and Days 281-336 
Study treatment is to be administered by the patient once daily, preferably in the morning after 
cleaning the affected area with non-medicated soap and patting dry with soft towel. The nails 
should be completely dry before applying product. A single dose is approximately 30 111 of 
topical solution. The material will be applied to toenails with a brush that will provide a 
maximum volume of up to 50 111 after a single fill. A volume of 30 111 to 50 111 of the solution will 
cover a single nail and nearby skin, depending on the size ofthe nail. Daily applications of a 10% 
concentration will provide between 3 - 5 mg of Novexatin per nail. The date and time of each 
dose must be recorded in the dosing section of the patient diary. 
Details of dose administration 
The study products will be administered at home by the patients according to the procedure 
below. The first dose will be applied by the patient in the clinic at Visit 2, with a clinic staff 
member observing. 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 30 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
• 
Apply the study product at approximately the same time each day, leaving sufficient time 
post-application for the solution to dry on the nail (the solution will dry in approximately the 
same time as required for cosmetic nail polish and will be dry to the touch) 
• 
Using the supplied brush, spread a liberal amount of the study product evenly across all 
toenails on feet with affected toenails and adjacent skin of the toes, working from the outside 
of the nail inwards to ensure the nail edges have made contact with the solution 
9.4.2 
Identity of Investigational Product 
The following products will be used in this study: 
Test: Novexatin® 10% Topical Solution (Taro Pharmaceuticals, USA) 
Placebo: Placebo (Vehicle) Topical Solution (Taro Pharmaceuticals, USA) 
The active ingredient in N ovexatin ® study products is presented as a 100 mg/ml (1 0%) solution of 
net peptide of Cyclo [7xArg] for topical application to the surface of the toenail. All study 
medication will be supplied in capped high-density glass amber bottles with a nylon brush. 
Ail randomized study product will be blinded and packaged in blinded sealed boxes or bags. Each 
bottle will be identified only by a label bearing the Sponsor name, protocol number, 
randomization number, treatment duration and a statement that the study product is for 
Investigational Use Only. The study staff wiil dispense the study product bottle only to those 
patients identified by the Investigator. The study staff will instruct the patients on the use and 
return of study product. 
Individual bottles of study product for Visit 2 (randomization) will be packaged in blocks. One 
block will consist of three boxes of study product containing 2 bottles (#1 & 2) according to the 
randomization code. Bottles# 3 &4 will be provided for all active patients at sites before Visit 5. 
The study product wiii be provided in three configurations: 
A. bottles #1 & 2- Test and bottles #3 & 4- Placebo 
B. bottles #1 & 2- Test and bottles #3 & 4- Test 
C. bottles # 1 & 2 - Placebo and bottles #3 & 4 - Placebo 
The study product wiil be shipped to each Investigator's site from a centralized pharmacy for the 
initial shipments. Site to site study product distribution and shipping is ailowable in cases 
approved by the sponsor. The Principal Investigator at each site is responsible for ensuring that 
ail study products are stored in a locked, secure location, with access limited to the Investigator 
and his/her designee(s). An accurate inventory of the study product will be maintained in 
accordance with federal regulations. 
Once the site has been notified that they may do so, ail unused study product and empty or 
partiaily used bottles of study product may be returned to the Sponsor or designee. 
Storage Conditions: 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 31 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
Study product will be stored at controlled room temperature, away from direct sunlight exposure, 
at 25°C (77°F), with excursions permitted between l5°C and 30°C (59°F and 86°F). The 
Principal Investigator at each site is responsible for ensuring that all study products are stored in a 
locked, secure location, with access limited to the Investigator and his/her designee(s). 
9.4.3 
Method of Assigning Patients to Treatment Groups 
9.4.3.1 Enrollment 
At Visit 2 eligible patients will be randomized to the study and assigned enrollment 
randomization number. Randomization numbers will consist of a 2-digit site number and 
4-digit randomization number. The 4-digit randomization numbers will be assigned in 
ascending order beginning with the lowest number at each study site. 
9.4.3.2 Randomization 
The study product will be packaged and blinded by an independent clinical packaging 
company. The randomization will be generated in blocks of 3, containing the study 
products in three configurations: 
A. bottles #1 & 2- Test and bottles #3 & 4- Placebo 
B. bottles #1 & 2 
Test and bottles #3 & 4- Test 
C. bottles #1 & 2- Placebo and bottles #3 & 4- Placebo. 
Three patients worth of study product bottles 1 & 2 will be packed into a larger box. This 
larger box will be designated "one block" of study product. The study product bottles 1 & 
2 will be blinded, packaged and delivered to the study site in blocks at the beginning of 
the enrollment. Bottles 3 & 4 will be delivered to the study site before Vis it 5 (2nd 
treatment start). 
At each Visit 2 and Visit 5 each patient will receive two 5 ml bottles of study product 
according to the randomization code. Patients will be randomized to a treatment regimen 
in a blinded fashion by assigning randomization numbers in ascending sequential order 
starting with the lowest available randomization number at each site. All patients 
randomized will be identified by initials, date of birth, and a unique six-digit patient 
number. The first two-digits will identity the Investigator site where the patient was 
enrolled and the last four will correspond with the randomization number of study 
product bottle assigned to the patient. A perforated or two-part label will be attached to 
each of the small sized boxes of study product supplies. Both pieces of the label will 
include the following information: Protocol number, randomization number, space for 
patient's initials, statement that the study product is for investigational use only, space for 
dispensing date and the Sponsor's name. In addition all patients will be provided with 
written instructions on how to use the study product. One part of the label shall remain 
attached to the box. The other pa11 will be removed prior to dispensing and attached to the 
study product log. 
71442603 Rev. 2 • July 08, 2016 • Novum Pharmaceutical Research Services • Page 32 of 62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens of N ovexatin ®' 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
9.4.4 
Study Blind 
The Investigator, staff at the study site, study monitors, and data analysis/management personnel 
will be blinded to the patient assignment. The patient will be requested not to discuss the 
appearance of the study product bottle with the Investigator or study staff. 
To ensure that information that could potentially bias handling of data is not disclosed, the 
clinical packaging company will hold the randomization scheme until database lock. 
Each bottle will be labeled with a blackout label in order to blind the bottle. Each bottle will be 
labeled with a two-part, double blind label and will display the following text: 
"content 
statement, protocol number, subject number, instructions for use and storage, Sponsor's name, an 
investigational use statement and warnings: "For Topical Use Only" and "Keep out of reach of 
children". Part 2 ofthe label will contain a sealed copy ofthe randomization scheme (as a scratch 
off portion of the product label). This label should be detached from the bottle prior to dispensing 
to the patient and retained in a secure location at the study site, to be opened in case of medical 
emergency only. 
Where possible, the Sponsor and Novum medical monitor should be contacted before breaking 
the blind for any patient. In the event the blind is broken for any reason Sponsor and Novum 
should be notified as soon as possible in writing of the details ofthe occurrence. 
At the conclusion of the study, after the database has been locked, each site will be sent the full 
study randomization scheme that should be retained with the study documents in the event of an 
FDA Inspection. 
The bottles used for all three study products are identical in size, shape and color. A standard 
label overlay will be used and there is no difference in odor of the products. Therefore, all three 
products are indistinguishable. This will allow the treatment phase of the study to be conducted 
under double-blind conditions, such that neither the patient nor the Investigator or study staff 
members will know the identity of each patient's treatment. 
9.4.5 
Compliance 
Patients will be provided with a diary to record the time and date of dosing, as well as any 
adverse events or concomitant medications. 
Patients are required to administer 75%-125% scheduled doses of study product for each of the 
two 56-day treatment periods as outlined in table below. If patients missed 4 or more consecutive 
doses, they will be considered non-compliant. A single dose is equivalent to single application of 
study product to each toenail (affected and non-affected). 
Compliance Criteria 
Duration 
Scheduled doses 
not more than 125% (doses) 
not less than 75% (doses) 
56 days 
56 
70 
42 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 33 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
All used and unused study product bottles will be returned by the patient at each study visit and 
assessed for drug accountability and treatment compliance. In addition, patient compliance with 
dosing will be calculated by analyzing the doses recorded in the Patient Diary. If the subject does 
not return the Patient Diary, patient-reported dosing compliance will be recorded in the source 
notes and will be used to derive compliance. 
9.5 
Study Conduct 
9.5.1 
Visit 1: Day -35 to -1 (Screening) 
1. Informed Consent: Patients who are willing to comply with study procedures will 
read and sign the informed consent form. 
2. Inclusion/Exclusion Criteria: Patients will be screened for eligibility based on 
inclusion/exclusion criteria. Those who fulfill all criteria will proceed to the steps 
below. 
3. Demographics and Medical History: Review patient's demographic and medical 
history. Review patient's use of medications within the last 6 months. 
4. Physical Examination: A general physical examination will be conducted to assess a 
good, general health status of the patient; examination of the lower extremities must 
be included. 
5. Vital Signs: Blood pressure (BP), heart rate (HR), respiratory rate (RR) and body 
temperature will be recorded. 
6. Clinical Laboratory Tests: Blood and urine sample for safety lab tests will be taken. 
The tests are outlined in Appendix D. 
7. Urine Pregnancy Test: For women of childbearing potential, a urine pregnancy test 
will be performed to evaluate pregnancy. Any patient with a positive pregnancy test 
will not be allowed participation in the study. 
8. KOH Test: Microscopic examination of specimens of affected toenails will be 
conducted to visualize the presence of pathogenic fungi. Collected nail specimens 
will be processed on site for KOH slide preparation as outlined in Appendix B. 
9. Fungal Culture Collection: If the onsite KOH prep test is positive, then the same 
site on the nail will be processed for fungal culture. All culture plates will be sent to 
central laboratory for testing. If the culture result is negative, the patient can be 
rescreened. 
10. Investigator Clinical Assessment: Perform an examination of the infected 
feet/toenail(s). The number of toenails infected should be counted. Nail appearance 
will be recorded. 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 34 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, I 0% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
11. Visual Assessment: 
The toenail that the investigator considers 
meeting 
Inclusion/Exclusion criteria will be identified and the investigator will assess the nail 
involvement. If the subject has a bilateral infection of both big toenails, both toenails 
can be used to assess nail involvement. 
12. Schedule Visit 2. 
9.5.2 
Visit 2: Day 1 (Baseline and Randomization I 1st Treatment start) 
1. Inclusion/Exclusion Criteria: Patients will be questioned to ensure they continue to 
meet all inclusion/exclusion criteria for the study. Patients with a negative result for 
the fungal culture test on Visit 1 will receive appointment cancellations for Visit 2, 
and will not participate in the study. 
2. 
Concomitant Medications: Review and record since Visit 1. 
3. Urine Pregnancy Test: For women of childbearing potential, a urine pregnancy test 
will be performed to evaluate pregnancy. Any patient with a positive pregnancy test 
will not be allowed to participate in the study. 
4. 
Trimming target nail, if needed. 
5. Investigator Clinical Assessment: Perform a foot/toenail exam. Infected toenail 
count will be recorded. Nail appearance will be recorded. 
6. Evaluation of Toenail Appearance and Condition: The investigator and patients 
will perform a visual assessment and rate target toenail appearance and condition per 
Appendix A. 
7. 
Visual Assessment: The target toenail involvement will be recorded. The toenail 
(one of the two great toenails) that meets inclusion/exclusion criteria will be 
identified and designated as the target toenail and used for all further evaluations. 
8. Planimetry Assessment: Appropriate photographic documentation will be obtained 
in accordance with Canfield Scientific Inc. guidelines for the planimetry assessment. 
9. Dispense Randomized Study Product and Administration Instructions: Patients 
will be randomly assigned to one of the three treatment groups of the study, and 
will receive a randomization number. Qualified patients will be provided with two 
bottles of randomized study product. A set of instructions to apply the study product 
at home will be provided, along with supplies including standardized non-medicated 
bar of soap and towel. 
10. Dispense Patient Diary: A diary along with instructions to record dose frequency 
and timing, adverse events and concomitant medications will be provided. 
11. Administer First Dose: Clinic staff member will observe the first application of 
study product by the patient in the clinic. 
71442603 Rev. 2 • July 08, 2016 • Novum Pharmaceutical Research Services • Page 35 of 62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
12. Adverse Events: Any adverse events following first dose will be recorded by patient 
in diary. 
13. Schedule Visit 3. 
9.5.3 
Visit 3: Day 57± 4 (1
81 Treatment completion; the last dose will· be on Day 56) 
1. Urine Pregnancy Test: For women of childbearing potential, a urine pregnancy test 
will be performed to evaluate pregnancy. Any patient with a positive pregnancy test 
will not be allowed participation in the study. 
2. 
Clinical Laboratory Tests: Blood and urine sample for safety lab tests will be taken. 
The tests are outlined in Appendix D. 
3. Vital Signs: BP, HR, RR and body temperature will be recorded. 
4. 
Collect Study Product Bottles: Bottles will be inspected for intentional tampering. 
5. 
Collect/Review Patient Diary: Collect patient diary and review for concomitant 
medications, adverse events and compliance with the protocol. 
6. Dispense new diary. 
7. Application Site Reactions: The Investigator will evaluate the patient for local 
application site reactions and question patient regarding symptoms experienced since 
the previous visit based on the scale provided in Appendix C. 
8. 
Trimming target nail, if needed. 
9. Investigator Clinical Assessment: Perform a foot/toenail exam. Record infected 
toenail count and nail appearance. 
10. Evaluation of Toenail Appearance and Condition: The investigator and patients 
will perform a visual assessment and rate target toenail appearance and condition per 
Appendix A. 
11. Visual Assessment: The investigator will assess the nail involvement of the "target 
toenail". 
12. Planimetry Assessment: Appropriate photographic documentation will be obtained 
in accordance with Canfield Scientific Inc. guidelines for the planimetry assessment. 
13. Place all records/ documents in patient's source folder. 
14. Schedule Visit 4. 
9.5.4 
Visit 4: Day 141 ± 7 (Interim) 
1. Urine Pregnancy Test: For women of childbearing potential, a urine pregnancy test 
will be performed to evaluate pregnancy. Any patient with a positive pregnancy test 
will not be allowed participation in the study. 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 36 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
2. 
Collect/Review Patient Diary: Collect patient diary and review for concomitant 
medications, adverse events and compliance with the protocol. 
3. Dispense new diary. 
4. Application Site Reactions: The Investigator will evaluate the patient for local 
application site reactions and question patient regarding symptoms experienced since 
the previous visit based on the scale provided in Appendix C. 
5. 
Trimming target nail, if needed. 
6. 
Investigator Clinical Assessment: Perform a foot/toenail exam. Record infected 
toenail count, target toenail involvement and nail appearance. 
7. 
Evaluation of Toenail Appearance and Condition: The investigator and patients 
will perform a visual assessment and rate target toenail appearance and condition per 
Appendix A. 
8. 
Visual Assessment: The investigator will assess the nail involvement of the "target 
toenail". 
9. Planimetry Assessment: Appropriate photographic documentation will be obtained 
in accordance with Canfield Scientific Inc. guidelines for the planimetry assessment. 
10. KOH Test: Microscopic examination of specimens of affected toe nails will be 
conducted to visualize the presence of pathogenic fungi. Collected nail specimens 
will be processed on-site for KOH slide preparation as outlined in Appendix B. 
11. Fungal Culture Collection: A sample for mycological testing should be obtained 
irrelevant of the results of the KOH stain. All culture plates will be sent to central 
laboratory for testing. 
12. Place all records/ documents in patient's source folder. 
13. Schedule Visit 5. 
9.5.5 
Visit 5: Day 281 ± 14 (2nd Treatment start) 
1. Urine Pregnancy Test: For women of childbearing potential, a urine pregnancy test 
will be performed to evaluate pregnancy. Any patient with a positive pregnancy test 
will not be allowed participation in the study. 
2. 
Collect/Review Patient Diary: Collect patient diary and review for concomitant 
medications, adverse events and compliance with the protocol. 
3. 
Dispense new diary. 
4. 
Vital Signs: BP, HR, RR and body temperature will be recorded. 
5. 
Trimming target nail, if needed. 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 37 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
6. Investigator Clinical Assessment: Perform a foot/toenail exam. Record infected 
toenail count, target toenail involvement and nail appearance. 
7. Evaluation of Toenail Appearance and Condition: The investigator and patients 
will perform a visual assessment and rate target toenail appearance and condition per 
Appendix A. 
8. Visual Assessment: The investigator will assess the nail involvement of the "target 
toenail". 
9. Planimetry Assessment: Appropriate photographic documentation will be obtained 
in accordance with Canfield Scientific Inc. guidelines for the planimetry assessment. 
10. Application Site Reactions: The Investigator will evaluate the patient for local 
application site reactions and question patient regarding symptoms experienced since 
the previous visit based on the scale provided in Appendix C. 
11. Dispense Randomized Study Product and Administration Instructions: Qualified 
patients will be provided with two bottles of randomized study product. A set of 
instructions to apply the study product at home will be provided, along with supplies 
including standardized non-medicated bar of soap and towel. 
12. Place all records/ documents in patient's source folder. 
13. Schedule Visit 6. 
9.5.6 
Visit 6: Day 337 ± 14 (2"
11 Treatment completion; the last dose should be applied the 
day before Visit 6) 
1. Urine Pregnancy Test: For women of childbearing potential, a urine pregnancy test 
will be performed to evaluate pregnancy. Any patient with a positive pregnancy test 
will not be allowed participation in the study. 
2. 
Collect/Review Patient Diary: Collect patient diary and review for concomitant 
medications, adverse events and compliance with the protocol. 
3. Dispense new diary. 
4. Vital Signs: BP, HR, RR and body temperature will be recorded. 
5. 
Collect Study Product bottles: Bottles will be inspected for intentional tampering or 
un-blinding. 
6. Trimming target nail, if needed. 
7. Investigator Clinical Assessment: Perform a foot/toenail exam. Record infected 
toenail count, target toenail involvement and nail appearance. 
8. Evaluation of Toenail Appearance and Condition: The investigator and patients 
will perform a visual assessment and rate target toenail appearance and condition per 
AJmendixA. 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 38 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
9. Visual Assessment: The investigator will assess the nail involvement of the "target 
toenail". 
10. Planimetry Assessment: Appropriate photographic documentation will be obtained 
in accordance with Canfield Scientific Inc. guidelines for the planimetry assessment. 
11. Application Site Reactions: The Investigator will evaluate the patient for local 
application site reactions and question patienJ regarding symptoms experienced since 
the previous visit based on the scale provided in Appendix C. 
12. Place all records/ documents in patient's source folder. 
13. Schedule Visit 7. 
9.5.7 
Visit 7: Day 365 ± 14 (4 weeks post-treatment or Early Termination) 
1. Urine Pregnancy Test: For women of childbearing potential, a urine pregnancy test 
will be performed to evaluate pregnancy. Any patient with a positive pregnancy test 
will not be allowed participation in the study. 
2. Clinical Laboratory Tests: Blood and urine sample for safety lab tests will be taken. 
The tests are outlined in Appendix D. 
3. Collect/Review Patient Diary: Collect patient diary and review for concomitant 
medications, adverse events and compliance with the protocol. 
4. Physical Exam: The Investigator will perform a general physical exam for each 
patient and any significant findings will be noted. The physical exam, at a minimum, 
must include an examination of the lower extremities. 
5. Vital Signs: BP, HR, RR and body temperature will be recorded. 
6. 
Trimming target nail, if needed. 
7. Investigator Clinical Assessment: Perform a foot/toenail exam. Record infected 
toenail count, target toenail involvement and nail appearance. 
8. 
Evaluation of Toenail Appearance and Condition: The investigator and patients 
will perform a visual assessment and rate target toenail appearance and condition per 
Appendix A. 
9. Visual Assessment: The investigator will assess the nail involvement ofthe "target 
toenail". If the nail involvement does not reach zero at the final visit, the investigator 
will visually assess the nail involvement based on the following range: 
• 
0% 
• 
> 0-5% 
• 
6-9% 
• 
10-35% 
• 
> 35% 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 39 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofN ovexatin ®' 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
10. Planimetry Assessment: Appropriate photographic documentation will be obtained 
in accordance with Canfield Scientific Inc. guidelines for the planimetry assessment. 
11. Application Site Reactions: The Investigator will evaluate the patient for local 
application site reactions and question patient regarding symptoms experienced since 
the previous visit based on the scale provided in Appendix C. 
12. KOH Test: Microscopic examination of specimens of affected toe nails will be 
conducted to visualize the presence of pathogenic fungi. Collected nail specimens 
will be processed on-site for KOH slide preparation as outlined in Appendix B. 
13. Fungal Culture Collection: A sample for mycological testing should be obtained 
irrelevant of the results of the KOH stain. All culture samples will be sent to central 
laboratory for testing. 
14. Place all records/ documents in patient's source folder. 
9.6 
Study Procedures 
9.6.1 
Informed Consent 
No patient will be entered into the study without reading, understanding, and signing an informed 
consent. For illiterate patients, verbal consent should be obtained in the presence of and be 
countersigned by a literate witness. If any other language is required, translation will be 
performed by a certified translator. 
9.6.2 
Demographics 
At Visit 1, each patient shall be required to provide basic demographic information: date of birth, 
gender, ethnicity and race. 
9.6.3 
Medical History 
At Visit 1, patients will be questioned about medical history, including acute and chronic medical 
history and medical history relevant to their onychomycosis, as well as all concomitant 
medication use within the previous 6 months. 
9.6.4 
Vital Signs 
The patient's vital signs will be recorded (pulse, blood pressure, temperature and respiration rate) 
at specified visits. 
9.6.5 
Physical Exam 
At each specified visit, the Investigator will perform a general physical exam for each qualified 
patient and any significant findings will be noted. The general physical exam is intended to assess 
a good, general health status of the patient and must include an examination of the lower 
extremities. 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 40 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofN ovexatin ®' 1 0% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
9.6.6 
Concomitant Medication Use 
At Visit 1, patients will be questioned about current and concomitant medication use over the 
previous 6 months. At all other clinic visits, patients will be questioned about ongoing or new 
concomitant medication use. 
9.6.7 
Pregnancy Test 
Urine pregnancy tests on women of childbearing potential will be performed at each clinic visit 
during the treatment period. The test must be negative for the patient to be eligible for inclusion 
in the study. If the patient is of non-childbearing potential, the source document must list the 
reason why she is of non-childbearing potential. 
Patients with a positive pregnancy test during screening will not be enrolled in the study. Patients 
who report they have become pregnant or who have a positive pregnancy test at the end of study 
visit will be followed to completion of the pregnancy. The pregnancy will be reported as an AE. 
9.6.8 
Dispensing Study Product 
At Visit 2 (Randomization) after the Investigator has determined that the study patient meets the 
inclusion/exclusion criteria for the study a clinic staff member will dispense two bottles (1 & 2) 
of the study product to the patient using the lowest patient randomization number available at that 
investigative site. Study product should not be dispensed at Visit 2 until it is confirmed that the 
patient meets all the inclusion/ exclusion criteria including positive results from the mycological 
culture. The patient will be dispensed bottles 3 & 4 of the study product at Visit 5. 
9.6.9 
Collecting Study Product 
At Visits 3 and 6 the study product bottles will be collected and inspected for evidence of 
tampering. 
9.6.10 Dosing Instructions and Diary 
Patients will be given a diary with instructions at each clinic visit from Visit 2 to Visit 6. Patients 
will be asked to record the time and date of each dose, AEs, and concomitant medications 
throughout the study. The diary will be reviewed at Visits 3-7 by the study staff. 
9.6.11 Dosing Compliance 
Patient diaries will be collected at Visits 3-7 so that the study staff may check compliance. 
Patients are required to administer 75%-125% scheduled doses of study product for each of the 
two 56-day treatment periods as outlined in table below. If patients missed 4 or more consecutive 
doses, they will be considered non-compliant. A single dose is equivalent to single application of 
study product to each toenail (affected and non-affected). At the end of the study they will be 
retained in the patient's file as source documentation. 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 41 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
9.6.12 Target Nail Trimming 
Patients will be expected to keep toenails trimmed as part of their standard foot care. The target 
nail will be trimmed prior to visual assessments if, in the opinion of the Investigator, the length of 
the nail could impact the assessment of onychomycosis. 
9.6.13 Visual Assessment and Planimetry 
At screening, both big toenails can be evaluated for nail involvement if the subject has a bilateral 
infection of the big toenails. At Visit 2, the target toenail will be identified and nail involvement 
of the target toenail over time will be monitored visually by an investigator at every visit. If the 
nail involvement does not reach zero at the final visit, the investigator will visually assess the nail 
involvement based on the following range: 
• 
0% 
• 
> 0-5% 
• 
6-9% 
• 
10-35% 
• 
>35% 
At Visit 2 and all subsequent visits, the target toenail will also be monitored by planimetry. 
Appropriate photographic documentation of the target toenail will be obtained for the planimetry 
assessment at Visit 2 and submitted to Canfield Scientific, Inc. to determine the nail involvement. 
At all subsequent visits, appropriate photographic documentation of the same target toenail will 
be obtained and submitted to Canfield Scientific, Inc. to determine the nail involvement. 
Photographs of the target toenail will be collected using the procedures provided by Canfield 
Scientific, Inc. The photographs from each visit will be processed and reviewed by an 
independent panel. An image analysis will be conducted and numerical values for the % affected 
(in terms of surface affected for both the healthy and pathologic area of the target nail) will be 
reported. The % affected will be used to judge Satisfactory Clinical Cure. 
9.6.14 Investigator Clinical Assessment: 
An investigator will perform an exam of foot/toenail at each visit. Infected toenails will be 
counted and recorded. Nail appearance will be recorded. 
9.6.15 Evaluation of Toenail Condition/ Appearance: 
The toenail, one of the two great toenails, that the investigator considers to be the most 
appropriate as the target toenail will be identified and designated as the "target toenail" at Visit 2 
and used for evaluations. 
The overall appearance of the target toenail over time will be monitored during the study: 
I. 
Self-assessed by patients. The results of the self-assessment will be recorded by the patient 
before beginning therapy at Visit 2 and at all subsequent visits. Patients will use a 5-point 
scale (see Appendix A) for target toenail appearance. 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 42 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
2. 
Assessed by Investigator: Investigators will rate the status of the target toenail before 
beginning therapy at Visit 2 and at all subsequent visits. Nail condition/appearance by 
investigator will be evaluated after nail trimming to the distal groove and before further 
trimming, if required, for the mycological evaluation. Investigators will use a 5-point scale 
(see Appendix A) target toenail appearance. 
9.6.16 KOH Stain 
At screening, a sample from both big toenails can be collected for subjects with a bilateral 
infection of the big toenai Is. At subsequent applicable visits, a sample from the target toenail will 
be collected and a KOH stain performed using standardized methodologies that will be provided 
to the Investigators. 
If at Visit 1 the result of the KOH stain is negative then no further assessments need be conducted 
on this patient as they will not be eligible for inclusion. If at Visit 1 the KOH stain test is positive 
then a sample for mycological culture must be obtained (see Section 9.6.14) to confirm the result. 
At Visits 4 and 7, a sample for KOH and mycological culture should be obtained so that 
subsequent analysis of the correlation between KOH stain and mycological culture results can be 
performed. 
9.6.17 Sample for Mycological Culture 
If at Visit 1 the result of the KOH stain is negative then no sample for mycological testing should 
be taken from this patient as they will not be eligible for inclusion. If at Visit 1 the KOH stain test 
is positive then a sample for mycological culture should be obtained to confirm the result. 
At subsequent visits when a sample is collected for KOH stain a sample for mycological culture 
must also be obtained irrelevant of the results of the KOH stain. 
At screening, samples for the mycological culture will be collected from the big toenail that 
resulted in a positive KOH stain. At subsequent visits, samples for mycological culture will be 
collected from the target toenail using the procedures provided by the central laboratory. The 
sample will be processed and sent to a central microbiological testing laboratory. It is anticipated 
that it will take 14 to 30 days for the microbiological laboratory to provide the investigator with 
the results of the culture. Refer to Appendix B. 
9.6.18 Application Site Reactions: 
At each visit following randomization the Investigator will evaluate the patient for local 
application site reactions and question patient regarding symptoms experienced since the previous 
visit based on the scale provided in Appendix C. Application Site reactions (see Appendix C) will 
be documented in the Source and CRF. 
Application site reactions will not be separately recorded as AEs since they are being captured at 
each visit for erythema, burning/stinging, erosion, edema, pain, itching or dryness unless the 
Investigator feels it is appropriate to do so. 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 43 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
9.6.19 Health Status/Adverse Events 
At each visit, starting at Day 1, patients will be questioned regarding any changes in their medical 
status since their previous visit. New medical conditions or the worsening in severity of any 
concurrent medical conditions repotied at baseline, or since the previous visit will be reported as 
new adverse events. 
9.7 
Adverse Events 
The patients will be monitored throughout the study for any Adverse Events. At each visit 
following screening, patients will be questioned regarding any changes in their medical status 
since their previous visit. Observed changes during the clinical assessments at each visit, should 
be reported as adverse events. Each patient will be observed for signs and symptoms of local 
irritation and documented appropriately. 
AEs will be collected through both solicited and unsolicited means and subsequently coded in 
tabular form using the MedDRA (Version 19 or higher) Adverse Event Dictionary. The patients 
will be encouraged to report signs, symptoms, and any changes in health to the clinic staff. Severity 
of each AE will be determined by the staff based on observation and questioning of the patients. 
The Investigator will judge the relationship of the event to the study treatments. 
9.7.1 
Definitions 
Adverse Event: Any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or 
disease, temporally associated with the use of a medicinal (investigational) product, whether or 
not related to this product. This includes events not seen at baseline, or worsened even if present 
at baseline. 
Unexpected Adverse Event: An adverse event where the nature or severity of is not consistent 
with the applicable product information (e.g., Investigator's Brochure for an unapproved 
investigational product or package insert/summary of product characteristics for an approved 
product). 
Adverse Drug Reaction: All noxious and unintended responses to a medical product related to 
any dose should be considered adverse drug reactions. The response to a 'medical product' means 
that a causal relationship between a medicinal product and an adverse event is at least a 
reasonable possibility, i.e. the relationship cannot be ruled out. 
Pregnancy: Female patients of childbearing potential must have been using and must agree to 
continue to use accepted methods of birth control, throughout the study. All female patients are 
considered to be of childbearing potential unless they are premenarchal, have been surgically 
sterilized or have been postmenopausal for at least 12 months. Abstinence is an accepted method 
of birth control. Alternatively, any of the following methods of birth control are acceptable: oral 
contraceptives, contraceptive patches/implants (e.g., Norplant®), Depo-Provera®, double barrier 
methods (e.g., condom plus diaphragm with spermicide) or IUD. Prior to study enrollment 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 44 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
women of childbearing potential must be advised of the importance of avoiding pregnancy during 
study participation. 
A negative result of a urine pregnancy test having a minimum sensitivity of at least 50 mlU/ml 
for hCG should be obtained, prior to study pmiicipation, at Visit 1. Pregnancy testing will also be 
performed at every study visit and the results of all pregnancy tests (positive or negative) will be 
documented. 
If following initiation of study treatment, it is subsequently discovered that a study patient is 
pregnant or may have been pregnant at the time of Investigational Product exposure, the 
Investigational Product will be permanently discontinued. The Principal Investigator must 
immediately notify the Medical Monitor of this event. 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
patient. Other appropriate pregnancy follow-up procedures should be considered if indicated. In 
addition, the Principal Investigator must repmi to the sponsor follow-up information regarding 
the course of the pregnancy, including perinatal and neonatal outcome. Infants should be 
followed for a minimum of eight weeks after bitih. 
9.7.2 
Severity of Adverse Event 
The severity of the adverse event will be graded by the Investigator using the following criteria as 
guidelines: 
• 
MILD: Awareness of symptom but does not interfere with routine activities 
• 
MODERATE: Discomfort sufficient to interfere with routine activities 
• 
SEVERE: Impossible to perform routine activities 
9.7.3 
Relationship of Adverse Event 
• 
NOT RELATED: Any AE that is clearly not related to use of the study product. 
• 
POSSIBLE: The association of the AE with the study product is unknown; however, a 
relationship between the drug and event cannot be ruled out. 
• 
PROBABLE: There is reasonable temporal relationship between the use of the study 
product and the AE. Based upon the Investigator's clinical experience, the association of 
the event with the study product seems likely. 
• 
DEFINITE: The AE occurs following the application of the study product and it cannot 
be reasonably explained by any other known characteristics of the patient's clinical state, 
environmental or toxic factors, or other modes of treatment administered to the patient. It 
disappears or decreases upon discontinuation of the study product and reappears on a re-
challenge of the study product. 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 45 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofN ovexatin ®' 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
9.8 Serious Adverse Events 
9.8.1 
Definition 
Serious Adverse Event: an Adverse Event or suspected adverse reaction is considered "Serious" 
if, in the view of either the Investigator or Sponsor, it results in the following outcomes: 
1. Results in death: includes all deaths, even those that appear to be completely unrelated to 
study treatment (e.g., car accident where patient is a passenger). 
2. Is life-threatening: in the view of the Investigator, the patient is at immediate risk of death at 
the time of the event. 
3. 
Results in persistent or significant disability or incapacity (substantial disruption of one's 
ability to conduct normal life). 
4. Requires inpatient hospitalization or prolongation of existing hospitalization. 
5. Causes congenital anomaly or birth defect. 
6. 
Is an important medical event that may not be immediately life-threatening or result in death 
or hospitalization, but may jeopardize the patient or may require medical or surgical 
intervention to prevent one of the serious outcomes listed above (e.g., intensive treatment in 
an emergency room, convulsions that do not result in hospitalizations). Emergency Room 
visits that require medical or surgical intervention to prevent one of the other serious 
outcomes listed above are considered a Serious Adverse Event. 
9.8.2 
Reporting 
Adverse events which are evaluated by the Investigator as "Serious" will be reported to the 
Sponsor within 24 hours, and the IRB as soon as is practically possible, preferably within 24 
hours, whether or not they are considered expected or drug-related. All Serious Adverse Events 
will be reported as required. All Serious Adverse Events encountered during the study will be 
reported on the appropriate form and summarized in the final report. 
Any serious or unexpected adverse events should be reported to Novum within 24 hours. 
Following is the contact information: 
Or 
Gail Gongas 
Vice President, Clinical Trials 
Cell Phone 412-606-1603 
Phone 412-363-3300 x 522 
Fax412-291-3171 
Paolo Maria Fanzio, MD 
Medical Monitor 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 46 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
Phone 412-363-3300 x 597 
Fax 412-924-0522 
Novum will repmi any Serious Adverse Event to Taro Pharmaceuticals U.S.A., Inc. 
Documentation of serious or unexpected adverse events and follow up information should be sent 
to Taro's SAE Coordinator and Taro's Drug Safety Manager within 24 hours from repmiing the 
event by the Investigator. Following is the contact information: 
Taro SAE Coordinator: 
Danielle Simpson 
Coordinator, Clinical Operation 
Taro Pharmaceuticals USA Inc. 
Tel: 914-345-9001 ext.6234 
Email: 
danielle.simpson@taro.com 
Taro Drug Safety Manager: 
Margo Wyatt, RN, BSN, 
Associate Director, Drug Safety Taro 
Pharmaceuticals U.S.A., Inc. 
Tel: 914-345-9001 Ext. 6758 
Email: margo.wyatt@taro.com and 
taropvus@taro.com 
Under 21 CFR 3 20.31 (d) (3 ), the Sponsor or CRO must inform other investigators involved in the 
study of the occurrence of the Serious AEs. The Sponsor must inform appropriate agencies as 
required once becoming aware of the occurrence of the Serious AEs. 
10.0 
STATISTICAL METHODS 
10.1 
Statistical Plan 
A statistical analysis plan, detailing the intended statistical analysis of the study data, will be 
prepared as a separate document and finalized before database lock. Any deviation from the 
original statistical plan will be described and justified in the final report, as appropriate. The 
procedure for accounting for missing, unused and spurious data will be included in the Statistical 
Analysis Plan (SAP). All statistical analysis will be conducted using SAS®, Version 9.4 or higher. 
10.2 
Determination of Sample Size 
The primary statistical analysis of interest is a comparison of the rates of therapeutic cure (as 
defined by "clinical cure" AND "mycological cure") of Novexatin® 10% topical solution to the 
rate of therapeutic cure of placebo in the Intent-to-Treat Population (ITT). The rate of therapeutic 
cure for the Novexatin® 10% topical solution 8-week regimens is expected to be approximately 
49%. The rate of therapeutic cure for placebo is expected to be approximately 21%. 
Approximately 46 patients in each treatment group in the ITT population will provide over 80% 
power to show a difference at p < 0.05 (two-sided Z test and a pooled response rate for the 
standard error of the difference in proportions) between each of the active treatment groups and 
the placebo group. To allow for a 23% drop-out rate, a total of 180 patients will be enrolled in the 
study, with up to 60 patients in each ofthe treatment groups. 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 47 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
10.3 
Study Populations 
10.3.1 Intent-to-Treat Population (ITT) 
• 
All randomized patients who applied at least one dose of assigned study product 
• 
Had a positive mycological culture screening (Visit 1) 
The primary analyses will be conducted on the ITT population. 
Patients who return randomized product bottles with evidence of intentional tampering or 
unblinding will be excluded from the ITT population and included in the Safety 
population. 
10.3.2 Safety Population 
All patients who were randomized and received study product will be included in the 
Safety population. 
10.4 
Baseline Comparability 
Baseline comparability of all treatment groups will be evaluated separately in the ITT and 
Safety populations. The following baseline demographics (determined from their initial 
study visit) will be evaluated: 
• 
Age (years) 
• 
Gender (male/female) 
• 
Ethnicity (Hispanic/non Hispanic) 
• 
Race (White, Black/African American, Native Hawaiian or Other Pacific Islander, 
Asian, American Indian or Alaska Native, Other) 
Descriptive statistics by treatment group will be presented. 
10.5 
Efficacy Endpoints 
The primary endpoint is the proportion of patients in each treatment group with a 
complete therapeutic cure of onychomycosis of the target toenail assessed at each of two 
test-of-cure visits (Day 14land Day 365). 
The secondary endpoint- I is the propmiion of patients in each treatment group with a 
complete or almost complete therapeutic cure of onychomycosis of the target toenail 
assessed at each of the two test-of-cure visits (Day 141 and Day 365). 
The secondary endpoint-2 is the proportion of patients in each treatment group with a 
mycologic cure of the target toenail assessed at each of the two test-of-cure visits (Day 
141 and Day 365). 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 48 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
The secondary endpoint-3 is the proportion of patients in each treatment group with a 
complete clinical cure of the target toenail assessed at each of three test-of-cure visits 
(Day 141, Day 281 and Day 365). 
The secondary endpoint-4 is the proportion of patients in each treatment group with a 
satisfactory clinical cure of the target toenail assessed at each of three test-of-cure visits 
(Day 141, Day 281 and Day 365). 
Complete therapeutic cure is defined as both complete clinical and mycological cure of 
the target toenail 
Almost complete therapeutic cure 1s defined as both mycological and satisfactory 
clinical cure of the target toenail 
Mycological cure is defined as a negative KOH test and a negative fungal culture. 
Complete clinical cure is defined as 0% nail involvement. 
Satisfactory clinical cure is defined as:::; 5% of the target toenail involvement. 
10.6 
Efficacy Analyses 
The ITT population will be used to evaluate the efficacy of Novexatin® 10% topical 
solution for the 8-week treatment regimens in Groups A, B and C. 
Descriptive statistics will be summarized for the primary and secondary endpoints 
(including planimetry data) by study group. As this is a multi-centered study, results may 
also be presented by study site. 
In order to preserve an overall type-I error (alpha) of 5% for evaluation of complete and 
almost complete therapeutic cure, complete and satisfactory clinical cure and mycologic 
cure, a hierarchical evaluation scheme will be employed for the primary and secondary 
endpoints. The four comparisons of interest for the primary endpoint and the secondary 
endpoints -1 and -2 are: 
1. Group B versus Group C-at the test-of-cure visit at Day 365 
2. Group A versus Group C -at the test-of-cure visit at Day 365 
3. 
Group B versus Group A- at the test-of-cure visit at Day 365 
4. 
(Group A+ Group B) versus Group C-at the test-of-cure visit at day 141 
The five comparisons of interest for the secondary endpoints -3 and -4 are: 
1. Group B versus Group C-at the test-of-cure visit at Day 365 
2. Group A versus Group C-at the test-of-cure visit at Day 365 
3. 
Group B versus Group A- at the test-of-cure visit at Day 365 
4. 
(Group A+ Group B) versus Group C-at the test-of-cure visit at Day 281 
5. (Group A+ Group B) versus Group C 
at the test-of-cure visit at Day 141 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 49 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, I 0% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
Statistical testing will begin with comparison 1. If statistical significance is attained with 
comparison 1 (p < 0.05), then a claim of superiority for comparison 1 can be made and 
the next comparison in the hierarchical evaluation scheme can be tested for statistical 
significance. If statistical significance is not attained for comparison 1 (p ~ 0.05), then 
testing of all subsequent comparisons is stopped. The hierarchical, conditional-stepwise 
evaluation scheme allows for each comparison to be evaluated at the 5% level, while 
preserving an overall type I error rate of no more than 5%. For the proportion of patients 
in each treatment group with a complete and almost complete therapeutic cure, complete 
and satisfactory clinical cure and mycological cure of onychomycosis of the target 
toenail, the statistical analysis for superiority will be conducted using two-sided Z-Tests 
and a pooled response rate for the standard error of the difference in proportions for each 
comparison of interest. The primary and secondary analyses will be performed using an 
observed case (OC) analysis in the ITT population. Patients discontinued because of lack 
of treatment effect will be included in the primary analysis as treatment failures. 
The following two sensitivity analyses will also be performed on the primary efficacy 
endpoint in the hierarchical, conditional-stepwise evaluation scheme: 
1. Analysis will be performed also including patients without an assessment at Day 365 
± 14. Patients with missing data at Day 365 ± 14 will be considered therapeutic 
failures. 
2. 
Analysis will be performed also including patients without an assessment at Day 365 
± 14. Patients in Group C with missing data at Day 365 ± 14 will be treated as 
therapeutic successes and patients from the Groups A and B with missing data at Day 
365 ± 14 will be treated as therapeutic failures. 
Similar sensitivity analyses will be conducted including patients without an assessment at 
Day 141 ± 7 for the 4th comparison in the hierarchical, conditional-stepwise evaluation 
scheme. 
Efficacy results will be used to calculate the sample size for the Phase 3 studies. 
10.6 
Safety Analysis 
All study patients who are randomized to the active treatment period of the study, and 
received study product will be included in the comparative safety analysis. The safety 
profile of each treatment group will be evaluated by comparing adverse events, 
application site reactions, vital signs and changes in clinical laboratory results obtained 
throughout the study. Data will also be collected during the study to compare the results 
of the KOH stains to the mycological culture results observed during the study. 
Adverse events will be classified using standard MedDRA terminology Version 19.0 or 
higher and summarized by treatment group. Adverse events reported during the study 
will be tabulated in a summary table listing the type, date of onset, date of resolution, 
incidence, severity, outcome, action taken, and Investigator's opinion of relationship to 
the study product. Signs and symptoms of onychomycosis will not be considered adverse 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 50 of62 
i' 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofN ovexatin ®' I 0% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
events, unless in the Investigator's opmwn, they have increased in frequency and/or 
severity to such an extent that the Investigator/patient considers that it is in the patient's 
best interest to be dropped from continued participation in the study and given alternative 
therapy for their condition. 
Should sufficient data exist, adverse event frequencies will be compared between 
treatments using Fisher's exact test or a similar test. 
Concomitant medication use during the randomized treatment period will be tabulated by 
patient. 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 51 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
11.0 
REGULATORY OBLIGATIONS 
11.1 
Institutional Review Board 
The study protocol, informed consent form, Investigator's Brochure, or package insert (as 
applicable), and any specific advertising will be submitted to, and approved by, an Institutional 
Review Board (IRB) before the start of the study. A form must be signed by the chairman or 
designee of the IRB noting the approvals. This notification of the board's approval along with a 
description by profession and gender of the board's composition will be provided to the Sponsor. 
11.2 
Study Documentation 
This study will be conducted in compliance with the protocol, Good Clinical Practices (GCPs) 
and all applicable regulations, including the Federal Food, Drug and Cosmetics Act, US 
applicable Code of Federal Regulations (title 21), parts 50, 56, 312, 320 and any IRB 
requirements relative to clinical studies and the Declaration of Helsinki, June 1964, as modified 
by the 591h World Medical Association General Assembly, October 2008. 
The Investigator will permit trial-related monitoring, audits, IRB review and regulatory 
inspections providing direct access to source data/documents. 
11.2.1 Protocol 
The Investigator indicated on FDA Form 1572 will act as the Principal Investigator at 
each study site. Protocols will be noted as approved by placement of the Novum 
Representative's signature on the cover page. The Sponsor of the study will also approve 
the protocol by having a study-responsible individual sign the protocol cover page. 
11.2.2 Informed Consent 
An Informed Consent Form (ICF) that includes all of the relevant elements currently 
required by FDA and local State regulations will be provided to each prospective study 
patient before enrollment into the study. The type and method of study, tests to be 
administered, any potential or possible hazards, and the patient's right to withdraw from 
the study at any time will be explained to the patients by the Investigator or designee. 
Once the Investigator or designee is assured that an individual candidate understands the 
implications of participating in this study, the patient will be asked to give consent by 
signing and dating in the appropriate areas of the ICF. The Investigator or designee will 
also sign and date the form, along with a staff member who will sign the ICF as a witness 
to verify that the patient has indeed received information. For illiterate patients, verbal 
consent should be obtained in the presence of and be countersigned by a literate witness. 
If any other language is required, translation will be performed by a ce1tified translator. A 
copy of the ICF wilL be provided to the patient. 
11.2.3 Protocol and Informed Consent Changes 
Revisions to the original protocol will be documented in amendments, incorporated as a 
preface to the new version and approved by the IRB. Any revision that substantially 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 52 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, I 0% Topical Solution 
(Taro Phannaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
alters the study design or increases potential risk to the patient requires the patient's 
consent to continue in the study. Revisions to the original ICF will also be approved by 
the IRB. The approvals will be processed in accordance with the established IRB 
procedures. Copies of all protocol and ICF amendments/revisions, along with letters 
noting IRB approval, will be submitted to the Sponsor. 
11.2.4 Source Documents and Case Report Forms 
All patients will be identified by initials, date of birth, and a unique patient number. 
Source documents will be used to record all study-related data. Source document entries 
will be used to complete Case Report Forms (CRFs). A set of CRFs will be completed for 
each patient enrolled in the study. All data and CRFs will be reviewed, evaluated and 
signed by the Investigator, as required. 
The original source documents and a copy of the corresponding CRFs will be retained by 
the Investigator. Patients who terminate early from the study will have end-of-study visit 
procedures and source/CRF completed. 
11.2.5 Drug Accountability 
All study product receipt, inventory, dispensing, dosing and reconciliation records will be 
maintained in compliance with Federal Regulations. The study product will be dispensed 
to qualified study patients according to established procedures. At the end of the study all 
used and unused study product will be returned to Novum. 
11.2.6 Drug Storage 
All study product will be stored at controlled room temperature, away from direct 
sunlight exposure at 25°C (77°F), with excursions permitted between l5°C and 30°C 
(59°F and 86°F) in a secure place with access by authorized individuals only. The 
Investigator will be responsible for maintaining accurate records of product receipt, 
dispensing, and return. At the end of the study, all pmiially used and unused study 
product product will be returned to Novum. 
11.2. 7 Pregnancies 
Patients with a positive pregnancy test during screening will not be enrolled in the study. 
Patients who report that they have become pregnant during the study or have a positive 
pregnancy test at clinic visit will be followed to completion of the pregnancy. The 
pregnancy will be reported as an AE. 
11.2.8 Withdrawals due to Adverse Events 
All AEs, both serious and non-serious, that result in the patient's early withdrawal from 
the study (either by the patient request or Investigator decision) must be reported to the 
Novum Medical Monitor. 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 53 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
11.2.9 Reporting Safety Information to the IRB 
The Investigator must promptly report to the Investigator's IRB all unanticipated 
problems involving risks to patients. This includes death from any cause and all serious 
adverse events occurring during the study, regardless of the assessed causality. 
11.2.10 Record Retention 
All drug accountability records, CRFs, source data and related regulatory documents 
must be retained for at least ten years following completion of the study or for two years 
after the test product has been approved for marketing by the Food and Drug 
Administration. 
11.2.11 Study Monitoring and Auditing 
Novum will be responsible for monitoring the study according to Good Clinical Practice 
and applicable regulations. Monitoring visits are for the purpose of confirming adherence 
to the protocol and to verifY complete and accurate data collection. The clinical site will 
make all records associated with the study available to Novum's representative during 
such visits and audits 
The study may be subject to audit by the Sponsor, Sponsor Representative or by 
regulatory authorities. If such an audit occurs the Investigator must agree to allow access 
to required patient records. By signing this protocol, the Investigator grants permission 
to personnel from the Sponsor, its representatives and appropriate regulatory authorities 
for on-site monitoring of all appropriate study documentation, as well as on-site review of 
study procedures. 
11.2.12 End of the Trial 
The end of the trial is defined as the time at which the last patient has completed their last 
visit in the study. Upon completion of the study, the study product will no longer be 
available to the patient but the Investigator can, at their discretion, discuss alternative 
treatments with the patient. 
11.2.13 Clinical Study Report 
At the end of the study a full repmi, in Taro's eCTD format, will be prepared that will 
include a narrative of the clinical conduct and results of the study, a statistical report 
including a description of the analysis performed, and other documentation as may be 
appropriate. 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 54 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, I 0% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
13.0 APPENDICES 
APPENDIX A 
The number of toenails infected should be counted. The toenail, one ofthe two great toenails, that the 
investigator considers to be the most appropriate as the target toenail will be identified at Visit 2 and 
designated as the "target toenail" and used for all further evaluations. 
Evaluation of Toenail condition/appearance 
The overall appearance of the target toenail over time will be monitored during the study: 
Self-assessed by patients. The results of the self-assessment will be recorded by the patient before 
beginning therapy at Visit 2 and at all subsequent visits .. Patients will use a 5-point scale for target toenail 
appearance: 
1. VeryPoor 
2. Poor 
3. Normal/acceptable 
4. 
Good 
5. Very good 
Assessed by Investigator. Investigators will rate the status of the target toenail before patient begins 
therapy at Visit 2 and at all subsequent clinic visits. Nail condition/appearance by investigator will be 
evaluated after nail trimming to the distal groove and before further trimming, if required, for the 
mycological evaluation. Investigators will use a 5-point scale target toenail appearance: 
1. Very Poor 
2. Poor 
3. N ormal/acceptab I e 
4. 
Good 
5. Very good 
71442603 Rev. 2 • July 08, 2016 • Novum Pharmaceutical Research Services • Page 55 of 62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
APPENDIXB 
At screening, a sample from both big toenails can be collected for subjects with a bilateral infection of the 
big toenails. At subsequent applicable visits, a sample from the target toenail will be collected and a KOH 
stain performed using standardized methodologies that will be provided to the Investigators. 
If a positive fungal culture was not previously confirmed and is not available at a screening, a fungal 
culture will be obtained from the toenail(s) with a positive KOH wet mount at the screening visit. 
The confirmation of a positive potassium hydroxide (KOH) wet mount preparation from target toenail 
will be conducted at the investigative site. 
At all subsequent visits, a nail fungal culture will be obtained at the Target toenail. All mycological 
samples will be sent to a centralized microbiology laboratory for analysis. The nail sample will be placed 
in a transport kit provided by the central laboratory. The kit should be sealed according to the directions 
on the back of the kit. The sample kit should be sent to the central laboratory as instructed in the 
laboratory manual provided by ACM: 
ACM Medical Lab, Inc. 
160 Elmgrove Park 
Rochester, NY 14624 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 56 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
APPENDIXC 
Application Site Reactions 
Monitoring of local tolerability (inflammation) will be based upon established methods including 
observation of the area of administration and response scoring by the study personnel. Upon the visits 
to the clinical study site, each patient will be examined for signs of local inflammation and irritation 
that may be associated with the study products. If any such signs are identified, the response will be 
graded as follows: 
Signs and Symptoms: 
Erythema (redness) 
Scaling/Dryness 
Stinging/Burning 
Erosion 
Edema (swelling) 
Pain 
Itching 
Grading Scale: 
Absent 0 
Mild 1 (slight, barely perceptible) 
Moderate 2 (distinct presence) 
Severe 3 (marked, intense) 
Application site reactions will not be separately recorded as AEs since they are being captured at each 
visit for erythema, burning/stinging, erosion, edema, pain, itching or dryness unless the Investigator 
feels it is appropriate to do so. 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 57 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
APPENDIXD 
Safety Laboratory variables 
Hematology 
Hemoglobin 
Hematocrit 
Red blood cell count (RBC) 
White blood cell count (WBC) 
Mean corpuscular volume (MCV) 
Mean corpuscular hemoglobin concentration (MCHC) 
Platelet count 
Differential white blood cell count 
Mean corpuscular hemoglobin (MCH) 
Urinalysis 
Bilirubin 
Glucose 
Ketone 
Leukocyte Esterase 
Nitrite 
Occult Blood 
pH 
Protein 
Specific Gravity 
Urobilinogen 
Clinical Chemistry 
Sodium 
Potassium 
Calcium 
Creatinine 
Blood Urea Nitrogen (BUN) 
Fasting Glucose 
Albumin 
Total Bilirubin 
Alkaline phosphatase 
Gamma-glutamyltransferase(GGT) 
Aspartate aminotransferase (AST, SGOT) 
Alanine aminotransferase (ALT, SGPT) 
Total protein 
Direct Bilirubin 
71442603 Rev. 2 • July 08, 2016 • Novum Pharmaceutical Research Services • Page 58 of 62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
APPENDIXE 
Investigator Brochure for Novexatin® 
71442603 Rev. 2 • July 08, 2016 • Novum Pharmaceutical Research Services • Page 59 of 62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
APPENDIXF 
AMENDMENTS TO THE PROTOCOL 
Revisions to the protocol after initial IRB approval are summarized in the amendment below. 
Amendment 
Date 
02/24/2016 
The following revisions were made to the protocol dated 1/13/2016. 
• 
Updated study schematic to reflect revised procedures 
• 
Updated the study population information. 
• 
Updated the Inclusion/Exclusion verbiage 
• 
Updated the study conduct to include the Planimetry Assessment 
• 
General administrative, formatting and spelling changes made throughout the protocol. 
• 
Updated the restricted medication information and washout timeframes 
• 
Updated the statistical section to include the planimetry involvement. 
• 
Updated procedures for early termination patients. 
• 
Removed the usage of an "Independent Dispenser" throughout the protocol. 
• 
Updated the Identity oflnvestigational Product 
• 
Updated the verbiage in Study Blind section. 
• 
Updated the study procedures to include Planimetry and Application Site Reaction. 
• 
Updated the verbiage of dosing compliance 
• 
Updated the nail appearance grading scale 
• 
Updated the KOH visit scheduling requirements. 
• 
Minor updates made to the statistical sections to clarifY the use of planimetry. 
• 
Addition of Investigator Clinical Assessment description to study procedures 
• 
Added "Place all records/ documents in patient's source folder" to visits 5, 6 and 7 to be 
consistent with previous visits. 
• 
Revised application site reactions scale and revised associated verbiage accordingly. 
Amendment 
Date 
2 
06/24/2016 
The following revisions were made to the protocol dated 02/24/2016. 
• 
Updated the Efficacy Endpoint verbiage 
• 
Updated the Safety Endpoint verbiage 
71442603 Rev. 2 • July 08,2016 • Novum Pharmaceutical Research Services • Page 60 of62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, 10% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
• 
Updated the verbiage for the Sample Size Determination 
• 
Updated the Statistical Analysis verbiage throughout the protocol. 
• 
Updated Study Schematic to reflect revised procedures 
• 
Updated the verbiage throughout the protocol to allow for bilateral toenail infections to be 
evaluated for all Visit 1 procedures. 
• 
Updated verbiage to determine the target toenail at Visit 2. 
• 
Updated verbiage to the Early Terminations and Protocol Deviations section. 
• 
Updated verbiage to the IndentifY of the Investigational Product. 
• 
Updated Study Conduct and Study Procedure sections to reflect updated procedures. 
• 
General administrative, formatting and spelling changes made throughout the protocol. 
• 
Updated the Study Procedures verbiage 
• 
Updated verbiage to Appendix B to reflect updated procedures. 
71442603 Rev. 2 • July 08, 2016 • Novum Pharmaceutical Research Services • Page 61 of 62 


CONFIDENTIAL PROTOCOL 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b Clinical Study to 
Assess the Efficacy, Safety and Tolerability of 8-Week Regimens ofNovexatin®, I 0% Topical Solution 
(Taro Pharmaceuticals, USA, Inc.) in Patients with Mild to Moderate Onychomycosis 
14.0 
REFERENCES 
Elewski, B. E. Onychomycosis: pathogenesis, diagnosis, and management. Clinical microbiology 
reviews 11, 415-429 (1998). 
2 
Rodgers, P. & Bassler, M. Treating onychomycosis. American family physician 63, 663-672, 677-
668 (2001). 
3 
Roberts, D. T., Taylor, W. D., Boyle, J. & British Association of, D. Guidelines for treatment of 
onychomycosis. The Britishjournal of dermatology 148,402-410 (2003). 
4 
Westerberg, D. P. & Voyack, M. J. Onychomycosis: Current trends in diagnosis and treatment. 
American family physician 88, 762-770 (2013). 
5 
Pires, C. A. et al. Clinical, epidemiological, and therapeutic profile of dermatophytosis. Anais 
brasileiros de dermatologia 89,259-264 (2014). 
6 
Gupta, A. K., Fleckman, P. & Baran, R. Ciclopirox nail lacquer topical solution 8% in the 
treatment of toenail onychomycosis. Journal of the American Academy of Dermatology 43, S70-
80 (2000). 
7 
Gupta, A. Terbinafine Nail Solution is Highly Effective for the Treatment of Onychomycosis: A 
Double-Blind, Randomized, Dose-Finding Clinical Trial. American Podiatric Medical 
Association, 96th Annual Scientific Meeting, Honolulu, Hawaii, USA Poster Presentation 
(2008). 
8 
FDA. Sporanox and Lamisil for the Treatment of Onychomycosis. Public Health Advisory 
(2001). 
9 
Ghannoum, M. & Isham, N. Fungal nail infections (onychomycosis): a never-ending story? PLoS 
pathogens 10, el 004105, doi: I 0.1371/journal.ppat.l 004105 (2014). 
10 
Perveze, Z. et al. Terbinafine-induced hepatic failure requiring liver transplantation. Liver 
transplantation : official publication of the American Association for the Study of Liver Diseases 
and the International Liver Transplantation Society 13, 162-164, doi:10.1002/lt.21034 (2007). 
11 
Lou, H. Y. et al. Hepatic failure related to itraconazole use successfully treated by corticosteroids. 
Hepatitis monthly 11, 843-846, doi:l0.5812/kowsar.1735143X.755 (2011). 
12 
N ovexatin (NP213) Investigator Brochure. 
13 
Duncan V., M. J., Turvey L., Miller L., Charrier C., Bamford C., Stewart C., Mercer D. K., 
O'Neil D. In Vitro & Ex Vivo Activity of NP213, a Fungicidal Peptide for the Treatment of 
Onychomycosis. (2009). 
14 
Bamford C., G. D., O'Neil D. Preclinical Toxicology of NP213, a Novel Fungicidal Peptide for 
the Treatment of Onychomycosis. (2009). 
15 
FDA. Guidance for Industry: Skin Irritation and Sensitization Testing of Generic Transdermal 
Drug Products. Center for Drug Evaluation and Research (1999). 
71442603 Rev. 2 • July 08, 2016 • Novum Pharmaceutical Research Services • Page 62 of 62 

SAP_000.pdf: 
NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
Novexatin 10% topical solution 
Protocol I Study No. NVXT 1404/71442603 
STATISTICAL ANALYSIS PLAN 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Multi-Site Phase 2b 
Clinical Stud~ to Assess the Efficacy, Safety and Tolerability of8-Week Regimens of 
Novexatin , 10% Topical Solution (Taro Pharmaceuticals, USA, Inc.) in Patients 
with Mild to Moderate Onychomycosis 
3/21/2018 
Protocol Number: NVXT 1404 
Novum Study Number: 71442603 
Sponsor: 
Taro Pharmaceuticals U.S.A., Inc. 
3 Skyline Drive, 
Hawthorne, NY 10532 
USA 
Contract Research Organization: 
Novum Pharmaceutical Research Services 
225 W. Station Square Drive, Suite 200 
Pittsburgh, PA 15219 
March 21,2018 
Final Version 3.0 
• Taro Pharmaceuticals U.S.A., Inc. • 
Page I of71 


NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
Novexatin 10% topical solution 
Protocol I Study No. NVXT 1404171442603 
SAP FINAL VERSION APPROVALS 
A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group. Multi-Site Phase 2b 
Clinical Stud~ to Assess the Efficacy. Safety and Tolerability of 8-Week Regimens of 
Novexatin . I 0% Topical Solution (Taro Pharmaceuticals, USA. Inc.) in Patients 
with Mild to Moderate Onychomycosis 
Written By: ~ 
Signature:------------
Jianhua Liu, MSc 
Senior Biostatistician 
Novum Pharmnceutica I Research Services 
Reviewed By: 
Signature: --:-="-:fjr-¥--'-'-t------
Pina D'Angelo, 
Executive Directo 
cientific Affairs (Biostatistics) 
Novum Pharmaceutical Research Services 
Approved By: 
Signature: 
#Yt~o~tlorsilf 
Natalie Yantovskiy 
Senior Director, Clinical Research 
Taro Pharmaceuticals U.S.A., Inc. 
Date:_<J_Cf.:_:_{ 0_3_,:./_W~f ~-
Date: 
.2 April 2010 
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Page 2 of71 


NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
Novexatin 10% topical solution 
Protocol I Study No. NVXT 1404/71442603 
Revision History 
Draft 1.0 
March 20, 2017 
Draft 2.0 
December 12, 2017 
Final 1.0 
February 26, 2018 
Final2.0 
March 1, 2018 
Final 3.0 
March 21, 2018 
New Document 
Incorporate Novum's comments 
Add additional analyses, incorporate client 
comments and finalize SAP 
Add summary table T14.3.1 0 Summary of 
Frequency of Evaluation ofToenail 
Condition/Appearance 
Incorporate client's comments 
3/2112018 
• Taro Pharmaceuticals U.S.A., Inc. • 
Jianhua Liu 
Jianhua Liu 
Jianhua Liu 
Jianhua Liu 
Jianhua Liu 
Page 3 of71 


NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
Novexatin 10% topical solution 
Protocol I Study No. NVXT 1404/71442603 
List of Abbreviations and Definition of Terms 
ADaM 
AE 
ANCOVA 
BP 
c 
CRF 
CDISC 
CRO 
F 
FDA 
HR 
Hg 
ICF 
ICH 
IND 
ITT 
LOCF 
MedDRA 
OGD 
pp 
SAE 
SAP 
SAS 
SDTM 
USA 
3/21/2018 
Analysis Data Model 
Adverse Event 
Analysis of Covariance 
Blood Pressure 
Celsius 
Case Report Form 
Clinical Data Interchange Standards Consortium 
Contract Research Organization 
Fahrenheit 
Food and Drug Administration 
Heart Rate 
Mercury 
Informed Consent Form 
International Conference on Harmonization 
Investigational New Drug 
Intent-to-Treat 
Last Observation Carried Forward 
Medical Dictionary for Regulatory Activities 
The Office of Generic Drugs 
Per-Protocol 
Serious Adverse Event 
Statistical Analysis Plan 
Statistical Analysis System 
Study Data Tabulation Model 
United States of America 
• Taro Pharmaceuticals U.S.A., Inc. • 
Page 4 of71 


NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
Novexatin 10% topical solution 
Protocol I Study No. NVXT 1404/71442603 
TABLE OF CONTENTS 
I. INTRODUCTION ....................................................................................................................... 8 
2. OBJECTIVES .............................................................................................................................. 8 
3. OVERALL STUDY DESIGN ..................................................................................................... 8 
4. RANDOMIZATION AND BLINDING .................................................................................... l2 
5. SAMPLE SIZE .......................................................................................................................... 12 
6. STUDY ENDPOINTS ............................................................................................................... 13 
7. STUDY POPULATIONS .......................................................................................................... l4 
8. STATISTICAL ANALYSIS METHODS ................................................................................. l4 
8.1 Baseline Characteristics ...................................................................................................... 14 
8.1.1 Patient Disposition ...................................................................................................... 14 
8.1.2 Demographic and Other Baseline Characteristics ....................................................... 15 
8.1.3 Medical History ........................................................................................................... l5 
8.1.4 Concomitant Medications ........................................................................................... 15 
8.2 Efficacy Analyses ................................................................................................................ IS 
8.2.1 Efficacy Analyses on Primary and Secondary Endpoints .......................................... .15 
8.2.2 Treatment-by-Site Interaction and Pooling of Clinical Sites ...................................... 17 
8.2.3 Additional Analyses .................................................................................................... 17 
8.3 Safety Analysis ............................................................................................................... l8 
8.3.1 Adverse Events ............................................................................................................ l8 
8.3.2 Vital Signs ................................................................................................................... I9 
8.3.3 Clinical Laboratory Results ......................................................................................... l9 
8.3.4 Application Site Reactions .......................................................................................... l9 
8.3 .5 Evaluation of Toenail Condition/ Appearance: ............................................................ 19 
8.4 Multiple Co1nparisons ......................................................................................................... 20 
8.5 Methods for Handling Missing Data ................................................................................... 20 
8.6 Interim Analyses ................................................................................................................. 20 
8.7 Changes to the Protocol Defined Statistical Analysis Plan ................................................. 21 
9. TABLE, LISTING AND FIGURE SHELLS ............................................................................ 21 
Tables for Report Body ............................................................................................................. 23 
Table I 
Nu1nber ofPatients ................................................................................................. .23 
Table II 
Summary of Patient Disposition .............................................................................. 24 
Table III 
Summary of Protocol Deviations ......................................................................... 25 
Table IV 
Summary of Patients Excluded from Efficacy Analysis ...................................... 26 
Table V 
Summary of Superiority Analysis Results of Primary Efficacy Endpoint 
(Proportion of Patients with Complete Therapeutic Cure at the Test-of-Cure 
Visits) (Intent-to-Treat Population- Observed Case Analysis) ........................................ 27 
Table VI 
Sensitivity Analysis # 1: Superiority Analysis Results of Primary Efficacy 
Endpoint (Proportion of Patients with Complete Therapeutic Cure at the Test-of-
Cure Visits) (Intent-to-Treat Population) ........................................................................... 28 
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
Novexatin 10% topical solution 
Protocol I Study No. NVXT 1404/71442603 
Table VII 
Sensitivity Analysis #2: Superiority Analysis Results of Primary Efficacy 
Endpoint (Proportion of Patients with Complete Therapeutic Cure at the Test-of-
Cure Visits) (Intent-to-Treat Population) ........................................................................... 29 
Table VIII 
Summary of Adverse Events (Safety Population) ............................................... 30 
Tables for section 14 ................................................................................................................. 31 
T14.1.1 Summary ofPatients Included in Analysis Population by Study Center .................... 31 
T14.1.2.1 Summary ofDemographic Data (Safety Population) ............................................. .32 
T14.1.2.2 Summary ofDemographic Data (Intent-to-Treat Population) .................................. 33 
T14.2.1 Summary of Superiority Analysis Results of Primary Efficacy Endpoint Using 
Canfield Evaluation (Proportion of Patients with Complete Therapeutic Cure at 
the Test-of-Cure Visits) (Intent-to-Treat Population- Observed Case Analysis) ............. 34 
T14.2.2 Sensitivity Analysis # 1: Superiority Analysis Results of Primary Efficacy 
Endpoint Using Canfield Evaluation (Proportion of Patients with Complete 
Therapeutic Cure at the Test-of-Cure Visits) (Intent-to-Treat Population) ....................... 35 
T14.2.3 Sensitivity Analysis #2: Superiority Analysis Results ofPrimary Efficacy 
EndpointUsing Canfield Evaluation (Proportion of Patients with Complete 
Therapeutic Cure at the Test-of-Cure Visits) (Intent-to-Treat Population) ....................... 36 
T14.2.4.1 Summary of Superiority Analysis Results of Secondary Efficacy Endpoint-! 
(Proportion ofPatients with Complete or Almost Complete Therapeutic Cure at 
the Test-of-Cure Visits) (Intent-to-Treat Population- Observed Case Analysis) ............. 37 
T14.2.4.2 Summary of Superiority Analysis Results of Secondary Efficacy Endpoint-1 
Using Canfield Evaluation (Proportion of Patients with Complete or Almost 
Complete Therapeutic Cure at the Test-of-Cure Visits) (Intent-to-Treat Population 
-Observed Case Analysis) ............................................................................................... .38 
T14.2.5 Summary of Superiority Analysis Results of Secondary Efficacy Endpoint-2 
(Proportion of Patients with Mycologic Cure at the Test-of-Cure Visits) (Intent-
to-Treat Population- Observed Case Analysis) ................................................................ 39 
Tl4.2.6.1 Summary of Superiority Analysis Results of Secondary Efficacy Endpoint-3 
(Proportion of Patients with Complete Clinical Cure at the Test-of-Cure Visits) 
(Intent-to-Treat Population - Observed Case Analysis) .................................................... 40 
T14.2.6.2 Summary of Superiority Analysis Results of Secondary Efficacy Endpoint-3 
Using Canfield Evaluation (Proportion of Patients with Complete Clinical Cure at 
the Test-of-Cure Visits) (Intent-to-Treat Population- Observed Case Analysis) ............ .41 
T14.2.7.1 Summary of Superiority Analysis Results of Secondary Efficacy Endpoint-4 
(Proportion of Patients with Satisfactory Clinical Cure at the Test-of-Cure Visits) 
(Intent-to-Treat Population- Observed Case Analysis) ................................................... .42 
T14.3.1.1 Summary ofFrequency of All Adverse Events by Body System: Day I to 
Day 141 ± 7 (Safety Population) ...................................................................................... 43 
Tl4.3.1.2 Summary ofFrequency of All Adverse Events by Body System: Day 1 to 
Day 365 ± 14 (Safety Population) .................................................................................... 43 
Tl4.3.2 Summary of Frequency of All Adverse Events by Relationship (Safety 
Population) ........................................................................................................................ .44 
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
Novexatin 10% topical solution 
Protocol I Study No. NVXT 1404/71442603 
T14.3.3 Summary of Frequency of All Adverse Events by Severity (Safety 
Population) ......................................................................................................................... 45 
T14.3.4 Summary ofFrequency of Serious Adverse Events (Safety Population) ................... 46 
Tl4.3.5 Summary of Vital Signs (Safety Population) ............................................................. 47 
T14.3.6 Summary of Clinical Laboratory Testing (Hematology) (Safety Population) ........... .48 
T14.3.7 Summary of Clinical Laboratory Testing (Chemistry) (Safety Population) .............. .48 
T14.3.8 Summary of Clinical Laboratory Testing (Urinalysis) (Safety Population) ............... .48 
T14.3.9 Summary ofFrequency of Application Site Reactions (Safety Population) ............... 49 
Tl4.3.10 Summary ofFrequency ofEvaluation ofToenail Condition/Appearance 
(Safety Population) ..................................................................... , ...................................... 50 
L 16.2.1 Listing of Discontinued Patients .................................................................................. 51 
L 16.2.2 Listing of Protocol Deviations ..................................................................................... 52 
Ll6.2.3 Listing of Patients Excluded from the Analysis Population ........................................ 53 
L16.2.4.1 Listing ofDemographic Data ............................................................. , .................... 54 
Ll6.2.4.2 Listing of Medical History .................................................................... ,. ................. 55 
L16.2.4.3 Listing of Concomitant Medication .......................................................................... 56 
L16.2.5 Listing ofDiary Entries and Study Compliance .......................................................... 57 
L 16.2.6.1 Listing of Investigator Clinical Assessment ............................................................. 58 
L16.2.6.2.1 Listing oflnvestigator Visual Assessment (Percent Nail Involvement of 
the Target Toenai\) ............................................................................................................. 59 
Ll6.2.6.2.2 Listing of Canfield Assessment (Percent Nail Involvement of the Target 
Toenail) .. , ........................................................................................................................... 59 
L16.2.6.3 Listing ofKOH Wet Mount & Mycological Culture ............................................... 60 
Ll6.2.6.4 Listing oflnvestigator & Patient Evaluation Of Toenail Appearance & 
Condition ............................................................................................................................ 61 
L 16.2.6.5.1 Listing of Efficacy Endpoints (Observed Case) .................................................... 62 
L16.2.6.5.2 Listing of Efficacy Endpoints Using Canfield Evaluation .................................... 62 
Ll6.2.6.5.3 Listing of Primary Efficacy Endpoints (Sensitivity Analysis) .............................. 63 
Ll6.2.7.1 Listing of Adverse Events by treatment group ......................................................... 64 
Ll6.2.7.2 Listing of Application Site Reactions ....................................................................... 65 
Ll6.2.7.3 Listing of Abnormal Physical Examination Results ................................................. 66 
L 16.2. 7.4 Listing of Positive Pregnancy Test Results .............................................................. 67 
Ll6.2.8.1 Listing of Clinical Laboratory Testing Results (Hematology) ................................. 68 
Ll6.2.8.2 Listing of Clinical Laboratory Testing Results (Chemistry) .................................... 68 
Ll6.2.8.3 Listing of Clinical Laboratory Testing Results (Urinalysis) .................................... 68 
L16.2.8.4 Listing of Vital Signs ................................................................................................ 69 
10. APPENDICES ......................................................................................................................... 70 
Appendix A: Evaluation of Toenail Condition/appearance ...................................................... 70 
Appendix B: Application Site Reactions .................................................................................. 71 
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
Novexatin 10% topical solution 
Protocol I Study No. NVXT 1404/71442603 
1. INTRODUCTION 
This Statistical Analysis Plan (SAP) is based on the final Clinical Study Protocol NVXT 1404 
(Novum Study No. 71442603) Rev. 2 dated July 8, 2016. The SAP provides details on the 
planned statistical methodology for the analysis of the study data. The SAP also outlines the 
statistical programming specifications for the tables, listings and figures. 
This SAP describes the study endpoints, derived variables, anticipated data transformations and 
manipulations, and other details of the analyses not provided in the study protocol. This SAP 
therefore outlines in detail all other aspects pertaining to the planned analyses and 
presentations for this study. 
The following documents were reviewed in preparation of this SAP: 
• 
Final Clinical Study Protocol NVXT 1404 (Novum Study No. 71442603) Rev. 2 dated 
July 8, 2016 
• 
Casebook for Novum Study No. 71442603 dated 11/30/2017 
The reader of this SAP is encouraged to also read the clinical protocol for details on the 
conduct of this study, and the operational aspects of clinical assessments and timing for 
completing a patient in this study. 
2. OBJECTIVES 
I. Determine the rates of complete therapeutic cure ofNovexatin® I 0% topical solution (Taro 
Pharmaceuticals, USA) after daily dosing for one 8-week treatment period (Treatment 
Group A) and two 8-week treatment periods separated by a 32-week rest period (Treatment 
Group B), and Placebo (vehicle) topical solution (Taro Pharmaceuticals, USA) after two 8-
week treatment periods separated by a 32-week rest period (Treatment Group C), at three 
test-of-cure visits (Day 141, Day 281 and Day 365) in patients with mild to moderate distal 
subungual onychomycosis of the target toenail. 
2. Compare rates of complete therapeutic cure between Treatment Groups according to a 
hierarchical evaluation scheme detailed in the statistical sections. 
3. Evaluate safety and tolerability of the two regimens of Novexatin® 10% topical solution 
(Treatment Groups A and B) in patients with mild to moderate distal subungual 
onychomycosis of the target toenail. 
3. OVERALL STUDY DESIGN 
This randomized, placebo-controlled, double-blind, parallel-group, multi-site study is designed 
to evaluate and compare the efficacy and safety of two dosing regimens ofNovexatin® 10% 
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
Novexatin 10% topical solution 
Protocol I Study No. NVXT 1404/71442603 
topical solution (Taro Pharmaceuticals USA) for the treatment of mild to moderate distal 
subungual onychomycosis of the target toenail. Additionally the active formulation in these 
regimens will be assessed for superiority to a placebo topical solution. 
Up to 180 eligible patients with distal subungual onychomycosis who meet all the inclusion 
criteria and none of the exclusion criteria will be randomized into the study at Visit 2. Patients 
must be at least 18 years of age, in overall good health. They should have a current diagnosis of 
distal subungual onychomycosis of mild-moderate severity. Before any study-specific 
procedures are performed all patients will read and sign the IRE-approved informed consent 
form. 
At least 60 qualified patients in each treatment group will receive randomized and blinded study 
product. The randomization scheme will be 1: I: 1 (Active Treatment A: Active Treatment B: 
Placebo C). The study products are: 
Test: Novexatin® 10% Topical Solution (Taro Pharmaceuticals, USA) 
Placebo: Placebo (Vehicle) Topical Solution (Taro Pharmaceuticals, USA) 
Patients will be assigned to one of the three treatment groups: 
Treatment Group A: Test treatment for Days I -56 and Placebo treatment for 
Days 28I - 336 
Treatment Group B: Test treatment for Days 1 -56 and Days 281 - 336 
Treatment Group C: Placebo treatment for Days I- 56 and Days 28I- 336 
Treatment and study durations will be as follows: 
Study Duration: 365 days (52 weeks) 
Patients will undergo evaluation for clinical and mycological cure of onychomycosis at the 7 
clinic visits as per study schematic. Randomized patients who withdraw from the study will not 
be replaced. The study will be conducted according to the following schedule: 
Visit Schedule: 
• 
Visit 1: Days -35 to -I (Screening) 
• 
Visit 2: Day I (Baseline and Randomization I I st Treatment start) 
• 
Visit 3: Day 57± 4 (I st Treatment completion) 
• 
Visit 4: Day I41 ± 7 (Interim) 
• 
Visit 5: Day 281 ± 14 (2nd Treatment start) 
• 
Visit 6: Day 337 ± I4 (2nd Treatment completion) 
• 
Visit 7: Day 365 ± 14 (4 weeks post- treatment) 
Unscheduled visits will be allowed as deemed necessary by Investigator. 
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
Novexatin 10% topical solution 
Protocol I Study No. NVXT 1404/71442603 
The primary efficacy endpoint is the proportion of patients in each treatment group with a 
complete therapeutic cure of onychomycosis of the target toenail assessed at each of the two test-
of-cure visits (Day 141 and Day 365). The safety profile of each treatment group will be 
evaluated by comparing adverse events, application site reactions, monitoring vital signs and 
changes in clinical laboratory results obtained throughout the study. 
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
Novexatin 10% topical solution 
Protocol I Study No. NVXT 1404/71442603 
Figure 1 Study Schematic 
PROCEDURE 
Day 
Informed Consent 
Inclusion/ Exclusion Criteria Review 
Demographics 
Medical History 
Physical Examination 
Vital Signs 
KOH test 
Fungal Culture collection 
Clinical Lab Tests 
Target Nail trimming (if needed) 
before nail involvement/appearance 
assessments 
Target toenail involvement (assessed 
by visual assessment)* 
Planimetry Assessment 
Evaluation of toenail 
condition/appearance (by patient and 
investigator) 
Investigator Clinical Assessment 
Urine Pregnancy Test** 
Dispense study product, supplies 
Dispense Diary/Instructions 
Application site reactions 
Collect unused/empty bottle 
Collect and Review Patient Diary 
Adverse Event Assessments 
Concomitant Medication Review 
Schedule next visit 
Visit I 
-35to-1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Visit 2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Visit 3 
57±4 
(Week 
8) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Visit 4 
141 ± 7 
(Wecl\ 20) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Visit 5 
281 ± 14 
(Wccl\ 
40) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
* At Visit I, both toena!ls wtll be assessed if a btlateralmfectlon of the btg toenalls are present. 
**All women of childbearing potential 
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• Taro Pharmaceuticals U.S.A., Inc. • 
Visit 6 
337 ± 14 
(Week 
48) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Visit 7 
365 ± 14 
(Weel\ 52) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Page 11 of71 


NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
Novexatin 10% topical solution 
Protocol I Study No. NVXT 1404/71442603 
4. RANDOMIZATION AND BLINDING 
The study product will be packaged and blinded by an independent clinical packaging company. 
The randomization will be generated in blocks of 3, containing the study products in three 
configurations: 
A. bottles #1 & 2- Test and bottles #3 & 4- Placebo 
B. bottles #1 & 2- Test and bottles #3 & 4- Test 
C. bottles #1 & 2- Placebo and bottles #3 & 4- Placebo. 
Three patients worth of study product bottles 1 & 2 will be packed into a larger box. This larger 
box will be designated "one block" of study product. The study product bottles I & 2 will be 
blinded, packaged and delivered to the study site in blocks at the beginning of the enrollment. 
Bottles 3 & 4 will be delivered to the study site before Visit 5 (2
11d treatment start). 
At each Visit 2 and Visit 5 each patient will receive two 5 ml bottles of study product according 
to the randomization code. Patients will be randomized to a treatment regimen in a blinded 
fashion by assigning randomization numbers in ascending sequential order starting with the 
lowest available randomization number at each site. All patients randomized will be identified by 
initials, date of birth, and a unique six-digit patient number. The first two-digits will identify the 
Investigator site where the patient was enrolled and the last four will correspond with the 
randomization number of study product bottle assigned to the patient. A perforated or two-part 
label will be attached to each of the small sized boxes of study product supplies. Both pieces of 
the label will include the following information: Protocol number, randomization number, space 
for patient's initials, statement that the study product is for investigational usc only, space for 
dispensing date and the Sponsor's name. In addition all patients will be provided with written 
instructions on how to use the study product. One part of the label shall remain attached to the 
box. The other part will be removed prior to dispensing and attached to the study product log. 
The Investigator, staff at the study site, study monitors, and data analysis/management personnel 
will be blinded to the patient assignment. 
At the end of the study, after all the clinical data has been entered and the study database has 
been locked, a copy of the randomization will be sent to the statistician. 
5. SAMPLE SIZE 
The primary statistical analysis of interest is a comparison ofthe rates of therapeutic cure (as 
defined by "clinical cure" AND "mycological cure") ofNovexatin® 10% topical solution to the 
rate oftherapeutic cure of placebo in the Intent-to-Treat Population (ITT). The rate oftherapeutic 
cure for the Novexatin® 10% topical solution 8-week regimens is expected to be approximately 
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
Novexatin 10% topical solution 
Protocol I Study No. NVXT 1404171442603 
49%. The rate of therapeutic cure for placebo is expected to be approximately 21%. 
Approximately 46 patients in each treatment group in the ITT population will provide over 80% 
power to show a difference at p < 0.05 (two-sided Z test and a pooled response rate for the 
standard error of the difference in proportions) between each of the active treatment groups and 
the placebo group. To allow for a 23% drop-out rate, a total of 180 patients will be enrolled in 
the study, with up to 60 patients in each of the treatment groups. 
6. STUDY ENDPOINTS 
Primary Endpoint: 
The proportion of patients in each treatment group with a complete therapeutic cure of 
onychomycosis of the target toenail assessed at each of the two test-of-cure visits (Day 141 and 
Day 365). 
Secondary Endpoints: 
1. The proportion of patients in each treatment group with a complete or almost complete 
therapeutic cure of onychomycosis of the target toenail assessed at each of the two test-
of-cure visits (Day 141 and Day 365). 
2. The proportion of patients in each treatment group with a mycological cure of the target 
toenail assessed at each of the two test-of-cure visits (Day 141 and Day 365). 
3. The proportion of patients in each treatment group with a complete clinical cure ofthe 
target toenail assessed at each ofthree test-of-cure visits (Day 141, Day 281 and Day 
365). 
4. The proportion of patients in each treatment group with a satisfactory clinical cure of the 
target toenail assessed at each of three test-of-cure visits (Day 141, Day 281 and Day 
365). 
Complete therapeutic cure is defined as both complete clinical and mycological cure ofthe 
target toenail 
Almost complete therapeutic cure is defined as both mycological and satisfactory clinical cure 
of the target toenail 
Mycological cure is defined as a negative KOH test and a negative fungal culture. 
Complete clinical cure is defined as 0% nail involvement. 
Satisfactory clinical cure is defined as~ 5% of the target toenail involvement. 
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
Novexatin 10% topical solution 
Protocol I Study No. NVXT 1404/71442603 
7. STUDY POPULATIONS 
Intent-to-Treat (ITT) Population 
• 
All randomized patients who applied at least one dose of assigned study product 
• 
Had a positive mycological culture screening (Visit 1) 
The primary analyses will be conducted on the ITT population. 
Patients who return randomized product bottles with evidence of intentional tampering or 
unblinding will be excluded from the ITT population and included in the Safety population. 
Safety Population 
All patients who were randomized and received study product will be included in the Safety 
population. 
8. STATISTICAL ANALYSIS METHODS 
If not otherwise specified, statistical significance is defined asp< 0.05 and is two-tailed. Data 
will be summarized with respect to demographic and baseline characteristics and safety 
variables. 
For categorical variables, the number and percent of each category within a parameter will be 
calculated for non-missing data. For continuous variables, statistics will include n, mean, 
standard deviation, median, minimum and maximum values. 
All statistical analyses will be conducted using SAS®, Version 9.4 or higher. Datasets will be 
prepared using headings from Clinical Data Interchange Consortium (CDISC) Study Data 
Tabulation Model (SDTM) implementation for human clinical trials and ADaM (Analysis 
Dataset Model). 
8.1 Baseline Characteristics 
8.1.1 Patient Disposition 
The patient disposition information will be summarized by treatment group. The number of 
patients randomized, treated with study medication will be tabulated by treatment group. In 
addition, completion status and primary reason for withdrawal will be summarized by treatment 
group. 
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
Novexatin 10% topical solution 
Protocol I Study No. NVXT 1404/71442603 
8.1.2 Demographic and Other Baseline Characteristics 
Baseline comparability of all treatment groups will be evaluated separately in the ITT and Safety 
populations. 
The following baseline demographics (determined from their initial study visit) will be 
evaluated: 
• 
Age (years) 
• 
Gender (male/female) 
• 
Ethnicity (Hispanic/non-Hispanic) 
• 
Race (White, Black/African American, Native Hawaiian or Other Pacific Islander, 
Asian, American Indian or Alaska Native, Other) 
Summary tables by treatment group will be presented. Continuous variables will be summarized 
using descriptive statistics (n, mean, standard deviation, median, minimum, maximum). 
Categorical variables will be summarized using frequencies and percentage. 
Baseline comparability of the treatments will be presented using Chi-square test for the 
categorical variables, and Analysis of Variance for the continuous variables. 
All data will be listed by treatment group and patient. 
8.1.3 Medical History 
At Visit l, patients will be questioned about medical history, including acute and chronic 
medical history and medical history relevant to their onychomycosis. 
Medical history data will be listed by treatment group and patient. 
8.1.4 Concomitant Medications 
At Visit 1, patients will be questioned about current and concomitant medication use over the 
previous 6 months. At all other clinic visits, patients will be questioned about ongoing or new 
concomitant medication use. 
All prior and concomitant medications taken since screening until the end of the study will be 
listed by treatment group and patient. 
8.2 Efficacy Analyses 
8.2.1 Efficacy Analyses on Primary and Secondary Endpoints 
The ITT population will be used to evaluate the efficacy ofNovexatin® 10% topical solution for 
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the 8-week treatment regimens in Groups A, B and C. 
Descriptive statistics will be summarized for the primary and secondary endpoints (including 
planimetry data) by study group. As this is a multi-centered study, results may also be presented 
by study site. 
In order to preserve an overall type-! error (alpha) of 5% for evaluation of complete and almost 
complete therapeutic cure, complete and satisfactory clinical cure and mycologic cure, a 
hierarchical evaluation scheme will be employed for the primary and secondary endpoints. The 
four comparisons of interest for the primary endpoint and the secondary endpoints -1 and -2 are: 
1. Group B versus Group C-at the test-of-cure visit at Day 365 
2. Group A versus Group C-at the test-of-cure visit at Day 365 
3. Group B versus Group A- at the test-of-cure visit at Day 365 
4. (Group A+ Group B) versus Group C-at the test-of-cure visit at day 141 
The five comparisons of interest for the secondary endpoints -3 and -4 are: 
1. Group B versus Group C -at the test-of-cure visit at Day 365 
2. Group A versus Group C-at the test-of-cure visit at Day 365 
3. Group B versus Group A- at the test-of-cure visit at Day 365 
4. (Group A+ Group B) versus Group C-at the test-of-cure visit at Day 281 
5. (Group A+ Group B) versus Group C-at the test-of-cure visit at Day 141 
Statistical testing will begin with comparison 1. If statistical significance is attained with 
comparison 1 (p < 0.05), then a claim of superiority for comparison 1 can be made and the next 
comparison in the hierarchical evaluation scheme can be tested for statistical significance. If 
statistical significance is not attained for comparison 1 (p ~ 0.05), then testing of all subsequent 
comparisons is stopped. The hierarchical, conditional-stepwise evaluation scheme allows for 
each comparison to be evaluated at the 5% level, while preserving an overall type I error rate of 
no more than 5%. For the proportion of patients in each treatment group with a complete and 
almost complete therapeutic cure, complete and satisfactory clinical cure and mycological cure 
of onychomycosis of the target toenail, the statistical analysis for superiority will be conducted 
using a two-sided Cochran-Mantel-Hacnszel (CMH) exact test, stratified by clinical site, at the 
5% significance level. The primary and secondary analyses will be performed using an observed 
case (OC) analysis in the ITT population. Patients discontinued because of lack of treatment 
effect will be included in the primary analysis as treatment failures. 
The following two sensitivity analyses will also be performed on the primary efficacy endpoint 
in the hierarchical, conditional-stepwise evaluation scheme: 
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1. Analysis will be performed also including patients without an assessment at Day 
365 ± 14. Patients with missing data at Day 365 ± 14 will be considered 
therapeutic failures. 
2. Analysis will be performed also including patients without an assessment at Day 
365 ± 14. Patients in Group C with missing data at Day 365 ± 14 will be treated 
as therapeutic successes and patients from the Groups A and B with missing data 
at Day 365 ± 14 will be treated as therapeutic failures. 
Similar sensitivity analyses will be conducted including patients without an assessment at Day 
141 ± 7 for the 4th comparison in the hierarchical, conditional-stepwise evaluation scheme. 
8.2.2 Treatment-by-Site Interaction and Pooling of Clinical Sites 
As this is a multiple-site study, the interaction of treatment-by-site may be evaluated for 
superiority testing by the Cochrim-Mantei-Haenszel test (stratified by site) using Breslow-Day 
test for the primary efficacy endpoint at the 5% significance level (p < 0.05, 2-sided) in the ITI 
population. A site(s) with a low enrollment rate(s) may be pooled with its geographically closest 
site, so as to avoid bias in the stratification of the sites in the CMH test and in the estimation of a 
treatment-by-site interaction effect. The pooling will be done for low enrolling sites that account 
for less than 4-7% of the total number of patients in the ITT population at the site with the 
highest enrolling rate. If no treatment-by-site interaction is identified with the primary endpoints 
then no adjustment will be made to any efficacy analysis. 
8.2.3 Additional Analyses 
In addition to the efficacy statistical analyses specified in the protocol, the analyses described in 
Section 8.2.1 above, including sensitivity analyses, will also be performed using the following 
endpoints: 
1. Primary endpoint (complete therapeutic cure) with Canfield's evaluation for % toenail 
involvement. 
2. Secondary endpoint #1 (complete or almost complete therapeutic cure) with Canfield's 
evaluation for% toenail involvement for complete cure in addition to the current 
evaluation for almost complete cure by Canfield's evaluation. 
3. Secondary endpoint #3 (complete clinical cure) with Canfield's evaluation for% toenail 
involvement for complete cure. 
Patients will only be included in analyses 1, 2 and 3 above if they meet inclusion criterion #6 
(Mild to moderate severity at Visit 1 as defined by Investigator's estimation of approximately 
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I 0% to 35% toenail involvement) on the basis of Canfield's evaluation to define mild to 
moderate severity instead ofby Investigator's estimation. 
8.3 Safety Analysis 
All study patients who are randomized to the active treatment period of the study, and received 
study product will be included in the comparative safety analysis. The safety profile of each 
treatment group will be evaluated by comparing adverse events, application site reactions, vital 
signs and changes in clinical laboratory results obtained throughout the study. Data will also be 
collected during the study to compare the results of the KOH stains to the mycological culture 
results observed during the study. 
8.3.1 Adverse Events 
All the adverse events (AEs) reported throughout the study will be coded and classified 
according to the MedDRA (Medical Dictionary for Regulatory Activities) coding dictionary 
(Version 19.0 or higher). Each adverse event is to be evaluated for date of start and end, 
seriousness, severity, causal relationship with the study drugs, action taken and outcome. 
All AEs will be listed by treatment group and patient. 
A summary table of the number and percent of patients with AEs by system organ class, 
preferred term, and treatment will be presented. Each patient will be counted only once within 
each preferred term. Other summaries may be added based on the obtained data. 
A frequency summary table of the number of AEs by system organ class, preferred term, 
severity, and treatment will be presented. Severity will be classified as "Mild", "Moderate", or 
"Severe". 
Similarly, a frequency summary table of the number of AEs by system organ class, preferred 
term, and relationship to a study drug, and treatment will be presented. Relationship to a study 
drug will be classified as "Not Related" or "Related" where "Related includes "Possible", 
"Probable", or "Definite". 
Should sufficient data exist, adverse event frequencies will be compared between treatments 
using Fisher's exact test. If the global Fisher's exact test is statistically significant among the 
three treatment groups at the 5% alpha level (i.e., p < 0.05), then Fisher's exact test using only 
the Group A and Group B may be performed to identifY any potential statistically significant 
differences that are clinically relevant between the two active treatment groups over the period 
from Day 1 to Day 141 ± 7 days (i.e., following completion of the first 8 weeks of treatment 
when both groups have the same test treatment regimen) and over the study duration from Day I 
to Day 365 ± 14 days. 
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8.3.2 Vital Signs 
The patient's vital signs will be recorded (heart rate, blood pressure, temperature and respiration 
rate) at Visits 1, 3, 5, 6 and 7. 
Descriptive summaries (number of observations, mean, standard deviation, minimum, median 
and maximum) will be provided by treatment group and visit. 
8.3.3 Clinical Laboratory Results 
Clinical laboratory results (hematology, chemistry and urinalysis) will be collected at Visits I, 3 
and 7. 
Descriptive summaries (number of observations, mean, standard deviation, minimum, median 
and maximum) will be provided by treatment group and visit. 
All data will be listed by treatment group and visit. 
8.3.4 Application Site Reactions 
At Visits 3, 4, 5, 6 and 7, the Investigator will examine the treatment area and complete the signs 
and symptoms of irritation assessment. 
A frequency summary table comparing the application site reactions for each treatment group 
will be presented by visit. 
All data will be listed by treatment group and patient. 
8.3.5 Evaluation of Toenail Condition/ Appearance: 
The toenail, one of the two great toenails, that the investigator considers to be the most 
appropriate as the target toenail will be identified and designated as the "target toenail" at Visit 2 
and used for evaluations. 
The overall appearance of the target toenail over time will be monitored during the study: 
1. Self-assessed by patients. The results of the self-assessment will be recorded by the 
patient before beginning therapy at Visit 2 and at all subsequent visits. Patients will 
use a 5-point scale (see Appendix A) for target toenail appearance. 
2. Assessed by Investigator: Investigators will rate the status of the target toenail before 
beginning therapy at Visit 2 and at all subsequent visits. Nail condition/appearance by 
investigator will be evaluated after nail trimming to the distal groove and before 
further trimming, if required, for the mycological evaluation. Investigators will use a 
5-point scale (see Appendix A) target toenail appearance. 
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A frequency summary table for each treatment group will be presented by visit. 
All data will be listed by treatment group, patient, and evaluation day. 
8.4 Multiple Comparisons 
No multiple comparison adjustment will be made in this study other than the pre-defined 
hierarchical testing for the primary and secondary endpoints. 
8.5 Methods for Handling Missing Data 
For demographic and baseline characteristics, each variable will be analyzed using all available 
data. Patients with missing data will be excluded only fi·om analyses for which data are not 
available. 
The following rules and conventions will be used for patients who terminate from the study early 
or are dropped from the study because of protocol deviations. 
Any patient who either requests to be dropped from the study because oflack of therapeutic 
efficacy or is dropped by the Investigator for Jack of therapeutic efficacy will automatically be 
considered a "clinical failure" regardless of their target toenail assessment score at the 
termination visit. 
Any patient who uses any protocol restricted medication specifically for the treatment of their 
infection will be discontinued from further participation in the study and automatically be 
considered a "clinical failure" regardless of their target toenail assessment score at the last visit. 
Any patient who uses any protocol restricted medication NOT specit1cally for the treatment of 
their onychomycosis will be discontinued from further participation in the study. The patient will 
be considered a "clinical cure" or "clinical failure" based on the target toenail assessments at the 
termination visit. 
Any patient who is dropped for any reason other than those covered above will be included in the 
ITT, provided they had a positive baseline culture and applied at least one dose of the study 
product. Examples would include: failure to use the study products as required by the protocol, 
patient withdraws consent for continued participation, patient fails to make study visits on a 
timely basis. 
8.6 Interim Analyses 
There is no interim analysis planned in this study. 
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8.7 Changes to the Protocol Defined Statistical Analysis Plan 
The protocol states that the statistical analysis for superiority will be conducted using two-sided 
Z-Tests and a pooled response rate for the standard error of the difference in proportions for each 
comparison of interest. The CMH exact test stratified by clinical site is preferred for a multi-site 
study for which the randomization is intended to be balanced among treatments within each site 
(i.e., stratified by site), because it accounts for the variability in clinical site whereas the Z-test 
does not account for site variability in the model. During the analysis, the statistical analysis for 
superiority will be conducted using a two-sided Cochran-Mantel-Haenszel (CMH) exact test, 
stratified by clinical site, at the 5% significance level. 
The wording in section 8.5 "Methods for Handling Missing Data" was updated to coincide with 
the ITT definition. The ITT states that patients will be included in the ITT as long as they have 
received one dose of assigned study product and had a positive mycological culture at Visit 1. 
Additional analyses that were not delineated in the protocol were included in section 8.2.3 of the 
SAP. 
9. TABLE, LISTING AND FIGURE SHELLS 
The following shells provide a framework for the display of data from this study. These shells 
may not be reflective of every aspect of this study but are intended to show the general layout of 
the Tables, Listings and Figures that will be included in the final clinical study report. Tables, 
Listings and Figures are numbered following the ICH structure. Table headers, variables names 
and footnotes will be modified as needed following data analyses. All descriptive and inferential 
statistical analyses will be performed using SAS® statistical software Version 9.4 or higher, 
unless otherwise noted. 
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TABLE, LISTING AND FIGURE SHELLS 
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Tables for Report Body 
3/21/2018 
Population 
Safety 
ITT 
Total 
XXX 
XXX 
Table I 
Number of Patients 
Treatment 
Treatment 
Treatment 
Group A 
Group B 
Group C 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
Treatment Group A: Novexatin® 10% Topical Solution for Days 1-56 and Placebo treatment for Days 281-336 
Treatment Group B: Novexatin® 10% Topical Solution for Days 1-56 and Days 281-336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days 1-56 and Days 281-336 
Source: Appendix 16.2.3 
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Protocol I Study No. NVXT 1404/71442603 
Patients 
Screened 
Randomized 
Completed Study 
Terminated Early 
Adverse event 
Lack of efficacy 
Lost to follow-up 
etc. 
Other 
Table II 
Summary of Patient Disposition 
Treatment 
Treatment 
Group A 
Group B 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
Treatment 
Group C 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
Treatment Group A: Novexatin® IO% Topical Solution for Days I- 56 and Placebo treatment for Days 28I- 336 
Treatment Group B: Novexatin® 10% Topical Solution for Days I -56 and Days 28 I - 336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days 1-56 and Days 281-336 
Source: Appendix 16.2.1 
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Total 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
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Protocol/ Study No. NVXT 1404171442603 
Table III 
Summary of Protocol Deviations 
Treatment 
Treatment 
Treatment 
Group A 
Group B 
Group C 
N=xxx 
N=xxx 
N=xxx 
Total Patients with Protocol Deviations 
XXX 
XXX 
XXX 
Total Deviations 
XXX 
XXX 
XXX 
Lost to Follow-up 
XXX 
XXX 
XXX 
Missed Visit 
XXX 
XXX 
XXX 
Non-compliance with study drug 
XXX 
XXX 
XXX 
etc 
XXX 
XXX 
XXX 
Other 
XXX 
XXX 
XXX 
Treatment Group A: Novexatin® 10% Topical Solution for Days 1-56 and Placebo treatment for Days 281 -336 
Treatment Group B: Novexatin® 10% Topical Solution for Days 1 -56 and Days 281-336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days 1-56 and Days 281 -336 
Source: Appendix 16.2.2 
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Total 
N=xxx 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
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Protocol I Study No. NVXT 1404/71442603 
Table IV 
Summary of Patients Excluded from Efficacy Analysis 
Treatment 
Treatment 
Treatment 
Group A 
Group B 
Group C 
N=xxx 
N=xxx 
N=xxx 
Safety Population 
XXX 
XXX 
XXX 
Excluded from Safety population 
XXX 
XXX 
XXX 
ITT Population 
XXX 
XXX 
XXX 
Excluded from ITT population 
XXX 
XXX 
XXX 
Inclusion/Exclusion criteria not met 
XXX 
XXX 
XXX 
etc. 
XXX 
XXX 
XXX 
Treatment Group A: Novexatin® I 0% Topical Solution for Days I- 56 and Placebo treatment for Days 28 I -336 
Treatment Group B: Novexatin® I 0% Topical Solution for Days I -56 and Days 28 I -336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days 1 -56 and Days 28I -336 
Source: Appendix 16.2.3 
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Total 
N=xxx 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
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Table V 
Summary of Superiority Analysis Results of Primary Efficacy Endpoint 
(Proportion of Patients with Complete Therapeutic Cure at the Test-of-Cure Visits) 
(Intent-to-Treat Population- Observed Case Analysis) 
Number of Patients 
Proportion of Patients 
Test of 
Number of Patients 
with Complete 
with Complete 
Cure 
Treatment Comparison 
(N) 
Therapeutic Cure (n) 
Therapeutic Cure(%) 
Difference 
Visit 
Group 1 versus Group 2 
Group 1 
Group 2 
Group 1 
Group 2 
Group 1 
Group 2 
(%) 
Day 365 Group B versus Group C 
XXX 
XXX 
XXX 
XXX 
xx.x 
xx.x 
xx.x 
Group A versus Group C 
XXX 
XXX 
XXX 
XXX 
xx.x 
xx.x 
XX .X 
Group B versus Group A 
XXX 
XXX 
XXX 
XXX 
xx.x 
xx.x 
xx.x 
Day 141 
Group A+B versus Group C 
XXX 
XXX 
XXX 
XXX 
xx.x 
xx.x 
xx.x 
Superiority testing was conducted at the 5% significance level (p < 0.05; using CMH exact test) in the ITT population using observed case. 
# P-value will not be presented if the preceding one is >=0.05. 
Treatment Group A: Novexatin® 10% Topical Solution for Days l- 56 and Placebo (Vehicle) Topical Solution for Days 281-336 
Treatment Group B: Novexatin® 10% Topical Solution for Days 1-56 and Days 281-336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days I- 56 and Days 281-336 
Source: Listing Ll6.2.6.5.1, adeff 
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P-value # 
0.0056 
0.0842 
NA 
NA 
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Protocol I Study No. NVXT 1404/71442603 
Table VI 
Sensitivity Analysis #1: Superiority Analysis Results of Primary Efficacy Endpoint 
(Proportion of Patients with Complete Therapeutic Cure at the Test-of-Cure Visits) 
(Intent-to-Treat Population) 
Number of Patients 
Proportion of Patients 
Test of 
Number of Patients 
with Complete 
with Complete 
Cure 
Treatment Comparison 
(N) 
Therapeutic Cure (n) 
Therapeutic Cure(%) 
Difference 
Visit 
Group 1 versus Group 2 
Group 1 
Group 2 
Group 1 
Group 2 
Group 1 
Day 365* 
Group B versus Group C 
XXX 
XXX 
XXX 
XXX 
XX. X 
Group A versus Group C 
XXX 
XXX 
XXX 
XXX 
xx.x 
Group B versus Group A 
XXX 
XXX 
XXX 
XXX 
xx.x 
Day 141 ** Group A+B versus Group C 
XXX 
XXX 
XXX 
XXX 
XX. X 
Superiority testing was conducted at the 5% significance level (p < 0.05; using CMH exact test) in the ITT population. 
# P-value will not be presented if the preceding one is >=0.05. 
*Patients with missing data at Day 365 ± 14 are considered therapeutic failures. 
**Patients with missing data at Day 141 ± 7 are considered therapeutic failures. 
Group 2 
xx.x 
xx.x 
XX. X 
XX. X 
Treatment Group A: Novexatin® 10% Topical Solution for Days 1-56 and Placebo (Vehicle) Topical Solution for Days 281 -336 
Treatment Group B: Novexatin® I 0% Topical Solution for Days 1-56 and Days 281-336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days 1-56 and Days 281-336 
Source: Listing L16.2.6.5.3, adeff 
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(%) 
XX. X 
xx.x 
xx.x 
xx.x 
P-value # 
0.0056 
0.0842 
NA 
NA 
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Taro Pharmaceuticals U.S.A., Inc. 
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Novum Pharmaceutical Research Services 
Protocol I Study No. NVXT 1404/71442603 
Table VII 
Sensitivity Analysis #2: Superiority Analysis Results of Primary Efficacy Endpoint 
(Proportion of Patients with Complete Therapeutic Cure at the Test-of-Cure Visits) 
(Intent-to-Treat Population) 
Number of Patients 
Proportion of Patients 
Test of 
Number of Patients 
with Complete 
with Complete 
Cure 
Treatment Comparison 
(N) 
Therapeutic Cure (n) 
Therapeutic Cure (%) 
Difference 
Visit 
Group 1 versus Group 2 
Group 1 
Group 2 
Group 1 
Group2 
Group 1 
Group 2 
(%) 
Day 365* 
Group B versus Group C 
XXX 
XXX 
XXX 
XXX 
XX. X 
xx.x 
xx.x 
Group A versus Group C 
XXX 
XXX 
XXX 
XXX 
XX. X 
xx.x 
xx.x 
Group B versus Group A 
XXX 
XXX 
XXX 
XXX 
XX. X 
xx.x 
XX. X 
Day 141** Group A +B versus Group C 
XXX 
XXX 
XXX 
XXX 
xx.x 
xx.x 
XX. X 
Superiority testing was conducted at the 5% significance level (p < 0.05; using C:MH exact test) in the ITT population. 
# P-value will not be presented if the preceding one is >=0.05. 
*Patients in Group C with missing data at Day 365 ± 14 are considered therapeutic successes and patients in Groups A and B with missing data 
at Day 365 ± 14 are considered therapeutic failures. 
**Patients in Group C with missing data at Day 141 ± 7 are considered therapeutic successes and patients in Groups A and B with missing data 
at Day 141 ± 7 are considered therapeutic failures. 
Treatment Group A: Novexatin® 10% Topical Solution for Days l- 56 and Placebo (Vehicle) Topical Solution for Days 281-336 
Treatment Group B: Novexatin® 10% Topical Solution for Days 1 -56 and Days 281 -336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days 1-56 and Days 281-336 
Source: Listing Ll6.2.6.5.3, adeff 
P-value # 
0.0056 
0.0842 
NA 
NA 
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Table VIII 
Summary of Adverse Events (Safety Population) 
Description 
Patients with AEs 
Patients with at least one AE 
Discontinued study drug due to 
aboveAE 
AEs reported 
Mild 
Moderate 
Severe 
Not Related 
Related 
Death 
Serious AE 
Related includes "Possible", "Probable", or "Definite" related. 
Treatment 
Group A 
N=xxx 
xx(xx.x%) 
xx (xx.x%) 
XX 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Treatment 
Treatment 
Group B 
Group C 
N=xxx 
N=xxx 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
XX 
XX 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx(xx.x%) 
xx (xx.x%) 
xx(xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Treatment Group A: Novexatin® 10% Topical Solution for Days 1-56 and Placebo 0fehicle) Topical Solution for Days 281-336 
Treatment Group B: Novexatin® 10% Topical Solution for Days 1 -56 and Days 281-336 
Treatment Group C: Placebo 0fehicle) Topical Solution for Days I -56 and Days 281-336 
Source: Listing 16.2.7.1 
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Total 
N=xxx 
xx(xx.x%) 
xx (xx.x%) 
XX 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx(xx.x%) 
xx(xx.x%) 
xx (xx.x%) 
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Tables for section 14 
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Protocol I Study No. NVXT 1404/71442603 
T14.1.1 Summary of Patients Included in Analysis Population by Study Center 
Safety 
ITT 
Site 
PI 
Total 
Group A 
Group B 
Group C 
Total 
Group A 
Group B 
Group C 
Total 
No. 
Name 
Randomized 
XX 
xxxx 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XX 
xxxx 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
Treatment Group A: Novexatin® 10% Topical Solution for Days I- 56 and Placebo (Vehicle) Topical Solution for Days 28I- 336 
Treatment Group B: Novexatin® I 0% Topical Solution for Days 1 -56 and Days 281 - 336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days 1-56 and Days 281 -336 
Source: Listing LI6.2.4.1, ads! 
Created on: ddmmmyy hh:mm 
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Age (years) 
Race 
Ethnicity 
Gender 
T14.1.2.1 Summary of Demographic Data 
(Safety Population) 
Treatment 
Treatment 
Treatment 
Group A 
Group B 
Group C 
N=xxx 
N=xxx 
N=xxx 
n 
XX 
XX 
XX 
Mean±SD 
xx.x±x.x 
xx.x±x.x 
xx.x±x.x 
Median 
XX. X 
XX. X 
xx.x 
Range 
xx-xx 
XX-XX 
xx-xx 
American Indian or Alaska Native 
xx (xx.x%) 
xx (xx.x%) 
xx(xx.x%) 
Asian 
xx (xx.x%) 
xx (xx.x%) 
xx(xx.x%) 
Black/African American 
xx (xx.x'%) 
xx(xx.x%) 
xx(xx.x%) 
Native Hawaiian or other Pacific 
xx (xx.x%) 
xx (xx.x%) 
xx(xx.x%) 
Islander 
White 
xx (xx.x"/o) 
xx (xx.x%) 
XX (xx.x%) 
Other 
XX (xx.x"/o) 
XX (xx.x"/o) 
xx (xx.x%) 
Hispanic or Latino 
xx (xx.x"/o) 
xx(xx.x%) 
xx(xx.x%) 
Not Hispanic or Latino 
xx (xx.x%) 
xx(xx.x%) 
xx(xx.x%) 
Female 
xx (xx.x%) 
xx (xx.x%) 
xx(xx.x%) 
Male 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
N= number of patients in the treatment; n= number of patients with data available; % is based on N 
Total 
N=xxx 
P-value 
XX 
x.xxxx 
xx.x±x.x 
xx.x 
XX·XX 
xx (xx.x%) 
x.xxxx 
xx (xx.x%) 
xx (xx.x%) 
xx(xx.x%) 
xx (xx.x%) 
xx(xx.x%) 
xx (xx.x%) 
x.xxxx 
xx(xx.x%) 
xx(xx.x%) 
x.xxxx 
xx (xx.x%) 
Treatment Group A: Novexatin® 10% Topical Solution for Days I- 56 and Placebo (Vehicle) Topical Solution for Days 281-336 
Treatment Group B: Novexatin® 10% Topical Solution for Days I -56 and Days 281 - 336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days I- 56 and Days 281-336 
Source: Listing Ll6.2.4.1 
Created on: ddmmmyy hh:mm 
3/21/2018 
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Page 1 ofN 
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Taro Pharmaceuticals U.S.A., Inc. 
Novexatin 10% topical solution 
Similar tables will be created for Tl4.1.2.2 
Novum Pharmaceutical Research Services 
Protocol I Study No. NVXT 1404/71442603 
T14.1.2.2 Summary of Demographic Data (Intent-to-Treat Population) 
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Taro Pharmaceuticals U.S.A., Inc. 
Novexatin 10% topical solution 
Novum Pharmaceutical Research Services 
Protocol I Study No. NVXT 1404/71442603 
T14.2.1 Summary of Superiority Analysis Results of Primary Efficacy Endpoint Using Canfield Evaluation 
(Proportion of Patients with Complete Therapeutic Cure at the Test-of-Cure Visits) 
(Intent-to-Treat Population- Observed Case Analysis) 
Number of Patients 
Proportion of Patients 
Number of Patients 
with Complete 
with Complete 
Test of 
Cure 
Visit 
Treatment Comparison 
Group l versus Group 2 
(N) 
Therapeutic Cure (n) 
Therapeutic Cure (%) 
Difference 
Group l 
Group 2 
Group I 
Group 2 
Group 1 
Group 2 
(%) 
Day 365 Group B versus Group C 
xxx 
xxx 
XXX 
XXX 
XX. X 
XX. X 
xx.x 
Group A versus Group C 
xxx 
xxx 
XXX 
XXX 
xx.x 
XX. X 
xx.x 
Group B versus Group A 
xxx 
xxx 
XXX 
XXX 
xx.x 
XX. X 
XX. X 
Day 141 Group A+B versus Group C 
xxx 
xxx 
XXX 
XXX 
xx.x 
xx.x 
xx.x 
Superiority testing was conducted at the 5% significance level (p < 0.05; using CMH exact test) in the ITT population using observed case. 
# P-value will not be presented if the preceding one is >=0.05. 
Treatment Group A: Novexatin® IO% Topical Solution for Days 1-56 and Placebo (Vehicle) Topical Solution for Days 28I- 336 
Treatment Group B: Novexatin® 10% Topical Solution for Days I -56 and Days 281 -336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days 1-56 and Days 281-336 
P-value # 
0.0056 
0.0842 
NA 
NA 
Source: Listing L 16.2.6.5 .3, adeff 
Created on: ddmmmyy hh:mm 
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Taro Pharmaceuticals U.S.A., Inc. 
Novexatin 10% topical solution 
Novum Pharmaceutical Research Services 
Protocol/ Study No. NVXT 1404/71442603 
T14.2.2 Sensitivity Analysis #1: Superiority Analysis Results of Primary Efficacy Endpoint Using Canfield Evaluation 
(Proportion of Patients with Complete Therapeutic Cure at the Test-of-Cure Visits) 
(Intent-to-Treat Population) 
Number of Patients 
Proportion of Patients 
Test of 
Number of Patients 
with Complete 
with Complete 
Cure 
Treatment Comparison 
(N) 
Therapeutic Cure (n) 
Therapeutic Cure (%) 
Difference 
Visit 
Group 1 versus Group 2 
Group 1 
Group 2 
Group 1 
Group2 
Group 1 
Day 365* 
Group B versus Group C 
XXX 
XXX 
XXX 
XXX 
xx.x 
Group A versus Group C 
XXX 
XXX 
XXX 
XXX 
xx.x 
Group B versus Group A 
XXX 
XXX 
XXX 
XXX 
xx.x 
Day 141 ** Group A +B versus Group C 
XXX 
XXX 
XXX 
XXX 
xx.x 
Superiority testing was conducted at the 5% significance level (p < 0.05; using C:tyiH exact test) in the ITT population. 
# P-value will not be presented if the preceding one is >=0.05. 
*Patients with missing data at Day 365 ± 14 are considered therapeutic failures. 
**Patients with missing data at Day 141 ± 7 are considered therapeutic failures. 
Group2 
xx.x 
xx.x 
XX .X 
xx.x 
Treatment Group A: Novexatin® 10% Topical Solution for Days 1-56 and Placebo (Vehicle) Topical Solution for Days 281-336 
Treatment Group B: Novexatin® 10% Topical Solution for Days 1 -56 and Days 281 - 336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days I- 56 and Days 281-336 
Source: Listing L16.2.6.5.3, adeff 
Created on: ddmmmyy hh:mm 
3/21/2018 
• Taro Pharmaceuticals U.S.A., Inc. • 
(%) 
P-value# 
xx.x 
0.0056 
xx.x 
0.0842 
xx.x 
NA 
xx.x 
NA 
Page I ofN 
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Taro Pharmaceuticals U.S.A., Inc. 
Novexatin 10% topical solution 
Novum Pharmaceutical Research Services 
Protocol I Study No. NVXT 1404/71442603 
T14.2.3 Sensitivity Analysis #2: Superiority Analysis Results of Primary Efficacy Endpoint Using Canfield Evaluation 
(Proportion of Patients with Complete Therapeutic Cure at the Test-of-Cure Visits) 
(Intent-to-Treat Population) 
Number of Patients 
Proportion of Patients 
Test of 
Number of Patients 
with Complete 
with Complete 
Cure 
Treatment Comparison 
(N) 
Therapeutic Cure (n) 
Therapeutic Cure(%) 
Difference 
Visit 
Group I versus Group 2 
Group 1 
Group 2 
Group 1 
Group2 
Group 1 
Group 2 
(%) 
Day 365* 
Group B versus Group C 
XXX 
XXX 
XXX 
XXX 
xx.x 
XX. X 
xx.x 
Group A versus Group C 
XXX 
XXX 
XXX 
XXX 
xx.x 
xx.x 
xx.x 
Group B versus Group A 
XXX 
XXX 
XXX 
XXX 
xx.x 
xx.x 
XX. X 
Day 141** Group A +B versus Group C 
XXX 
XXX 
XXX 
XXX 
xx.x 
xx.x 
xx.x 
Superiority testing was conducted at the 5% significance level (p < 0.05; using Cl"v1H exact test) in the ITT population. 
# P-value will not be presented if the preceding one is >=0.05. 
*Patients in Group C with missing data at Day 365::: 14 are considered therapeutic successes and patients in Groups A and B with missing data 
at Day 365 ± 14 are considered therapeutic failures. 
**Patients in Group C with missing data at Day 141 ± 7 are considered therapeutic successes and patients in Groups A and B with missing data 
at Day 141 ± 7 are considered therapeutic failures. 
Treatment Group A: Novexatin® 10% Topical Solution for Days 1-56 and Placebo (Vehicle) Topical Solution for Days 281 -336 
Treatment Group B: Novexatin® 10% Topical Solution for Days 1-56 and Days 281-336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days 1-56 and Days 281-336 
P-value# 
0.0056 
0.0842 
NA 
NA 
Source: Listing Ll6.2.6.5.3, adeff 
Created on: ddmmmyy hh:mm 
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Taro Pharmaceuticals U.S.A., Iuc. 
Novexatin 10% topical solution 
Novum Pharmaceutical Research Services 
Protocol I Study No. NVXT 1404/71442603 
T14.2.4.1 Summary of Superiority Analysis Results of Secondary Efficacy Endpoint-! 
(Proportion of Patients with Complete or Almost Complete Therapeutic Cure at the Test-of-Cure Visits) 
(Intent-to-Treat Population- Observed Case Analysis) 
Number of Patients 
Proportion of Patients 
Test of 
Number of Patients 
with Complete or 
with Complete or 
Cure 
Treatment Comparison 
(N) 
Almost Complete 
Almost Complete 
Visit 
Group I versus Group 2 
Therapeutic Cure (n) 
Therapeutic Cure(%) 
Difference 
Group I 
Group 2 
Group 1 
Group 2 
Group I 
Group 2 
(%) 
Day 365 Group B versus Group C 
XXX 
XXX 
XXX 
XXX 
xx.x 
xx.x 
xx.x 
Group A versus Group C 
XXX 
XXX 
XXX 
XXX 
xx.x 
xx.x 
xx.x 
Group B versus Group A 
XXX 
XXX 
XXX 
XXX 
xx.x 
XX. X 
xx.x 
Day 141 
Group A+B versus Group C 
XXX 
XXX 
XXX 
XXX 
xx.x 
xx.x 
xx.x 
Superiority testing was conducted at the 5% significance level (p < 0.05; using Cl\1H exact test) in the ITT population using observed case. 
# P-value will not be presented if the preceding one is >=0.05. 
Treatment Group A: Novexatin® 10% Topical Solution for Days 1-56 and Placebo (Vehicle) Topical Solution for Days 281-336 
Treatment Group B: Novexatin® 10% Topical Solution for Days 1-56 and Days 281-336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days 1-56 and Days 281-336 
P-value # 
0.0056 
0.0842 
NA 
NA 
Source: Listing L16.2.6.5 .1, adeff 
Created on: ddmmmyy hh:mm 
Page 1 ofN 
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Taro Pharmaceuticals U.S.A., Inc. 
Novexatin 10% topical solution 
Novum Pharmaceutical Research Services 
Protocol I Study No. NVXT 1404/71442603 
T14.2.4.2 Summary of Superiority Analysis Results of Secondary Efficacy Endpoint-I Using Canfield Evaluation 
(Proportion of Patients with Complete or Almost Complete Therapeutic Cure at the Test-of-Cure Visits) 
(Intent-to-Treat Population- Observed Case Analysis) 
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• Taro Pharmaceuticals U.S.A., Inc. • 
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Taro Pharmaceuticals U.S.A., Inc. 
Novexatin 10% topical solution 
Novum Pharmaceutical Research Services 
Protocol/ Study No. NVXT 1404/71442603 
Test of 
T14.2.5 Summary of Superiority Analysis Results of Secondary Efficacy Endpoint-2 
(Proportion of Patients with Mycologic Cure at the Test-of-Cure Visits) 
(Intent-to-Treat Population- Observed Case Analysis) 
Number of 
Proportion of 
Number of Patients 
Patients with 
Patients with 
Cure 
Treatment Comparison 
(N) 
Mycologic Cure (n) 
Mycologic Cure(%) 
Difference 
Visit 
Group l versus Group 2 
Group 1 
Group 2 
Group 1 
Group 2 
Group l 
Group 2 
(%) 
Day 365 Group B versus Group C 
XXX 
XXX 
XXX 
XXX 
xx.x 
XX.X 
XX. X 
Group A versus Group C 
XXX 
XXX 
XXX 
XXX 
xx.x 
XX. X 
xx.x 
Group B versus Group A 
XXX 
XXX 
XXX 
XXX 
xx.x 
xx.x 
xx.x 
Day 141 
Group A +B versus Group C 
XXX 
XXX 
XXX 
XXX 
xx.x 
XX. X 
xx.x 
Superiority testing was conducted at the 5% significance level (p < 0.05; using CMH exact test) in the ITT population using observed case. 
# P-value will not be presented if the preceding one is >=0.05. 
Treatment Group A: Novexatin® 10% Topical Solution for Days 1-56 and Placebo (Vehicle) Topical Solution for Days 281-336 
Treatment Group B: Novexatin® 10% Topical Solution for Days I -56 and Days 281 -336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days 1-56 and Days 281-336 
P-value # 
0.0056 
0.0842 
NA 
NA 
Source: Listing LI6.2.6.5.l, adeff 
Created on: ddmmmyy hh:mm 
Page 1 ofN 
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Taro Pharmaceuticals U.S.A., Inc. 
Novexatin 10% topical solution 
Novum Pharmaceutical Research Services 
Protocol I Study No. NVXT 1404/71442603 
Test of 
T14.2.6.1 Summary of Superiority Analysis Results of Secondary Efficacy Endpoint-3 
(Proportion of Patients with Complete Clinical Cure at the Test-of-Cure Visits) 
(Intent-to-Treat Population- Observed Case Analysis) 
Number of Patients 
Proportion of Patients with 
Number of Patients 
with Complete 
Complete 
Cure 
Treatment Comparison 
(N) 
Clinical Cure (n) 
Clinical Cure(%) 
Difference 
Visit 
Group I versus Group 2 
Group l 
Group 2 
Group l 
Group2 
Group l 
Group 2 
(%) 
Day 365 Group B versus Group C 
XXX 
XXX 
XXX 
XXX 
XX. X 
xx.x 
xx.x 
Group A versus Group C 
XXX 
XXX 
XXX 
XXX 
xx.x 
XX. X 
XX. X 
Group B versus Group A 
XXX 
XXX 
XXX 
XXX 
XX. X 
XX. X 
XX. X 
Day 281 
Group A+B versus Group C 
XXX 
XXX 
XXX 
XXX 
xx.x 
xx.x 
XX. X 
Day 141 Group A+B versus Group C 
XXX 
XXX 
XXX 
XXX 
xx.x 
XX. X 
XX. X 
Superiority testing was conducted at the 5% significance level (p < 0.05; using CMH exact test) in the ITT population using observed case. 
# P-value will not be presented if the preceding one is >=0.05. 
Treatment Group A: Novexatin® 10% Topical Solution for Days 1-56 and Placebo (Vehicle) Topical Solution for Days 281-336 
Treatment Group B: Novexatin® 10% Topical Solution for Days I- 56 and Days 281-336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days 1-56 and Days 281-336 
P-value # 
0.0056 
0.0842 
NA 
NA 
NA 
Source: Listing Ll6.2.6.5.1, adeff 
Created on: ddmmmyy hh:mm 
Page 1 ofN 
3/2!/2018 
• Taro Pharmaceuticals U.S.A., Inc. • 
Page40 of71 


Taro Pharmaceuticals U.S.A., Inc. 
Novexatin 10% topical solution 
Novum Pharmaceutical Research Services 
Protocol I Study No. NVXT 1404/71442603 
T14.2.6.2 Summary of Superiority Analysis Results of Secondary Efficacy Endpoint-3 Using Canfield Evaluation 
(Proportion of Patients with Complete Clinical Cure at the Test-of-Cure Visits) 
(Intent-to-Treat Population- Observed Case Analysis) 
3/2ll2018 
• Taro Pharmaceuticals U.S.A., Inc. • 
Page 41 of71 


Taro Pharmaceuticals U.S.A., Inc. 
Novexatin 10% topical solution 
Novum Pharmaceutical Research Services 
Protocol I Study No. NVXT 1404/71442603 
T14.2.7 Summary of Superiority Analysis Results of Secondary Efficacy Endpoint-4 
(Proportion of Patients with Satisfactory Clinical Cure at the Test-of-Cure Visits) 
(Intent-to-Treat Population- Observed Case Analysis) 
Number of Patients 
Proportion of Patients with 
Number of Patients 
with Satisfactory 
Satisfactory 
Test of 
Cure 
Visit 
Treatment Comparison 
Group 1 versus Group 2 
(J'<) 
Clinical Cure (n) 
Clinical Cure (%) 
Difference 
Group l 
Group 2 
Group 1 
Group 2 
Group 1 
Group 2 
(%) 
Day 365 Group B versus Group C 
xxx 
xxx 
XXX 
XXX 
xx.x 
xx.x 
XX. X 
Group A versus Group C 
xxx 
xxx 
XXX 
XXX 
XX. X 
xx.x 
xx.x 
Group B versus Group A 
xxx 
xxx 
XXX 
XXX 
xx.x 
XX. X 
XX. X 
Day 281 
Group A+B versus Group C 
xx:x 
xxx 
XXX 
XXX 
XX. X 
XX. X 
XX. X 
Day 141 
Group A +B versus Group C 
xxx 
xxx 
XXX 
XXX 
xx.x 
XX. X 
xx.x 
Superiority testing was conducted at the 5% significance level (p < 0.05; using Cl\.1H exact test) in the ITT population using observed case. 
# P-value will not be presented if the preceding one is >=0.05. 
Treatment Group A: Novexatin® 10% Topical Solution for Days J- 56 and Placebo (Vehicle) Topical Solution for Days 281-336 
Treatment Group B: Novexatin® 10% Topical Solution for Days 1-56 and Days 281-336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days 1-56 and Days 281-336 
P-value# 
0.0056 
0.0842 
NA 
NA 
NA 
Source: Listing Ll6.2.6.5.1, adeff 
Created on: ddmmmyy hh:mm 
Page 1 ofN 
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Taro Pharmaceuticals U.S.A., Inc. 
Novexatin 10% topical solution 
Novum Pharmaceutical Research Services 
Protocol/ Study No. NVXT 1404/71442603 
T14.3.1.1 Summary of Frequency of All Adverse Events by Body System: Day 1 to Day 141 ± 7 
(Safety Population) 
Treatment Group A 
Treatment Group B 
Treatment Group C 
(N = xxx) 
(N = xxx) 
(N = xxx) 
Body System 
MedDRA Term 
E 
Patients 
E 
Patients 
E 
t 
Patients 
Fisher's 
vents 
(01 ) 
vents 
co/) 
ven s 
(o") 
1 
n to 
n to 
n 10 
p-va ue 
Patients with at least one AE 
Total 
XX 
XX (XX.X) 
XX 
XX (xx.x) 
XX 
XX (xx.X) 
X.XXXX 
Ear and labyrinth disorders 
Ear pain 
XX 
XX (XX.X) 
XX 
XX (xx.X) 
XX 
XX (xx.X) 
X.XXXX 
etc. 
etc. 
Treatment Group A: Novexatin® 10% Topical Solution for Days 1-56 and Placebo (Vehicle) Topical Solution for Days 281-336 
Treatment Group B: Novexatin® 10% Topical Solution for Days 1-56 and Days 281-336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days 1-56 and Days 281-336 
Source: Listing Ll6.2.7.1 
Created on: ddmmmyy hh:mm 
Page I ofN 
3/21/2018 
T14.3.1.2 Summary of Frequency of All Adverse Events by Body System: Day 1 to Day 365 ± 14 
(Safety Population) 
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Taro Pharmaceuticals U.S.A., Inc. 
Novexatin 10% topical solution 
Novum Pharmaceutical Research Services 
Protocol I Study No. NVXT 1404/71442603 
T14.3.2 Summary of Frequency of All Adverse Events by Relationship 
(Safety Population) 
Body System 
MedDRA Term 
Patients with at least one AE 
Total 
Ear and labyrinth disorders 
Ear pain 
etc. 
etc. 
Treatment Group A 
#of Events 
(N=xxx) 
Treatment Group B 
Treatment Group C 
#of Events 
# of Events 
(N = xxx) 
(N = xxx) 
Related 
n(%) 
xx (xx.x) 
xx (xx.x) 
Not 
Not 
R 1 ted 
Related 
Not Related 
Related 
R 1 t d 
:(~) 
n(%) 
n(%) 
n(%) 
:(~~ 
xx (xx.x} 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
N =Total number of events in each treatment group; Percentage is based on total number of events. 
Related includes "Possible", "Probable", or "Definite" related. 
Treatment Group A: Novexatin® 10% Topical Solution for Days 1-56 and Placebo (Vehicle) Topical Solution for Days 281-336 
Treatment Group B: Novexatin® 10% Topical Solution for Days 1 -56 and Days 281-336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days 1-56 and Days 281-336 
Source: Listing Ll6.2. 7.1 
Created on: ddmmmyy hh:mm 
3/21/2018 
• Taro Pharmaceuticals U.S.A., Inc. • 
Page 1 ofN 
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Taro Pharmaceuticals U.S.A., Inc. 
Novexatin 10% topical solution 
Novum Pharmaceutical Research Services 
Protocol I Study No. NVXT 1404/71442603 
T14.3.3 Summary of Frequency of All Adverse Events by Severity 
(Safety Population) 
MedORA 
Mild 
Body System 
Term 
n(%) 
Patients with at 
Total 
xx (xx.x) 
least one AE 
Ear and labyrinth 
Ear pain 
xx (xx.x) 
disorders 
etc. 
etc. 
Treatment Group A 
#of Events 
(N=xxx) 
Treatment Group B 
#of Events 
(N=xxx) 
Treatment Group C 
#ofEvents 
(N=xxx) 
Moderate 
Severe 
Mild 
Moderate 
Severe 
Mild 
Moderate 
Severe 
n(%) 
n(%) 
_n(')fo}_ 
__nlli} 
n(%) 
_11_~ 
n(%) 
n(%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx(xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
N =Total number of events in each treatment group; Percentage is based on total number of events. 
Treatment Group A: Novexatin® 10% Topical Solution for Days 1-56 and Placebo (Vehicle) Topical Solution for Days 281-336 
Treatment Group B: Novexatin® 10% Topical Solution for Days I -56 and Days 281 -336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days 1-56 and Days 281 -336 
Source: Listing L16.2.7.1 
Created on: ddmmmyy hh:mm 
3/21/2018 
• Taro Pharmaceuticals U.S.A., Inc. • 
Page 1 ofN 
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Taro Pharmaceuticals U.S.A., Inc. 
Novexatin 10% topical solution 
Novum Pharmaceutical Research Services 
Protocol/ Study No. NVXT 1404/71442603 
Body System 
Injury, poisoning and 
procedural complications 
T14.3.4 Summary of Frequency of Serious Adverse Events 
(Safety Population) 
Treatment 
Treatment 
MedDRA Term 
Group A 
Group B 
N=xx 
N=xx 
#of Events 
#of Events 
Alcohol poisoning 
XX 
Treatment 
Group C 
N=xx 
#of Events 
XX 
Treatment Group A: Novexatin® 10% Topical Solution for Days 1-56 and Placebo (Vehicle) Topical Solution for Days 281-336 
Treatment Group B: Novexatin® 10% Topical Solution for Days 1-56 and Days 281-336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days 1-56 and Days 281 -336 
Source: Listing L 16.2. 7.1 
Created on: ddmmmyy hh:mm 
3/21/2018 
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Page 1 ofN 
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Taro Pharmaceuticals U.S.A., Inc. 
Novexatin 10% topical solution 
Vital Sign (unit) 
Systolic Blood Pressure (mmHg) 
Diastolic Blood Pressure (mmHg) 
Heart Rate (beats/min) 
Respiration Rate (breaths/min) 
Temperature (F) 
Visit 
3 
5 
6 
7 
T14.3.5 Summary of Vital Signs 
(Safety Population) 
Treatment 
Statistic 
Group A 
N=xx 
n 
XX 
Mean±SD 
xxx.x±xx.x 
Median 
XXX. X 
Range 
xxx-xxx 
Novum Pharmaceutical Research Services 
Protocol/ Study No. NVXT 1404/71442603 
Treatment 
Group B 
N=xx 
XX 
xxx.x± xx.x 
xxx.x 
XXX-XXX 
Treatment 
Group C 
N=xx 
XX 
xxx.x±xx.x 
XXX. X 
XXX-XXX 
Treatment Group A: Novexatin® 10% Topical Solution for Days 1-56 and Placebo (Vehicle) Topical Solution for Days 281-336 
Treatment Group B: Novexatin® 10% Topical Solution for Days I -56 and Days 281 -336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days 1-56 and Days 281-336 
Source: Listing L16.2.8.4 
Created on: ddmmmyy hh:mm 
3/21/2018 
• Taro Pharmaceuticals U.S.A., Inc. • 
Pagel ofN 
Page 47 of71 


Taro Pharmaceuticals U.S.A., Inc. 
Novexatin 10% topical solution 
Novum Pharmaceutical Research Services 
Protocol/ Study No. NVXT 1404/71442603 
Lab Test (unit) 
Hemoglobin (giL) 
Hematocrit (LIL) 
etc 
T14.3.6 Summary of Clinical Laboratory Testing (Hematology) 
(Safety Population) 
Treatment 
Treatment 
Visit 
Statistic 
Group A 
Group B 
N=xx 
N=xx 
1 
n 
XX 
XX 
Mean± SD 
xxx.x±xx.x 
xxx.x±xx.x 
Median 
xxx.x 
xxx.x 
Range 
XXX-XXX 
XXX-XXX 
3 
7 
Treatment 
Group C 
N=xx 
XX 
xxx.x±xx.x 
xxx.x 
XXX-XXX 
Treatment Group A: Novexatin"' 10% Topical Solution for Days I -56 and Placebo (Vehicle) Topical Solution for Days 281-336 
Treatment Group B: Novexatin® 10% Topical Solution for Days 1-56 and Days 281-336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days 1 -56 and Days 281 -336 
Source: Listing L16.2.8.1 
Created on: ddmmmyy hh:mm 
Page 1 ofN 
3/21/2018 
T14.3.7 Summary of Clinical Laboratory Testing (Chemistry) 
(Safety Population) 
T14.3.8 Summary of Clinical Laboratory Testing (Urinalysis) 
(Safety Population) 
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Taro Pharmaceuticals U.S.A., Inc. 
Novexatin 10% topical solution 
Novum Pharmaceutical Research Services 
Protocol/ Study No. NVXT 1404/71442603 
Signs and Symptoms 
Erythema (redness) 
Scaling/Dryness 
Stinging/Burning 
Erosion 
Edema (swelling) 
Pain 
Itching 
T14.3.9 Summary of Frequency of Application Site Reactions 
(Safety Population) 
Visit 
3 
4 
5 
6 
7 
Scale 
Absent 
Mild 
Moderate 
Severe 
Treatment 
Group A 
N=xx 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Treatment 
Group B 
N=xx 
xxx(xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Treatment 
Group C 
N=xx 
xxx (xx.x"/o) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Treatment Group A: Novexatin® 10% Topical Solution for Days 1-56 and Placebo (Vehicle) Topical Solution for Days 281-336 
Treatment Group B: Novexatin® 10% Topical Solution for Days 1-56 and Days 281-336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days 1-56 and Days 281-336 
Source: Listing Ll6.2.7.2 
Created on: ddmmmyy hh:mm 
3/2!/2018 
• Taro Pharmaceuticals U.S.A., Inc. • 
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Taro Pharmaceuticals U.S.A., Inc. 
Novexatin 10% topical solution 
Novum Pharmaceutical Research Services 
Protocol I Study No. NVXT 1404171442603 
Visit 
Visit2 
Visit3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
T14.3.10 Summary of Frequency of Evaluation of Toenail Condition/Appearance 
(Safety Population) 
Treatment 
Treatment 
Treatment 
Group A 
Group B 
Group C 
Scale 
N=xx 
N=xx 
N=xx 
Self-assessed by Patients 
Very Poor 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Poor 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Normal 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Good 
xxx (xx.x%) 
xxx(xx.x%) 
xxx (xx.x%) 
Very Good 
xxx (xx.x%) 
xxx(xx.x%) 
xxx (xx.x%) 
Assessed by Investigator 
Very Poor 
xxx (xx.x%) 
XXX (xx.x%) 
xxx (xx.x%) 
Poor 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Normal 
xxx (xx.x%) 
xxx (xx.x%) 
xxx(xx.x%) 
Good 
xxx (xx.x%) 
xxx (xx.x"/o) 
xxx (xx.x%) 
Very Good 
xxx (xx.x%) 
xxx (xx.x"/o) 
xxx (xx.x%) 
Treatment Group A: Novexatin® 10% Topical Solution for Days 1-56 and Placebo (Vehicle) Topical Solution for Days 281-336 
Treatment Group B: Novexatin® 10% Topical Solution for Days 1 -56 and Days 281 - 336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days 1 -56 and Days 281 -336 
Source: Listing Ll6.2.6.4 
Created on: ddmmmyy hh:mm 
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Taro Pharmaceuticals U.S.A., Inc. 
Novexatin 10% topical solution 
Treatment 
Treatment Group A 
Treatment Group B 
Treatment Group C 
L16.2.1 Listing of Discontinued Patients 
Patient 
Randomization 
Number 
xx-xxxx 
xx-xxxx 
Discontinuation 
Reason 
Withdrawal by Patient 
Lost to Follow-up 
Novum Pharmaceutical Research Services 
Protocol/ Study No. NVXT 1404/71442603 
Population 
Per-Protocol 
Safety 
Treatment Group A: Novexatin® IO% Topical Solution for Days 1-56 and Placebo (Vehicle) Topical Solution for Days 28I -336 
Treatment Group B: Novexatin® IO% Topical Solution for Days I -56 and Days 281-336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days I- 56 and Days 28I- 336 
Created on: ddmmmyy hh:mm 
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Taro Pharmaceuticals U.S.A., Inc. 
Novexatin 10% topical solution 
Treatment 
Group 
Treatment Group A 
Treatment Group B 
Treatment Group C 
L16.2.2 Listing of Protocol Deviations 
Patient 
Randomization 
Number 
Event Description 
Novum Pharmaceutical Research Services 
Protocol/ Study No. NVXT 1404/71442603 
Population 
xx-xxxx 
Outside Visit Window (Visit 3) 
Safety 
Treatment Group A: Novexatin® 10% Topical Solution for Days 1-56 and Placebo (Vehicle) Topical Solution for Days 281-336 
Treatment Group B: Novexatin® 10% Topical Solution for Days 1-56 and Days 281-336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days 1-56 and Days 281-336 
Created on: ddmmmyy hh:mrn 
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Taro Pharmaceuticals U.S.A., Inc. 
Novexatin 10% topical solution 
Novum Pharmaceutical Research Services 
Protocol I Study No. NVXT 1404/71442603 
Treatment 
Group 
Treatment Group A 
Treatment Group B 
Treatment Group C 
L16.2.3 Listing of Patients Excluded from the Analysis Population 
Patient 
Randomization 
Number 
xx-xxxx 
Included in 
Reason. IfNot 
Included in 
Reason. IfNot 
Safety 
Included in Safety 
ITT 
Included in ITT 
Population? 
Population 
Population? 
Population 
Yes 
No 
xxxxxxxxxxx 
Treatment Group A: Novexatin ® 10% Topical Solution for Days 1 - 56 and Placebo (Vehicle) Topical Solution for Days 281 - 336 
Treatment Group B: Novexatin® 10%-Topical Solution for Days 1 -56 and Days 281 - 336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days 1-56 and Days 281-336 
Created on: ddmmmyy hh:mm 
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Taro Pharmaceuticals U.S.A., Inc. 
Novexatin 10% topical solution 
Treatment 
Group 
Patient 
Randomization 
Number 
Treatment Group A xx-xxxx 
Treatment Group B 
Treatment Group C 
L16.2.4.1 Listing of Demographic Data 
Age 
Gender 
Ethnicity 
30 
Female 
Not Hispanic or Latino 
Novum Pharmaceutical Research Services 
Protocol I Study No. NVXT 1404/71442603 
Race 
Black or African American 
Treatment Group A: Novexatin® 10% Topical Solution for Days 1 -56 and Placebo (Vehicle) Topical Solution for Days 281-336 
Treatment Group B: Novexatin® 10% Topical Solution for Days 1 -56 and Days 281 - 336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days 1-56 and Days 281-336 
Created on: ddmmmyy hh:mm 
Page 1 ofN 
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Taro Pharmaceuticals U.S.A., Inc. 
Novexatin 10% topical solution 
Treatment 
Group 
Treatment Group A 
Treatment Group B 
Treatment Group C 
Patient 
Randomization 
Number 
xx-xxxx 
Novum Pharmaceutical Research Services 
Protocol I Study No. NVXT 1404/71442603 
L16.2.4.2 Listing of Medical History 
Diagnosis or 
System 
Start Date 
Surgical Procedure 
End Date 
Ongoing 
Gynecologic 
Menopause 
--/--12012 
yyyy-mm-dd 
Treatment Group A: Novexatin® 10% Topical Solution for Days 1-56 and Placebo (Vehicle) Topical Solution for Days 281-336 
Treatment Group B: Novexatin® 10% Topical Solution for Days 1-56 and Days 281-336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days 1-56 and Days 281-336 
Created on: ddmmmyy hh:mm 
Page 1 ofN 
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Taro Pharmaceuticals U.S.A., Inc. 
Novexatin 10% topical solution 
Treatment 
Group 
Treatment Group A 
Treatment Group B 
Treatment Group C 
Patient 
Randomization 
Number 
xx-xxxx 
Novum Pharmaceutical Research Services 
Protocol I Study No. NVXT 1404171442603 
L16.2.4.3 Listing of Concomitant Medication 
Treatment 
Start/End 
Area 
Medication 
Dosage 
Frequency* Route 
Date 
Indication 
No 
Advil 
2TAB 
QD 
Oral 
--/--/20171 
Cold 
08/12/2017 
Treatment Group A: Novexatin® 10% Topical Solution for Days I- 56 and Placebo (Vehicle) Topical Solution for Days 281-336 
Treatment Group B: Novexatin® I 0% Topical Solution for Days 1- 56 and Days 281 - 336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days 1-56 and Days 281 -336 
*PRN- As needed; QD -Daily (once per day); Q4H- Every 4 hours; Q8H- Every 8 hours; Ql2H- Every 12 hours; BID- Twice per day; TID- 3 
times per day; QID - 4 times per day; QOD - Every other day; QS - Every week; QM - Every month; Q3M- Every 3 months 
Created on: ddmmmyy hh:mm 
Page 1 ofN 
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Taro Pharmaceuticals U.S.A., Inc. 
Novexatin 10% topical solution 
Novum Pharmacentical Research Services 
Protocol/ Study No. NVXT 1404/71442603 
L16.2.5 Listing of Diary Entries and Study Compliance 
Treatment 
Group 
Treatment Group A 
Treatment Group B 
Treatment Group C 
Patient 
Randomization 
Number 
xxxx 
Date of 
Date of 
Period 
First Dose 
Last Dose 
Period 1 
yyyy-mm-dd yyyy-mm-dd 
Period 2 
yyyy-mm-dd yyyy-mm-dd 
Total 
Did the patient have 
Did the patient miss 
the scheduled 
Doses 
between 75%- 125% 
applications for 4 or 
Applied 
dosing compliance? more consecutive days? 
XX 
No 
No 
XX 
No 
No 
Treatment Group A: Novexatin® 10% Topical Solution for Days 1-56 and Placebo (Vehicle) Topical Solution for Days 281-336 
Treatment Group B: Novexatin® 10% Topical Solution for Days 1-56 and Days 281-336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days l- 56 and Days 281-336 
Created on: ddmmmyy hh:mm 
Page 1 ofN 
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Taro Pharmaceuticals U.S.A., Inc. 
Novexatin 10% topical solution 
Novum Pharmaceutical Research Services 
Protocol/ Study No. NVXT 1404/71442603 
L16.2.6.1 Listing of Investigator Clinical Assessment 
Treatment 
Group 
Treatment Group A 
Treatment Group B 
Treatment Group C 
Patient 
Randomization 
Number 
xx-xxxx 
Visit 
1 
3 
4 
5 
6 
7 
Exam 
Result 
Area 
Foot (Left) 
Abnormal 
Foot (Right) Normal 
Number of 
Toenails 
Infected 
2 
Nail 
Appearance 
xxxxxxxxx 
Target Toenail 
Left big toe 
Treatment Group A: Novexatin® 10% Topical Solution for Days 1-56 and Placebo (Vehicle) Topical Solution for Days 281 -336 
Treatment Group B: Novexatin® 10% Topical Solution for Days I- 56 and Days 281-336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days 1-56 and Days 281-336 
Created on: ddmmmyy hh:mm 
Page 1 ofN 
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Taro Pharmaceuticals U.S.A., Inc. 
Novexatin 10% topical solution 
Novum Pharmaceutical Research Services 
Protocol I Study No. NVXT 1404/71442603 
L16.2.6.2.1 Listing of Investigator Visual Assessment (Percent Nail Involvement of the Target Toenail) 
Treatment 
Group 
Treatment Group A 
Treatment Group B 
Treatment Group C 
Patient 
Randomization 
Number 
xx-xxxx 
Visit! 
Visit2 
XXX 
XXX 
Visit3 
Visit4 
VisitS 
Visit6 
Visit7 
XXX 
XXX 
XXX 
XXX 
XXX 
Treatment Group A: Novexatin® 10% Topical Solution for Days 1-56 and Placebo (Vehicle) Topical Solution for Days 281-336 
Treatment Group B: Novexatin® 10% Topical Solution for Days 1-56 and Days 281-336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days 1-56 and Days 281-336 
Created on: ddmmmyy hh:mm 
Page 1 ofN 
L16.2.6.2.2 Listing of Canfield Assessment (Percent Nail Involvement of the Target Toenail) 
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Taro Pharmaceuticals U.S.A., Inc. 
Novexatin 10% topical solution 
Novum Pharmaceutical Research Services 
Protocol/ Study No. NVXT 1404/71442603 
Treatment 
Group 
Patient 
Randomization 
Number 
L16.2.6.3 Listing ofKOH Wet Mount & Mycological Culture 
Was the KOH Wet Mount 
KOH Wet 
Was the fungal culture 
Visit 
sample taken from the 
Mount Result 
sample taken from the 
designated Target Toenail? 
designated Target Toenail? 
Fungal 
Culture 
Result 
Reason 
Not Done 
Treatment Group A 
xx-xxxx 
1 
4 
5 
7 
Yes 
Positive 
Yes 
Positive 
Treatment Group B 
Treatment Group C 
Treatment Group A: Novexatin® 10% Topical Solution for Days 1-56 and Placebo (Vehicle) Topical Solution for Days 281 -336 
Treatment Group B: Novexatin® 10% Topical Solution for Days 1 -56 and Days 281 - 336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days 1-56 and Days 281-336 
Created on: ddmmmyy hh:mm 
3/21/2018 
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Page 1 ofN 
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Taro Pharmaceuticals U.S.A., Inc. 
Novexatin 10% topical solution 
Novum Pharmaceutical Research Services 
Protocol I Study No. NVXT 1404171442603 
L16.2.6.4 Listing oflnvestigator & Patient Evaluation Of Toenail Appearance & Condition 
Treatment 
Group 
Treatment Group A 
Treatment Group B 
Treatment Group C 
Patient 
Randomization 
Number 
xxxx 
Visit 
2 
3 
4 
5 
6 
7 
Investigator 
Evaluation 
I Very Poor 
2 Poor 
Patient 
Evaluation 
2 Poor 
2 poor 
Treatment Group A: Novexatin® 10% Topical Solution for Days 1-56 and Placebo 0/ehicle) Topical Solution for Days 281-336 
Treatment Group B: Novexatin® 10% Topical Solution for Days 1-56 and Days 281-336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days 1-56 and Days 281-336 
Created on: ddmmmyy hh:mm 
Page I ofN 
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Taro Pharmaceuticals U.S.A., Inc. 
Novexatin 10% topical solution 
Novum Pharmaceutical Research Services 
Protocol I Study No. NVXT 1404/71442603 
Treatment 
Group 
Treatment Group A 
Treatment Group B 
Treatment Group C 
Patient 
Randomization 
Number 
xx-xxxx 
L16.2.6.5.1 Listing of Efficacy Endpoints (Observed Case) 
Secondary End2oints 
Test of Mycological 
Complete 
Satisfactory Almost Complete Complete or Almost 
Cure 
Clinical 
Clinical 
Therapeutic 
Complete 
Visit 
Cure 
Cure 
Cure 
Cure 
Thera2eutic Cure 
Day 141 
No 
No 
Yes 
No 
No 
Day 281 
N/A 
No 
Yes 
N/A 
N/A 
Day 365 
Yes 
Yes 
Yes 
Yes 
Yes 
Treatment Group A: Novexatin® 10% Topical Solution for Days 1-56 and Placebo (Vehicle) Topical Solution for Days 281-336 
Treatment Group B: Novexatin® 10% Topical Solution for Days 1-56 and Days 281-336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days 1-56 and Days 281-336 
Created on: ddmmmyy hh:mm 
L16.2.6.5.2 Listing of Efficacy Endpoints Using Canfield Evaluation 
3/21/2018 
• Taro Pharmaceuticals U.S.A., Inc. • 
Primary End2oint 
Complete 
Therapeutic 
Cure 
No 
N/A 
Yes 
Page 1 ofN 
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Taro Pharmaceuticals U.S.A., Inc. 
Novexatin 10% topical solution 
Novum Pharmaceutical Research Services 
Protocol I Study No. NVXT 1404/71442603 
L16.2.6.5.4 Listing of Primary Efficacy Endpoints (Sensitivity Analysis) 
Sensitivi!,y Anal,}:'sis 1 
Sensitivi!,y Anal,l'sis 2 
Treatment 
Group 
Treatment Group A 
Treatment Group B 
Treatment Group C 
Patient 
Randomization 
Number 
xx-xxxx 
Test of 
Cure 
Visit 
Day 141 
Day281 
Day 365 
Per-Protocol 
Canfield 
Per-Protocol 
Evaluation 
Evaluation 
Evaluation 
No 
No 
No 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
Treatment Group A: Novexatin® 10% Topical Solution for Days 1-56 and Placebo (Vehicle) Topical Solution for Days 281 -336 
Treatment Group B: Novexatin® 10% Topical Solution for Days I- 56 and Days 28I- 336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days I- 56 and Days 281-336 
Created on: ddmmmyy hh:mm 
3/21/2018 
• Taro Pharmaceuticals U.S.A., Inc. • 
Canfield 
Evaluation 
No 
Yes 
Yes 
Page 1 ofN 
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Taro Pharmaceuticals U.S.A., Iuc. 
Novexatin 10% topical solution 
Novum Pharmaceutical Research Services 
Protocol I Study No. NVXT 1404/71442603 
L16.2.7.1 Listing of Adverse Events by treatment group 
Treatment 
Patient 
Body System I 
Treatment Start /End 
Relationship 
Action 
Other 
Group 
Randomization 
MedDRA Term I 
Area 
Date 
Severity to Study 
Outcome 
Taken 
Action SAE? 
Number 
AE Term 
Drug 
Taken 
Treatment Group A 
xx-xxxx 
Nervous system disorders I No 
yyyy-mm-dd I Mild 
Possible 
Recovered Dose 
None 
No 
Treatment Group B 
Treatment Group C 
Headache/ 
Headache 
yyyy-mm-dd 
Treatment Group A: Novexatin® 10% Topical Solution for Days I- 56 and Placebo (Vehicle) Topical Solution for Days 281-336 
Treatment Group B: Novexatin® 10% Topical Solution for Days I- 56 and Days 281 -336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days 1-56 and Days 281-336 
Created on: ddmmmyy hh:mm 
3/21/2018 
• Taro Pharmaceuticals U.S.A., Inc. • 
Not 
Changed 
Page 1 ofN 
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Taro Pharmaceuticals U.S.A., Inc. 
Novexatin 10% topical solution 
Novum Pharmaceutical Research Services 
Protocol I Study No. NVXT 1404/71442603 
L16.2.7.2 Listing of Application Site Reactions 
Signs and Symptoms* 
Treatment Group 
Treatment Group A 
Treatment Group B 
Treatment Group C 
Patient 
Randomization 
Number 
xxxx 
Visit 
Erythema 
3 
0 
4 
0 
5 
0 
6 
0 
7 
0 
Scalino-/ 
. 
. 
. 
D 
"" 
Stmgmg/ ErosiOn 
ryness 
Bumin 
0 
0 
1 
1 
0 
0 
0 
0 
1 
0 
0 
1 
0 
0 
1 
*Signs and symptoms: 0 =Absent; I =Mild; 2 =Moderate; 3 = Severe 
Edema 
(swelling) 
0 
0 
0 
0 
0 
Pain 
Itching 
0 
0 
0 
0 
0 
0 
2 
2 
2 
2 
Treatment Group A: Novexatin® 10% Topical Solution for Days 1-56 and Placebo (Vehicle) Topical Solution for Days 281-336 
Treatment Group B: Novexatin® 10% Topical Solution for Days 1 -56 and Days 281 - 336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days 1 -56 and Days 281-336 
Created on: ddmmmyy hh:mm 
Page 1 ofN 
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Taro Pharmaceuticals U.S.A., Inc. 
Novexatin 10% topical solution 
Novum Pharmaceutical Research Services 
Protocol I Study No. NVXT 1404/71442603 
Treatment 
Group 
Treatment Group A 
Treatment Group B 
Treatment Group C 
L16.2.7.3 Listing of Abnormal Physical Examination Results 
Patient 
Randomization 
Number 
xx-xxxx 
Visit 
System 
Result 
Visit4 
Cardiovascular 
Abnormal (NCS) 
If Abnormal, provide 
comment 
xxxxxxxxxxxxxxxxx 
Treatment Group A: Novexatin® 10% Topical Solution for Days 1-56 and Placebo (Vehicle) Topical Solution for Days 281-336 
Treatment Group B: Novexatin® 10% Topical Solution for Days 1 -56 and Days 281-336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days 1 -56 and Days 281 -336 
Created on: ddmmmyy hh:mm 
Page I ofN 
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Taro Pharmaceuticals U.S.A., Inc. 
Novexatin 10% topical solution 
Treatment 
Group 
Treatment Group A 
Treatment Group B 
Treatment Group C 
Novum Pharmaceutical Research Services 
Protocol/ Study No. NVXT 1404171442603 
L16.2.7.4 Listing of Positive Pregnancy Test Results 
Patient 
Randomization 
Visit 
Results 
Number 
xx-xxxx 
Visit4 
Positive 
Treatment Group A: Novexatin® 10% Topical Solution for Days 1-56 and Placebo (Vehicle) Topical Solution for Days 281-336 
Treatment Group B: Novexatin® 10% Topical Solution for Days 1-56 and Days 281-336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days I- 56 and Days 281-336 
Created on: ddmmmyy hh:mm 
Page 1 ofN 
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Taro Pharmaceuticals U.S.A., Inc. 
Novexatin 10% topical solution 
Novum Pharmaceutical Research Services 
Protocol I Study No. NVXT 1404/71442603 
Treatment 
Group 
Treatment Group A 
Treatment Group B 
Treatment Group C 
L16.2.8.1 Listing of Clinical Laboratory Testing Results (Hematology) 
Patient 
Randomization 
Lab 
Number 
Visit 
Date 
Test 
SI Results 
SI Unit 
xx-xxxx 
1 
yyyy-mm-dd 
Hemoglobin 
XXX 
g/L 
3 
yyyy-mm-dd 
Hemoglobin 
XXX 
g/L 
7 
yyyy-mm-dd 
Hemoglobin 
XXX 
g/L 
Normal Range 
XXX, XXX 
XXX, XXX 
XXX, XXX 
Treatment Group A: Novexatin® 10% Topical Solution for Days 1-56 and Placebo (Vehicle) Topical Solution for Days 281 -336 
Treatment Group B: Novexatin® 10% Topical Solution for Days 1-56 and Days 281-336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days 1-56 and Days 281 -336 
Created on: ddmmmyy hh:mm 
Page 1 ofN 
L16.2.8.2 Listing of Clinical Laboratory Testing Results (Chemistry) 
L16.2.8.3 Listing of Clinical Laboratory Testing Results (Urinalysis) 
3/2!/2018 
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Taro Pharmaceuticals U.S.A., Inc. 
Novexatin 10% topical solution 
L16.2.8.4 Listing of Vital Signs 
Novum Pharmaceutical Research Services 
Protocol I Study No. NVXT 1404/71442603 
Treatment 
Group 
Patient 
Randomization Visit 
Number 
Systolic BP 
Diastolic BP 
Heart Rate 
Respiration 
Temperature 
Rate 
Treatment Group A 
Treatment Group B 
Treatment Group C 
xx-xxxx 
1 
3 
5 
6 
7 
(mmHg) 
(mmHg) 
120 
70 
140 
80 
(beats/min) 
{breath/min} 
(F) 
84 
18 
98.6 
74 
18 
97.0 
Treatment Group A: Novexatin® I 0% Topical Solution for Days 1 -56 and Placebo (Vehicle) Topical Solution for Days 281-336 
Treatment Group B: Novexatin® 10% Topical Solution for Days l- 56 and Days 281-336 
Treatment Group C: Placebo (Vehicle) Topical Solution for Days I- 56 and Days 281-336 
Created on: ddmmmyy hh:mm 
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
Novexatin 10% topical solution 
Protocol I Study No. NVXT 1404/71442603 
10. APPENDICES 
Appendix A: Evaluation ofToenail Condition/appearance 
The number of toenails infected should be counted. The toenail, one of the two great toenails, 
that the investigator considers to be the most appropriate as the target toenail will be identified at 
Visit 2 and designated as the "target toenail" and used for all further evaluations. 
Evaluation of Toenail condition/appearance 
The overall appearance of the target toenail over time will be monitored during the study: 
Self-assessed by patients. The results of the self-assessment will be recorded by the patient 
before beginning therapy at Visit 2 and at all subsequent visits .. Patients will use a 5-point scale 
for target toenail appearance: 
I. Very Poor 
2. Poor 
3. Normal/acceptable 
4. Good 
5. Very good 
Assessed by Investigator. Investigators will rate the status of the target toenail before patient 
begins therapy at Visit 2 and at all subsequent clinic visits. Nail condition/appearance by 
investigator will be evaluated after nail trimming to the distal groove and before further 
trimming, if required, for the mycological evaluation. Investigators will use a 5-point scale target 
toenail appearance: 
1. Very Poor 
2. Poor 
3. Normal/acceptable 
4. Good 
5. Very good 
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
Novexatin 10% topical solution 
Protocol/ Study No. NVXT 1404/71442603 
Appendix B: Application Site Reactions 
Monitoring of local tolerability (inflammation) will be based upon established methods 
including observation of the area of administration and response scoring by the study 
personnel. Upon the visits to the clinical study site, each patient will be examined for signs of 
local inflammation and irritation that may be associated with the study products. If any such 
signs are identified, the response will be graded as follows: 
Signs and Symptoms: 
Erythema (redness) 
Scaling/Dryness 
Stinging/Burning 
Erosion 
Edema (swelling) 
Pain 
Itching 
Grading Scale: 
Absent 0 
Mild I (slight, barely perceptible) 
Moderate 2 (distinct presence) 
Severe 3 (marked, intense) 
Application site reactions will not be separately recorded as AEs since they are being 
captured at each visit for erythema, burning/stinging, erosion, edema, pain, itching or dryness 
unless the Investigator feels it is appropriate to do so. 
3/2112018 
• Taro Pharmaceuticals U.S.A., Inc. • 
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