Clinical trial NCT03824912
Conditions: Tinea Pedis
Sponsor: Encube Ethicals Pvt. Ltd.
Start date: 2018-08-23; Completion date: 2019-01-24
Enrollment: 831 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Clinical Study to Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% in the Treatment of Tinea Pedis

Detailed description:
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to Ketoconazole Cream 2% (G\&W Laboratories Inc.) in the Treatment of Tinea Pedis

Arms: arm 1: Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) arm 2: Ketoconazole Cream 2% (G\&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) arm 3: Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd)
Interventions: intervention 1: Ketoconazole Cream 2% intervention 2: Ketoconazole Cream 2% (G&W Laboratories Inc.) intervention 3: Placebo
Intervention descriptions: intervention 1: Patients will be instructed to apply sufficient study product to cover affected and immediate surrounding areas once daily for 42 ± 4 days. Each patient is expected to receive 42 ± 4 doses. intervention 2: Patients will be instructed to apply sufficient study product to cover affected and immediate surrounding areas once daily for 42 ± 4 days. Each patient is expected to receive 42 ± 4 doses. intervention 3: Patients will be instructed to apply sufficient study product to cover affected and immediate surrounding areas once daily for 42 ± 4 days. Each patient is expected to receive 42 ± 4 doses.

Protocol documents:
Prot_001.pdf: 
 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
71875502  11/08/2018  Rev. 1  Encube Ethicals Pvt Ltd.  Page 1 of 45 
 
 
 
COVER PAGE 
 
PROTOCOL 
 
Rev. 1.0 
 
November 8, 2018 
 
NCT03824912 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
Protocol Number: 71875502 
 
Novum Study Number: 71875502 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
71875502  11/08/2018  Rev. 1  Encube Ethicals Pvt Ltd.  Page 2 of 45 
 
 
1.0 TITLE PAGE 
 
Drug Product 
 
Ketoconazole Cream 2% 
Population 
 
Approximately 830 males and non-pregnant females, 18 years of age and 
older, with a clinical diagnosis of tinea pedis 
Study Design 
 
A randomized, double-blind, vehicle-controlled, parallel-group, multiple-
site bioequivalence study with clinical endpoints 
Sponsor 
 
Encube Ethicals Pvt Ltd 
Protocol Number 
 
71875502 
Novum Study Number 
 
71875502 
Protocol Date 
 
11/08/2018 
 
 
 
 
 
 
 
 
 
 
 
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. 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
71875502  11/08/2018  Rev. 1  Encube Ethicals Pvt Ltd.  Page 3 of 45 
 
 
2.0 KEY STUDY PERSONNEL AND FACILITIES 
Sponsor: 
Encube Ethicals Pvt Ltd 
803, B Wing, HDIL Kaledonia, Sahar Road, 
Andheri (E), Mumbai – 400069, 
Maharashtra, India 
CRO: 
Novum Pharmaceutical Research Services (Novum) 
225 W. Station Square Drive, Suite 200 
Pittsburgh, PA 15219 
Sponsor’s Representative: 
Dr. Lalatendu Panigrahi 
Chief Scientific Officer 
Encube Ethicals Pvt Ltd 
Phone: +91-22-6264-7002 
Fax: +91-22-66935230 
Email: lalatendu.p@encubeethicals.com 
CRO Representative: 
Gail Gongas 
Vice President, Clinical Trials and Data Management 
Novum Pharmaceutical Research Services 
Phone: 412-363-3300 Ext. 522 
Fax: 412-291-3171 
Email: gdgongas@novumprs.com   
Medical Monitor: 
Christian P. Urrea, MD 
Medical Monitor, Clinical Trials 
Novum Pharmaceutical Research Services 
Cell: 412-667-1472 
Phone: 412-363-3300 Ext. 597 
Fax: 412-291-3171 
Email: cpurrea@novumprs.com   
Biostatistician: 
Jianhua Liu, MSc 
Senior Biostatistician 
Novum Pharmaceutical Research Services 
Phone: 613-876-4672 
Fax: 412-924-0522 
Email: jliu@novumprs.com   


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
71875502  11/08/2018  Rev. 1  Encube Ethicals Pvt Ltd.  Page 4 of 45 
 
 
3.0 SIGNATURE PAGE 
We, the undersigned, have carefully read this protocol and agree that it contains all the necessary 
information required to conduct the study. The study will be performed according to this protocol, 
all applicable Food and Drug Administration (FDA) regulations, International Conference on 
Harmonisation (ICH) guidelines and Good Clinical Practice (GCP) standards. 
 
 
 
 
 
 
 
Gail Gongas 
 
 
 
 
 
 
Date 
 
 
 
Vice President, Clinical Trials and Data Management 
Novum Pharmaceutical Research Services 
 
 
 
 
 
 
 
Christian P. Urrea, MD  
 
 
 
 
Date 
Medical Monitor, Clinical Trials 
Novum Pharmaceutical Research Services 
 
 
 
 
 
 
 
Keith D. Gallicano, PhD 
 
 
 
 
Date 
Chief Scientific Officer 
Novum Pharmaceutical Research Services 
 
 
 
 
 
 
 
Dr. Lalatendu Panigrahi  
 
 
 
 
Date 
Chief Scientific Officer 
Encube Ethicals Pvt Ltd 
 
 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
71875502  11/08/2018  Rev. 1  Encube Ethicals Pvt Ltd.  Page 5 of 45 
 
 
PRINCIPAL INVESTIGATOR’S SIGNATURE 
 
 
I _______________________________________, agree to conduct protocol 71875502 Rev 0 in 
accordance with FDA regulations, ICH guidelines and GCPs. I understand that no deviations from the 
protocol may be made without the prior permission of the Sponsor (Encube Ethicals Pvt Ltd) or Novum 
Pharmaceutical Research Services, the company managing the study. 
 
 
 
 
 
___________________________________ 
 
 
 __________ 
Principal Investigator 
 
 
 
 
 
Date 
 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
71875502  11/08/2018  Rev. 1  Encube Ethicals Pvt Ltd.  Page 6 of 45 
 
 
4.0 TABLE OF CONTENTS 
1.0 TITLE PAGE .......................................................................................................................................... 1 
2.0 KEY STUDY PERSONNEL AND FACILITIES .................................................................................. 3 
3.0 SIGNATURE PAGE .............................................................................................................................. 4 
4.0 TABLE OF CONTENTS ........................................................................................................................ 6 
5.0 SYNOPSIS .............................................................................................................................................. 9 
6.0 STUDY SCHEMATIC ......................................................................................................................... 16 
7.0 LIST OF ABBREVIATIONS AND TERMS ....................................................................................... 17 
8.0 INTRODUCTION ................................................................................................................................ 18 
8.1 Disease Being Treated ...................................................................................................................... 18 
8.2 Availability and Efficacy of Already Approved Therapies .............................................................. 18 
8.3 Scientific and Statistical Considerations ........................................................................................... 18 
8.4 Justification for Use of Placebo ........................................................................................................ 19 
8.5 Risks and Benefits ............................................................................................................................. 19 
9.0 STUDY OBJECTIVES ......................................................................................................................... 19 
10.0 INVESTIGATIONAL PLAN ............................................................................................................. 20 
10.1 Study Design and Plan Description ................................................................................................ 20 
10.2 Selection of Study Design ............................................................................................................... 20 
10.3 Selection of Study Population ......................................................................................................... 20 
10.3.1 Inclusion Criteria...................................................................................................................... 20 
10.3.2 Exclusion Criteria .................................................................................................................... 21 
10.3.3 Restrictions During the Study .................................................................................................. 22 
10.3.4 Removal of Patients from the Study ........................................................................................ 22 
10.4 Treatments....................................................................................................................................... 23 
10.4.1 Identity of Investigational Product ........................................................................................... 23 
10.4.2 Method of Assigning Patients to Treatment Groups ................................................................ 23 
10.4.3 Study Blind .............................................................................................................................. 24 
10.4.4 Treatment Administration ........................................................................................................ 24 
10.4.5 Study Product Shipment, Storage, and Retention .................................................................... 25 
10.4.6 Compliance .............................................................................................................................. 25 
10.5 Study Conduct ................................................................................................................................. 26 
10.5.1 Visit 1 (Day 1): Screening/Baseline ......................................................................................... 26 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
71875502  11/08/2018  Rev. 1  Encube Ethicals Pvt Ltd.  Page 7 of 45 
 
 
10.5.2 Visit 2 (Day 42 ± 4 Days): End of Treatment .......................................................................... 27 
10.5.3 Visit 3 (Day 56 ± 4 Days): Test-of-Cure/End of Study ........................................................... 27 
10.6 Study Procedures ............................................................................................................................ 28 
10.6.1 Informed Consent ..................................................................................................................... 28 
10.6.2 Medical History and Demographics ........................................................................................ 28 
10.6.3 Perform Pregnancy Test ........................................................................................................... 28 
10.6.4 Record Vital Signs ................................................................................................................... 28 
10.6.5 Review and Assessment of Concomitant Medications ............................................................ 28 
10.6.6 Review and Assessment of Adverse Events ............................................................................ 29 
10.6.7 Designate Target Lesion .......................................................................................................... 29 
10.6.8 Assess Local Signs and Symptoms .......................................................................................... 29 
10.6.9 Collect Sample for KOH Wet Mount....................................................................................... 29 
10.6.10 Inclusion/Exclusion Criteria Review ..................................................................................... 30 
10.6.11 Collect Sample for Mycological Culture ............................................................................... 30 
10.6.12 Dispense Study Product ......................................................................................................... 30 
10.6.13 Provide Patient Diary ............................................................................................................. 31 
10.6.14 Collect and Review Patient Diary .......................................................................................... 31 
10.6.15 Collecting Study Product ....................................................................................................... 31 
10.7 Adverse Events ............................................................................................................................... 31 
10.7.1 Adverse Event Definitions ....................................................................................................... 31 
10.7.2 Severity of Adverse Event ....................................................................................................... 31 
10.7.3 Relationship of Adverse Event ................................................................................................ 32 
10.7.4 Patient’s Participation Stopping Criteria .................................................................................. 32 
10.8 Serious Adverse Events .................................................................................................................. 32 
10.8.1 Definition of a Serious Adverse Event..................................................................................... 32 
10.8.2 Reporting Serious Adverse Events .......................................................................................... 33 
11.0 STATISTICAL METHODS ............................................................................................................... 34 
11.1 Statistical Plan ................................................................................................................................. 34 
11.2 Sample Size Determination ............................................................................................................. 34 
11.3 Study Populations ........................................................................................................................... 35 
11.3.1 Per-Protocol Population ........................................................................................................... 35 
11.3.2 Modified Intent-to-Treat Population ........................................................................................ 35 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
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11.3.3 Safety Populations.................................................................................................................... 36 
11.4 Baseline Comparability ................................................................................................................... 36 
11.5 Efficacy Variables ........................................................................................................................... 36 
11.6 Efficacy Endpoints .......................................................................................................................... 37 
11.7 Efficacy Analysis ............................................................................................................................ 37 
11.8 Safety Analysis ............................................................................................................................... 38 
12.0 REGULATORY OBLIGATIONS ...................................................................................................... 39 
12.1 Institutional Review Board ............................................................................................................. 39 
12.2 Study Documentation ...................................................................................................................... 39 
12.2.1 Protocol .................................................................................................................................... 39 
12.2.2 Informed Consent ..................................................................................................................... 39 
12.2.3 Protocol and Informed Consent Changes ................................................................................. 40 
12.2.4 Source Documents and Electronic Case Report Forms ........................................................... 40 
12.2.5 Drug Accountability ................................................................................................................. 40 
12.2.6 Retention of Reserve Samples ................................................................................................. 40 
12.2.7 Pregnancies .............................................................................................................................. 40 
12.2.8 Reporting Safety Information to the IRB ................................................................................. 41 
12.2.9 Record Retention...................................................................................................................... 41 
12.2.10 Study Monitoring and Auditing ............................................................................................. 41 
12.2.11 End of the Trial ...................................................................................................................... 41 
12.2.12 Clinical Study Report ............................................................................................................. 41 
13.0 REFERENCES ................................................................................................................................... 42 
14.0 APPENDICES .................................................................................................................................... 43 
14.1 Appendix A: Local Signs and Symptoms ....................................................................................... 43 
14.2 Appendix B: KOH Wet Mount Test and Mycological Culture Collection Schedule ..................... 44 
14.3 Appendix C: Ketoconazole Cream 2% Product Insert .................................................................... 44 
14.4 Appendix D: Amendments to the Protocol ..................................................................................... 45 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
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5.0 SYNOPSIS 
Protocol Number 
71875502 
Title 
A 
Randomized, 
Double-Blind, 
Vehicle-Controlled, 
Parallel-Design, 
Multiple-Site Clinical Study to Evaluate the Therapeutic Equivalence of 
Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to Ketoconazole Cream 
2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
Objectives 
The objectives of this study are to: 
1. Evaluate the therapeutic equivalence of a generic Ketoconazole 
Cream 2% (Encube Ethicals Pvt Ltd) to the Reference product, 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the treatment of 
tinea pedis. 
2. Demonstrate the superiority of the clinical effect of the Test and 
Reference (active) products over that of the Placebo (vehicle) in the 
treatment of tinea pedis. 
3. Compare the safety of the Test, Reference and Placebo products in the 
treatment of tinea pedis. 
Sponsor 
Encube Ethicals Pvt Ltd 
Study Products 
 
Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) 
 
Reference: Ketoconazole Cream 2% (G&W Laboratories Inc.; 
Registrant: Teva Pharmaceuticals USA Inc.) 
 
Placebo: Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) 
Route of 
Administration 
Topical 
Treatment 
Randomization 
2:2:1 (Test: Reference: Placebo) 
Dosage Regimen 
Patients will be instructed to apply sufficient study product to cover affected 
and immediate surrounding areas once daily for 42 ± 4 days. Each patient is 
expected to receive 42 ± 4 doses. 
Patient Population 
Approximately 830 males and non-pregnant females, 18 years of age and 
older, with a microbiologically-confirmed clinical diagnosis of tinea pedis 
Study Design 
A randomized, double-blind, vehicle-controlled, parallel-group, multiple-
site bioequivalence study with clinical endpoints 
Study Conduct 
Eligible patients will be randomized in a 2:2:1 ratio to one of three 
treatments (Test, Reference or Placebo) at Visit 1. Patients will complete 
three clinic visits as follows: 
 
Visit 1 (Day 1): Screening/Baseline  
 
Visit 2 (Day 42 ± 4): End of Treatment  
 
Visit 3 (Day 56 ± 4): Test-of-Cure/End of Study 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
71875502  11/08/2018  Rev. 1  Encube Ethicals Pvt Ltd.  Page 10 of 45 
 
 
Patients will be instructed to apply the study product to the affected and 
immediate surrounding areas once daily for a total of 42 ± 4 days starting on 
the day of enrollment (i.e., Day 1). The last dose should be applied on the 
day of Visit 2 (Day 42 ± 4). Evaluations will be performed in accordance 
with the study schematic. Safety assessments will include monitoring of 
adverse events (AEs), vital signs measurement, and urine pregnancy tests 
(for females of childbearing potential). Clinical assessments will include the 
potassium hydroxide (KOH) wet mount, mycological culture, and rating of 
signs and symptoms. The Investigator should identify the most severe lesion 
(i.e., target lesion) at baseline. Although the study product should be applied 
to all infected areas (both feet), only the target lesion will be evaluated for 
analysis. 
Inclusion Criteria 
1. Healthy male or non-pregnant, non-lactating female, ≥ 18 years of age. 
2. Signed informed consent form (ICF) that meets all criteria of current 
Food and Drug Administration regulations. 
3. Female patient of childbearing potential must not be pregnant or 
lactating at Visit 1 (as confirmed by a negative urine pregnancy test 
with a sensitivity of less than 50 mIU/mL or equivalent units of human 
chorionic gonadotropin). 
4. Female patient of childbearing potential must agree to the use of a 
reliable method of contraception throughout the study (e.g., total 
abstinence, intrauterine device, a double-barrier method, oral, 
transdermal, injected, or implanted non-hormonal or hormonal 
contraceptive) throughout the study. A sterile sexual partner is not 
considered an adequate form of birth control. If the female is using any 
estrogen or oral contraceptive therapy, the same product must have been 
taken for at least one month before Visit 1. 
5. Have clinical diagnosis of tinea pedis with lesions localized to the 
interdigital spaces or predominantly interdigital, but may extend to other 
areas of the foot (the non-interdigital lesions should not be 
hyperkeratotic, i.e., characteristic of tinea pedis moccasin). 
6. The presence of tinea pedis infection provisionally confirmed at 
baseline by a positive KOH wet mount preparation (i.e., skin scrapings 
from the target site are placed on a microscope slide with a drop of 10% 
KOH, and microscopic examination reveals segmented fungal hyphae). 
7. The sum of clinical signs and symptoms scores of the target lesion ≥ 4. 
See Appendix A for scoring scale: 
a. Signs: Fissuring/cracking, erythema, maceration and scaling 
b. Symptoms: pruritus and burning/stinging 
In addition the target lesion must have a minimum score ≥ 2 for 
erythema and a minimum score ≥ 2 for either pruritus or scaling. 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
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Exclusion Criteria 
1. Females who are pregnant, lactating or planning to become pregnant 
during the study period. 
2. History of or current psoriasis, Lichen planus or contact dermatitis 
involving the feet within the previous 12 months. 
3. History of dermatophyte infections with a lack of response to antifungal 
therapy (recurrent tinea pedis [i.e., more than 3 infections in the past 
12 months] that were unresponsive to previous antifungal therapy). 
4. History of allergy, hypersensitivity, or intolerance to ketoconazole, 
other imidazoles, sulfites or any other component of the study product. 
5. Confluent, diffuse moccasin-type tinea pedis of the entire plantar 
surface. 
6. Current uncontrolled diabetes. 
7. Presence of any other infection of the foot or other disease process that, 
in the Investigator’s opinion, may interfere with the evaluation of the 
patient’s tinea pedis. 
8. Known history of or current impaired wound healing, presence of 
peripheral vascular disease and/or trophic changes of the lower limbs to 
an extent that, in the opinion of the Investigator, would make the patient 
unsuitable for the study or compromise patient’s safety. 
9. Significant history or current evidence of chronic infectious disease, 
system disorder, organ disorder, immunosuppression (due to disease or 
therapy, including history of organ transplant), or other medical 
condition that, in the Investigator’s opinion, would place the patient at 
undue risk by participating or compromise the integrity of the study 
data. 
10. Use of antipruritics, including antihistamines, within 72 hours before 
Visit 1. 
11. Use of topical corticosteroids, topical antibiotics or topical antifungal 
therapy (e.g., clotrimazole, econazole, fluconazole) within 2 weeks 
before Visit 1. 
12. Use of systemic (e.g., oral or injectable) antibiotics, systemic antifungal 
therapy, or systemic corticosteroids within 30 days before Visit 1. The 
use of intranasal, inhaled or ophthalmic corticosteroids for acute or 
chronic conditions (e.g., allergic conjunctivitis, asthma/chronic 
obstructive pulmonary disease maintenance) is acceptable to the extent 
that, in the opinion of the Investigator, does not compromise safety of 
patient or integrity of data. 
13. Use of oral terbinafine or itraconazole within 2 months before Visit 1. 
14. Use of immunosuppressive medication or radiation therapy within 
3 months before Visit 1. 
15. Receipt of any drug as part of a research study within 30 days before 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
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Visit 1. 
16. Previous participation in this study. 
17. Employee of the Investigator or research center or their immediate 
family members. 
18. Inability to understand the requirements of the study and the relative 
information or are unable or unwilling to comply with the study 
protocol. 
Efficacy Variables 
The primary and secondary efficacy variables are the outcome of the KOH 
test (negative or positive), outcome of the mycological culture (negative or 
positive), and signs and symptoms scores. 
Efficacy Endpoints 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of patients in each treatment 
group with a Therapeutic Cure of tinea pedis at the test-of-cure visit 
conducted two weeks after the end of treatment (Day 56 ± 4). 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
 
The proportion of patients in each treatment group with a Clinical 
Cure at Day 56 ± 4. 
 
The proportion of patients in each treatment group with a 
Mycological Cure at Day 56 ± 4. 
Definitions 
1. Therapeutic Cure: To be considered a Therapeutic Cure, the patient 
must have both Clinical and Mycological Cure of tinea pedis. 
2. Therapeutic Failure: A patient will be considered a Therapeutic Failure 
if: 
a. the patient is a Clinical or Mycological Failure 
b. the patient was considered to have an insufficient therapeutic 
response 
c. the patient used topical drug therapy for irritation or pruritus on 
the feet after the treatment phase of the study 
3. Clinical Cure: To be considered a clinical cure the patient’s total 
severity score must be ≤ 2 with no individual severity score > 1. 
4. Clinical Failure: A patient will be considered a Clinical Failure if the 
patient’s total severity score is > 2 or any individual score is > 1. 
5. Mycological Cure: To be considered a mycological cure the patient 
must have a negative KOH test and a negative fungal culture. 
6. Mycological Failure: A patient will be considered a Mycological Failure 
if the patient’s KOH test is positive or the patient’s fungal culture is 
positive. 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
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Evaluation of 
Therapeutic 
Equivalence and 
Superiority 
Therapeutic Equivalence 
Therapeutic equivalence will be evaluated for the primary endpoint in the 
per-protocol (PP) population. If the 90% confidence interval (calculated 
using Yates’ continuity correction) on the absolute difference between the 
proportion of patients with a Therapeutic Cure in the Test and Reference 
groups (pT - pR) is contained within the range [-20%, +20%] then 
therapeutic equivalence of the Test product to the Reference product will be 
considered to have been demonstrated. 
The same statistical approach will be conducted for analyses of the secondary 
endpoints in the PP population. 
To declare therapeutic equivalence of the Test product to the Reference 
product, equivalence must be demonstrated for only the primary endpoint in 
the PP population. 
Patients who are missing mycological culture data at the test-of-cure visit 
will not be included in the analysis for the secondary endpoint of 
Mycological Cure. 
Superiority to Placebo 
Superiority of the Test and Reference products against the Placebo product 
for the primary endpoint will be evaluated in the modified Intent-to-Treat 
(mITT) population using, if necessary, last observation carried forward 
(LOCF) as described in section 11.3.2. If the proportions of patients with a 
Therapeutic Cure in the Test and the Reference product groups are 
numerically and statistically superior to that of the Placebo (p < 0.05; using 
a two-sided Cochran-Mantel-Haenszel [CMH] test, stratified by clinical 
site) then superiority of the Test and Reference products over Placebo will 
be concluded. 
The same statistical approach will be conducted for analyses of the 
secondary endpoints in the mITT population. 
To declare superiority of the Test and Reference products over Placebo, 
their superiority must be demonstrated for only the primary endpoint in the 
mITT population. 
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 the primary efficacy endpoint in the PP population for 
equivalence testing. The treatment-by-site interaction will be evaluated by 
the Breslow-Day test for homogeneity of the odds ratio at the 5% 
significance level (p < 0.05, 2-sided). 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 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
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in the PP population at the site with the highest enrolling rate in the 
PP population. If the treatment-by-site interaction term is found to be 
statistically significant (p < 0.05) for the primary endpoint, then the 
interaction term will also be assessed for clinical relevance before pooling 
the data across sites. This will include examination of Therapeutic Cure 
rates at each site where sample sizes per treatment may be influential in the 
assessment of the interaction. The treatment-by-site interaction may also be 
evaluated for the analyses of the secondary endpoints in the PP population 
for equivalence testing if the treatment-by-site interaction is found to be 
significant in the primary analysis. 
Safety Analysis 
Adverse events (AEs) will be classified using standard Medical Dictionary 
for Regulatory Activities (MedDRA) terminology Version 21.0 or higher 
and summarized by treatment group. Summary tables comparing the type, 
date of onset, date of resolution, incidence, severity, relationship to the 
study product, outcome, and action taken will be prepared by treatment 
group. If sufficient data exist, then AE frequencies will be compared among 
the three treatments using Fisher’s exact test; if this test is statistically 
significant at the 5% significance level, then a pairwise Fisher’s exact test 
comparing Test and Reference will be conducted.  
Signs and symptoms of tinea pedis will not be considered AEs, 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 discontinued from further participation in the study and 
given alternative therapy for their condition. 
Concomitant medication use will be tabulated by patient. 
Sample Size 
Determination 
For the primary endpoint analysis (proportion of patients in the PP 
population with a Therapeutic Cure at the test-of-cure visit), sample size is 
estimated for therapeutic equivalence of the Test to the Reference product 
and superiority of each of the active treatments groups over Placebo. The 
sample size estimations are based on previous studies conducted for 
ketoconazole cream.1 
In the PP population, the proportion of patients with a Therapeutic Cure in 
the Reference group is expected to be 50%. Assuming that the Therapeutic 
Cure rate for the Test treatment group is an absolute difference of 5% lower 
than the Reference Responder rate (i.e., pT - pR = -5%), a sample size of 
172 patients in each active group in the PP population will provide 
approximately 85% power to demonstrate therapeutic equivalence (i.e., the 
90% confidence interval [Yates’ continuity-corrected] on the pT - pR 
difference is within a defined equivalence range [-20%, +20%]). 
The Therapeutic Cure rates for the Placebo and active treatment groups at 
the test-of-cure visit are anticipated to be approximately 10% and at least 
40% (Test = 40%, Reference = 45%), respectively, in the mITT population. 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
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Using a 2:1 (Active: Placebo) randomization scheme, and assuming the 
conversion rate from mITT to PP will be approximately 80%, 216 patients 
in each active treatment group (Test and Reference) and 108 patients in the 
Placebo group of the mITT population will provide at least 99% power to 
demonstrate superiority of active treatments over Placebo (p < 0.05; using 
two-sided, continuity-corrected Z-test and a pooled response rate for the 
standard error of the difference in proportions). 
Under the above assumptions, the overall study power to demonstrate 
therapeutic equivalence and superiority is estimated to be at least 85% 
(100% × 0.85 × 0.999), assuming 100% correlation between the two 
superiority tests. 
To allow for approximately 35% of patients who may have negative fungal 
cultures post-randomization, drop out from the study or are otherwise non-
evaluable, approximately 830 patients may be randomized (332 in each 
active group and 166 in the Placebo group) to yield 540 patients in the 
mITT population. 
More than 50% of the patients should have baseline fungal cultures that test 
positive for T .rubrum. If fewer than 50% of enrolled patients have a 
positive T .rubrum culture or the number of patients with negative fungal 
cultures is more than anticipated, then additional patients may be enrolled to 
ensure that at least 430 (172:172:86) patients are eligible in the 
PP population, of which > 50% have a positive T. rubrum culture at 
baseline. 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
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6.0 STUDY SCHEMATIC 
 
PROCEDURE 
VISIT 1 
(Day 1) 
Screening/ 
Baseline 
VISIT 2 
(Day 42 ± 4 Days)* 
End of Treatment 
VISIT 3 
(Day 56 ± 4 Days) 
Test-of-Cure/ 
End of Study 
Informed Consent 
X 
 
 
Medical History and Demographics 
X 
 
 
Perform Pregnancy Test** 
X 
X 
X 
Record Vital Signs 
X 
X 
X 
Review and Assessment of 
Concomitant Medications 
X 
X 
X 
Review and Assessment of Adverse 
Events 
 
X 
X 
Designate Target Lesion 
X 
 
 
Assess Local Signs and Symptoms 
X 
X 
X 
Collect Sample for KOH Wet 
Mount 
X 
 
X
† 
Inclusion/Exclusion Criteria Review 
X 
 
 
Collect Sample for Mycological 
Culture‡ 
X 
 
X 
Dispense Study Product 
X 
 
 
Provide Patient Diary 
X 
X 
 
Collect/Review Patient Diary 
 
X 
X 
Collect Study Product 
 
X 
X§ 
Discharge from Study 
 
 
X 
*Dosing regimen is once daily for 42 ± 4 days starting on the day of enrollment (Day 1) through the day 
of Visit 2 (Day 42 ± 4). 
**For females of childbearing potential 
†KOH sample will not be collected if baseline culture is negative. 
‡Mycological culture sample will not be sent if KOH is negative at baseline or positive at Visit 3. See 
Appendix B. 
§Study product will be collected at Visit 3 if it is not returned at Visit 2. 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
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7.0 LIST OF ABBREVIATIONS AND TERMS 
ADaM 
Analysis Dataset Model 
AE 
Adverse Event 
C 
Celsius 
CDISC 
Clinical Data Interchange Consortium 
CMH 
Cochran-Mantel-Haenszel 
CRO  
Clinical Research Organization 
eCRF  
electronic Case Report Form 
eCTD 
electronic Common Technical Document 
F 
Fahrenheit 
FDA 
Food and Drug Administration 
g 
Gram 
GCP 
Good Clinical Practices 
ICF  
Informed Consent Form 
ICH 
International Council on Harmonisation 
IRB 
Institutional Review Board 
KOH 
Potassium Hydroxide 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified Intent-to-Treat 
mL 
Milliliter 
OTC 
Over-The-Counter 
PP 
Per-Protocol 
RS 
Reference Standard 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SDTM 
Study Data Tabulation Model 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
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8.0 INTRODUCTION 
8.1 Disease Being Treated 
Tinea pedis is a superficial fungal infection (dermatophytosis) of the foot caused by one or more of 
the following genera of dermatophytes: Trichophyton rubrum, Trichophyton mentagrophytes and 
Epidermophyton floccosum.2 The dermatophytes require keratin for growth and thus their invasion is 
restricted to hair, nails and the stratum corneum of the skin.  
It is estimated that an individual’s lifetime risk of acquiring a tinea infection on some part of the 
body, is approximately 10-20%, affecting up to 70% of the world’s population at some point. 
Occurrences of fungal infection overall appear to be increasing, with an estimated 29-59 million 
people experiencing at least one mycotic infection per any given year, in the United States alone.3,4 
Tinea pedis is one of the most common dermatophytoses and is most frequently caused by T. 
rubrum.5,6 Skin affected by tinea pedis is usually pruritic, and other symptoms can include burning, 
erythema, scaling, fissuring/cracking and bulla formation of the skin around the toes or plantar 
surface of the feet. Athlete’s foot is the common name for tinea pedis, as the infection is typically 
spread through the use of common bathing and changing areas, such as sports locker rooms. 
8.2 Availability and Efficacy of Already Approved Therapies 
There are a number of prescription and over-the-counter (OTC) therapies available for the treatment 
of tinea pedis. For mild cases, improved foot hygiene may be sufficient to control the signs and 
symptoms. Depending on the severity of infection, tinea pedis can be treated with oral or topical 
antifungal agents, or a combination of both when necessary. Oral antifungal agents may be used in 
very severe cases, such as those with the involvement of larger body areas or in conjunction with 
other superficial fungal infections. Treatment with topical agents can last up to six weeks depending 
on the recommendation of the manufacturer. 
Topical antifungal agents are currently considered the most effective and safest forms of treatment. 
The two principal pharmacologic groups used to treat dermatophyte infections are the allylamines, 
which include naftifine and terbinafine, and the azoles, which include econazole, oxiconazole and 
clotrimazole.7,8 
8.3 Scientific and Statistical Considerations 
Ketoconazole is not considered to be sufficiently absorbed from the skin to provide measureable 
systemic concentrations.9 The 21 Code of Federal Regulations Sections 320.24 (Revised April 1, 
2014) requires that in-vivo pharmacokinetic testing in humans is the preferred method in evaluating 
bioequivalence. However, circumstances for which measurement of the active moieties in biological 
fluids is not possible, a pharmacodynamic response study indicative of clinical efficacy can be 
considered.10,11 Therefore, a comparative clinical endpoint study is considered the most appropriate 
method to evaluate the clinical (therapeutic) effect of two ketoconazole topical cream formulations. 
Sample size estimations for this study are based on studies conducted for Teva Pharmaceuticals 
Abbreviated New Drug Application (ANDA) #075-581 for Ketoconazole Cream 2%.1 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
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8.4 Justification for Use of Placebo 
Tinea pedis is a very common infection that affects the superficial layers of the epidermis and is 
limited in its extension. Symptoms are primarily dermatological and present no serious risk to the 
patient. It is not uncommon for an infection to go unnoticed and untreated for an extended period of 
time.12 Patients receiving placebo would not be harmed by the lack of active treatment and would still 
benefit by participating and being compliant with the hygiene procedure as described in the protocol. 
By complying with the inclusion and exclusion criteria, all participating patients are expected to be 
overall healthy and not suffering from conditions that could increase the risk of complications from 
an underlying tinea infection on the feet. 
Furthermore, and as per the Food and Drug Administration (FDA) guidance, a Placebo group is 
included to confirm the sensitivity of the study and minimize the possibility of a false positive result 
of bioequivalence.13 Therefore, in addition to demonstrating therapeutic equivalence between Test 
and Reference products, both active products must show statistical superiority to the Placebo.14 
8.5 Risks and Benefits 
The risks and benefits to patients enrolled in clinical research studies that include a Placebo treatment 
group must be carefully considered based on three main criteria, namely: the disease being treated, 
the availability, efficacy and safety of approved therapies, and the scientific and statistical 
requirements of the desired outcome of the research study. The Office of Human Rights Protection, a 
Division of the United States Federal Government’s Department of Health and Human Services, has 
issued a detailed guidebook to Institutional Review Boards (IRBs) that includes discussion on the use 
of placebos in clinical studies.15 
Qualified patients have a 20% chance they may be randomized to Placebo. Randomized patients will 
be treated with study product for 42 ± 4 days. Although the potential for any drug-related side effects 
of significance occurring during the study is low, the risk is higher in the two active treatment groups 
than in the Placebo group. 
All patients enrolled in this study will receive the benefit of free specialized medical care beyond 
standard medical treatment that would be expected through most health insurance plans. In addition, 
the patient will receive a stipend for participation to cover costs and expenses associated with trips to 
the medical facility.  
9.0 STUDY OBJECTIVES 
The objectives of this study are to: 
1. Evaluate the therapeutic equivalence of a generic Ketoconazole Cream 2% (Encube Ethicals Pvt 
Ltd) to the Reference product, Ketoconazole Cream 2% (G&W Laboratories Inc.) in the treatment 
of tinea pedis. 
2. Demonstrate the superiority of the clinical effect of the Test and Reference (active) products over 
that of the Placebo (vehicle) in the treatment of tinea pedis. 
3. Compare the safety of the Test, Reference and Placebo products in the treatment of tinea pedis. 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
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10.0 INVESTIGATIONAL PLAN 
10.1 Study Design and Plan Description 
This randomized, double-blind, vehicle-controlled, parallel-group, multiple-site study has been 
designed to evaluate the clinical (therapeutic) effect of a generic Ketoconazole Cream 2% (Encube 
Ethicals Pvt Ltd) compared to the Orange Book Reference Standard (RS) product, Ketoconazole 
Cream 2% (G&W Laboratories Inc.) in patients with tinea pedis. Additionally, both the Test and 
Reference (i.e., the RS) treatments will be tested for superiority to a Placebo. 
Before any study-specific procedures are performed, all patients will read and sign the IRB-approved 
informed consent form (ICF). 
Approximately 830 eligible patients, 18 years of age and older, will be randomized in a 2:2:1 ratio 
(Test: Reference: Placebo) to one of the three study products as follows: 
 
Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) 
 
Reference: Ketoconazole Cream 2% (G&W Laboratories Inc.; Registrant: Teva 
Pharmaceuticals USA Inc.)) 
 
Placebo: Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) 
Patients will complete three clinic visits as follows: 
 
Visit 1 (Day 1): Screening/Baseline  
 
Visit 2 (Day 42 ± 4): End of Treatment  
 
Visit 3 (Day 56 ± 4): Test-of-Cure/End of Study 
Patients will be instructed to apply the study product to affected and immediate surrounding areas 
once daily for a total of 42 ± 4 days starting on the day of enrollment (i.e., Day 1). The last dose 
should be applied on the day of Visit 2 (Day 42 ± 4). Evaluations will be performed in accordance 
with the study schematic. Safety assessments will include monitoring of adverse events (AEs), vital 
signs measurement, and urine pregnancy tests (for females of childbearing potential). Clinical 
assessments will include the potassium hydroxide (KOH) wet mount, mycological culture, and rating 
of signs and symptoms. The Investigator should identify the most severe lesion (i.e., target lesion) at 
baseline. Although the study product should be applied to all infected areas (both feet), only the target 
lesion will be evaluated for analysis. 
10.2 Selection of Study Design 
This protocol is designed based on the FDA draft guidance for Ketoconazole Topical Cream released in 
March 2010.13 
Statistical analyses of the clinical data will be based on recommendations in the FDA Guidances.13,16 
10.3 Selection of Study Population 
10.3.1 Inclusion Criteria 
1. Healthy male or non-pregnant, non-lactating female, ≥ 18 years of age. 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
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2. Signed ICF that meets all criteria of current FDA regulations. 
3. Female patient of childbearing potential must not be pregnant or lactating at Visit 1 (as 
confirmed by a negative urine pregnancy test with a sensitivity of less than 50 mIU/mL or 
equivalent units of human chorionic gonadotropin). 
4. Female patient of childbearing potential must agree to the use of a reliable method of 
contraception throughout the study (e.g., total abstinence, intrauterine device, a double-barrier 
method, oral, transdermal, injected, or implanted non-hormonal or hormonal contraceptive) 
throughout the study. A sterile sexual partner is not considered an adequate form of birth 
control. If the female is using any estrogen or oral contraceptive therapy, the same product 
must have been taken for at least one month before Visit 1. 
5. Have clinical diagnosis of tinea pedis with lesions localized to the interdigital spaces or 
predominantly interdigital, but may extend to other areas of the foot (the non-interdigital 
lesions should not be hyperkeratotic, i.e., characteristic of tinea pedis moccasin). 
6. The presence of tinea pedis infection provisionally confirmed at baseline by a positive KOH 
wet mount preparation (i.e., skin scrapings from the target site are placed on a microscope 
slide with a drop of 10% KOH, and microscopic examination reveals segmented fungal 
hyphae). 
7. The sum of clinical signs and symptoms scores of the target lesion ≥ 4. See Appendix A for 
scoring scale: 
a. Signs: Fissuring/cracking, erythema, maceration and scaling 
b. Symptoms: pruritus and burning/stinging 
In addition the target lesion must have a minimum score ≥ 2 for erythema and a minimum 
score ≥ 2 for either pruritus or scaling. 
10.3.2 Exclusion Criteria 
1. Females who are pregnant, lactating or planning to become pregnant during the study period. 
2. History of or current psoriasis, Lichen planus or contact dermatitis involving the feet within 
the previous 12 months. 
3. History of dermatophyte infections with a lack of response to antifungal therapy (recurrent 
tinea pedis [i.e., more than 3 infections in the past 12 months] that were unresponsive to 
previous antifungal therapy). 
4. History of allergy, hypersensitivity, or intolerance to ketoconazole, other imidazoles, sulfites 
or any other component of the study product. 
5. Confluent, diffuse moccasin-type tinea pedis of the entire plantar surface. 
6. Current uncontrolled diabetes. 
7. Presence of any other infection of the foot or other disease process that, in the Investigator’s 
opinion, may interfere with the evaluation of the patient’s tinea pedis. 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
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8. Known history of or current impaired wound healing, presence of peripheral vascular disease 
and/or trophic changes of the lower limbs to an extent that, in the opinion of the Investigator, 
would make the patient unsuitable for the study or compromise patient’s safety. 
9. Significant history or current evidence of chronic infectious disease, system disorder, organ 
disorder, immunosuppression (due to disease or therapy, including history of organ 
transplant), or other medical condition that, in the Investigator’s opinion, would place the 
patient at undue risk by participating or compromise the integrity of the study data. 
10. Use of antipruritics, including antihistamines, within 72 hours before Visit 1. 
11. Use of topical corticosteroids, topical antibiotics or topical antifungal therapy (e.g., 
clotrimazole, econazole, fluconazole) within 2 weeks before Visit 1. 
12. Use of systemic (e.g., oral or injectable) antibiotics, systemic antifungal therapy, or systemic 
corticosteroids within 30 days before Visit 1. The use of intranasal, inhaled or ophthalmic 
corticosteroids for acute or chronic conditions (e.g., allergic conjunctivitis, asthma/chronic 
obstructive pulmonary disease maintenance) is acceptable to the extent that, in the opinion of 
the Investigator, does not compromise safety of patient or integrity of data. 
13. Use of oral terbinafine or itraconazole within 2 months before Visit 1. 
14. Use of immunosuppressive medication or radiation therapy within 3 months before Visit 1. 
15. Receipt of any drug as part of a research study within 30 days before Visit 1. 
16. Previous participation in this study. 
17. Employee of the Investigator or research center or their immediate family members. 
18. Inability to understand the requirements of the study and the relative information or are 
unable or unwilling to comply with the study protocol. 
10.3.3 Restrictions During the Study 
The following concomitant medications will not be allowed while enrolled in the study: 
 
Any topical products applied to the treatment area 
 
Any systemic (e.g., oral or injectable) antibiotics or anti-fungals 
 
Systemic corticosteroids or immunosuppressive drugs. 
 
Anti-pruritics, including antihistamines, within 24 hours of study visits. 
Patients will be instructed not to use any occlusive wrappings or dressings over the treatment area 
during the study. 
The use of hormonal contraceptives should not be initiated or changed during the study. 
10.3.4 Removal of Patients from the Study 
Patients will be informed that they are free to withdraw from the study at any time. If necessary, 
the Investigator may withdraw a patient from the study to protect the health of that patient. The 
clinical report will include all reasons for early withdrawals. 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
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Reasons for removal may include the following: 
 
Patient withdrew consent. 
 
Significant AE that led the Investigator or patient to withdraw for safety reasons. 
 
Non-compliance with protocol requirements (e.g., use of restricted medication, not 
following dosing procedures, failure to make scheduled study visits in a timely fashion). 
 
Pregnancy 
 
Negative baseline culture results 
 
Development of an intercurrent condition or complication that could affect the safety of 
the patient or the validity of evaluation of the patient’s clinical state to an extent 
considered significant by the Investigator 
 
Significant worsening of tinea pedis such that the Investigator and/or patient believe it is 
in the best interest of the patient to withdraw from the study and be provided alternative 
treatment. 
 
Patient enrolls in another clinical trial, or is found to have previously enrolled in this 
clinical trial. 
Patients who withdraw or are removed from the study will not be replaced. 
10.4 Treatments 
10.4.1 Identity of Investigational Product 
The following products will be used in the study: 
 
Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) 
 
Reference: Ketoconazole Cream 2% (G&W Laboratories Inc.; Registrant: Teva 
Pharmaceuticals USA Inc.) 
 
Placebo: Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) 
10.4.2 Method of Assigning Patients to Treatment Groups 
All randomized study product will be blinded and packaged in sealed boxes by an independent 
packaging company. Randomization will be pre-planned according to a computer-generated 
randomization schedule. The randomization will be generated in blocks, each containing five 
patients’ worth of study product (2 Test, 2 Reference, and 1 Placebo).  
The randomization number will be a unique four-digit number. Patient numbers will be assigned 
immediately before dispensing of study product and in ascending sequential order, beginning 
with the lowest available number at the study site. Each patient kit and each dispensed study tube 
should include the four-digit patient number on the label. 
At the end of the study, after all the clinical data have been entered and the study database has 
been locked, a copy of the randomization schedule will be sent to the statistician. 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
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10.4.3 Study Blind 
The study product will be randomized, packaged and blinded by an independent packaging 
company. The Investigator, staff at the study site, study monitors, and data analysis/management 
personnel will be blinded to the patient assignment. Each study site will have at least one 
Independent Dispenser. The role of the Independent Dispenser is to dispense and collect study 
product to/from the patients, maintain dispensing records and ensure the study product logs are 
complete and accurate. 
The patient will be requested not to discuss the appearance of the study product with the 
Investigator or study staff outside of the Independent Dispenser. A perforated or two-part label 
will be attached to the study product supplies for each patient. Both pieces of the label should 
include the following information: 
 
Protocol number 
 
Randomization number 
 
Space for patient’s initials 
 
Statement that the product is for investigational use only 
 
Space for dispensing date and the Sponsor’s name 
One part of the label will remain attached to the box. The other part will be removed before 
dispensing and attached to patient’s source documentation. 
To ensure information that could potentially bias handling of data is not disclosed, the clinical 
packaging company will hold the randomization scheme until database lock. A perforated tear-off 
label containing the unblinding information will be placed in the patient’s chart, to be opened in 
case of medical emergency only and should be kept at the site with the study documents when the 
study is completed. 
Whenever possible, the Novum Medical Monitor must be contacted before breaking the blind for 
any patient. The unblinding labels should be stored in a secure location at all times and 
maintained at the site for all randomized patients after the completion of the study. 
At the end of the study, after the database has been locked, each site will be sent a sealed 
envelope containing the full study randomization that should be retained with the study 
documents in the event of an FDA inspection. 
10.4.4 Treatment Administration 
At Visit 1, eligible patients will receive three 30 g tubes of randomized study product (i.e., Test, 
Reference, or Placebo). Patients will be instructed to use sufficient amount of the study product to 
cover all affected and immediate surrounding areas on the feet once daily for a total 
of 42 ± 4 days, starting on the day of enrollment (i.e., Day 1). The last dose should be applied on 
the day of Visit 2. It is important that patients adhere to the entire dosing regimen, even in the 
eventuality of a rapid relief of the symptoms. 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
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Patients will be instructed to cleanse their feet with warm water and soap, dry feet completely 
before applying the study product. Patients should avoid bathing, showering or washing the 
treated areas of the feet for at least 4 hours after applying the study product. In addition, all 
patients will be provided with verbal advice on basic foot hygiene (e.g., change socks regularly, 
try and keep feet as dry as possible during the day, wash feet thoroughly after using communal 
bathing, showering areas). 
Each patient will be provided with a dosing diary in which they will be required to record dosing 
dates and times. The dosing diary should be brought to Visit 2 so that the study staff may check 
compliance and filed in the patient’s source documentation. At the end of the study they will be 
retained in the patient’s file as source documentation. 
10.4.5 Study Product Shipment, Storage, and Retention 
The study product will be shipped to each Investigator’s site from a central location. The 
Principal Investigator at each site is responsible for ensuring that all study products are stored in 
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. 
Storage Conditions 
Study product will be stored at controlled room temperature 20-25°C (68-77°F) in a secure place 
with access by authorized individuals only. 
Retention 
For every study product shipment received at the site, the Investigator (or designee) will 
randomly select at least one block of study product for retention. The selection process will 
ensure a sufficient amount of retention samples are retained as per Sponsor requirement. Each 
block selected for retention will be labeled as a retention sample and should not be dispensed to 
study patients. The selected retention samples will be retained by each site under FDA regulations 
for a minimum of five years .17 
Once the site has been notified that they may do so, all unused study product and empty or 
partially used tubes of study product, other than that randomly selected for retention samples will 
be returned to the Sponsor’s designee. It is important that retention samples not be returned to 
Novum, the Sponsor or the packaging company during or at the end of the study. 
10.4.6 Compliance 
Patients will be provided with a diary to record the time and date of dosing. Patients taking fewer 
than 75% or more than 125% of the required doses will be considered non-compliant with dosing 
and excluded from the PP population. Compliance with dosing will be verified by the use of the 
patient diaries. Compliance criteria are outlined in the table below: 
For patients who have completed the study: 
Study Design 
Compliance Criteria 
Study 
Period 
Treatment 
Duration 
Scheduled 
Doses 
Not more than 
125% (doses) 
Not less than 
75% (doses) 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
71875502  11/08/2018  Rev. 1  Encube Ethicals Pvt Ltd.  Page 26 of 45 
 
 
Randomized 
Treatment 
38-46 Days 
42 
52 
32 
For patients who are early terminated, compliance will be determined from their duration in the 
study, up to the time they are considered early terminated. For example, if a patient is 
discontinued after 20 days of participation and doses 18 times, their percent compliance is 90%. 
10.5 Study Conduct 
10.5.1 Visit 1 (Day 1): Screening/Baseline 
1. Informed Consent: Patients who are willing to comply with study procedures will read, 
understand and sign the informed consent. 
2. Medical History and Demographics: Collect the patient’s demographic information and 
medical history, including tinea pedis history. 
3. Perform Pregnancy Test: A urine pregnancy test will be required of all female patients of 
childbearing potential before starting treatment. 
4. Record Vital Signs: Record the patient’s vital signs (blood pressure, pulse, temperature and 
respiration rate). 
5. Review and Assessment of Concomitant Medications: Review the patient’s use of 
concomitant medication within the last six months. 
6. Designate Target Lesion: The Investigator should identify and record the interdigital space 
with the most severe interdigital infection. This will be designated the target lesion and will 
be followed and evaluated at each visit. 
7. Assess Local Signs and Symptoms: Clinical signs and symptoms of tinea pedis at the target 
lesion site will be evaluated using the static scale in Appendix A. Wherever possible, the 
same Investigator should attempt to perform all clinical exams at all visits for an individual 
patient. 
8. Collect Sample for KOH Wet Mount: If the clinical signs and symptoms of interdigital 
tinea pedis are present, then samples for the KOH wet mount should be obtained from the 
designated target lesion site as per instructions in section 10.6.9. The KOH wet mount review 
should be performed by the Investigator or appropriately trained and qualified delegated staff. 
9. Inclusion/Exclusion Criteria Review: Review inclusion/exclusion criteria and confirm 
patient is eligible for randomization, pending results of the fungal culture. 
10. Collect Sample for Mycological Culture: If the patient meets all of the other 
inclusion/exclusion criteria then a sample will be sent to the centralized laboratory for fungal 
culture. 
11. Dispense Study Product: The Independent Dispenser will dispense study product to eligible 
patients with along with dosing instructions. 
12. Provide Patient Diary: The site will provide a diary to each patient with instructions on how 
to complete the diary. 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
71875502  11/08/2018  Rev. 1  Encube Ethicals Pvt Ltd.  Page 27 of 45 
 
 
13. Schedule Visit 2. 
10.5.2 Visit 2 (Day 42 ± 4 Days): End of Treatment 
1. Perform Pregnancy Test: A urine pregnancy test will be required of all female patients of 
childbearing potential. 
2. Record Vital Signs: The patient’s vital signs will be recorded (blood pressure, pulse, 
temperature and respiration rate). 
3. Review and Assessment of Concomitant Medications: Review the patient’s use of any new 
or ongoing concomitant medications since last visit. 
4. Review and Assessment of Adverse Events: Patients will be questioned about any health 
status changes/AEs since last visit. All AEs will be recorded. 
5. Assess Local Signs and Symptoms: Clinical signs and symptoms of tinea pedis at the target 
lesion site identified at Visit 1 will be evaluated using the static scale in Appendix A. 
Wherever possible, the same Investigator should attempt to perform all clinical exams at all 
visits for an individual patient. 
6. Collect and Review Patient Diary: Collect the diary from the patient and review for 
compliance with the protocol requirements. 
7. Collect Study Product: Collect previously dispensed tubes of study product. 
8. Provide Patient Diary: The site will provide a diary to each patient with instructions on how 
to complete the diary. 
9. Schedule Visit 3. 
10.5.3 Visit 3 (Day 56 ± 4 Days): Test-of-Cure/End of Study 
1. Perform Pregnancy Test: A urine pregnancy test will be required of all female patients of 
childbearing potential. 
2. Record Vital Signs: The patient’s vital signs will be recorded (blood pressure, pulse, 
temperature and respiration rate). 
3. Review and Assessment of Concomitant Medications: Review the patient’s use of any new 
or ongoing concomitant medications since last visit. 
4. Review and Assessment of Adverse Events: Patients will be questioned about any health 
status changes/AEs since last visit. All AEs will be recorded. 
5. Assess Local Signs and Symptoms: Clinical signs and symptoms of tinea pedis at the target 
lesion site identified at Visit 1 will be evaluated using the static scale in Appendix A. 
Wherever possible, the same Investigator should attempt to perform all clinical exams at all 
visits for an individual patient. 
6. Collect Sample for KOH Wet Mount: Patients with positive baseline culture results will 
have a sample for the KOH wet mount obtained from the designated target lesion site as per 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
71875502  11/08/2018  Rev. 1  Encube Ethicals Pvt Ltd.  Page 28 of 45 
 
 
instructions in section 10.6.9. The KOH wet mount review should be performed by the 
Investigator or appropriately trained and qualified delegated staff. 
7. Collect Sample for Mycological Culture: Patients with positive baseline culture results will 
have a sample sent to the centralized laboratory for fungal culture. Patients with a positive 
KOH wet mount at this visit will not have a mycological culture sample collected. 
 
8. Collect and Review Patient Diary: Collect previously dispensed diary and review for 
compliance with the protocol. 
9. Collect Study Product: Study product tubes that were not returned at Visit 2 will be 
collected. 
10. Discharge from study. 
10.6 Study Procedures 
10.6.1 Informed Consent 
At Visit 1, before performing any study-related procedures the study patient must sign the IRB-
approved ICF. The ICF will be reviewed and approved by an IRB before study commencement. 
No patient will be entered into the study without reading, understanding, and signing an ICF. If 
any other language is required, translation will be performed by a certified translator. 
10.6.2 Medical History and Demographics 
At Visit 1, each patient will be required to provide basic demographic information: date of birth, 
sex, ethnicity and race. Patients will also be questioned about personal medical history, including 
tinea pedis history. 
10.6.3 Perform Pregnancy Test 
All females of childbearing potential will have a urine pregnancy test performed at each visit. The 
test must be negative at Visit 1 for the patient to be eligible for inclusion in the study. If the 
patient is female and not considered of childbearing potential, then the reason must be 
documented in the patient’s source documents. 
Any patient who becomes pregnant during the study should be discontinued and end of study 
procedures (Visit 3 procedures) completed. The outcome of the pregnancy should be followed by 
the Investigator to the conclusion of the pregnancy. The pregnancy will be reported as an AE. 
10.6.4 Record Vital Signs 
The patient’s vital signs will be recorded (pulse, blood pressure, temperature and respiration rate) 
at each visit. 
10.6.5 Review and Assessment of Concomitant Medications 
At Visit 1, patients will be questioned about medication use over the previous six months. At all 
subsequent visits, patients will be questioned about ongoing or new concomitant medication use. 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
71875502  11/08/2018  Rev. 1  Encube Ethicals Pvt Ltd.  Page 29 of 45 
 
 
At Visit 2, any patient who has used medications restricted by the protocol may be discontinued 
from the study. If discontinued, all end of study procedures (Visit 3 procedures) should be 
performed. 
10.6.6 Review and Assessment of Adverse Events 
At Visits 2 and 3, patients will be questioned regarding any changes in their medical status since 
their previous visit. Any significant health changes observed after dosing will be reported as AEs, 
as deemed appropriate by the Investigator. 
10.6.7 Designate Target Lesion 
At Visit 1, an examination of the feet will be performed to determine the type and severity of the 
infection. The clinical staff will record the affected areas in the source document. They will 
identify the foot and interdigital space with the most severe interdigital infection. This will be 
designated the target lesion and its location noted in the source documentation. The target lesion 
will be followed and evaluated at each visit. 
10.6.8 Assess Local Signs and Symptoms 
Using the identified target lesion the following clinical signs and symptoms will be rated: 
 
Signs: fissuring/cracking, erythema, maceration, and scaling 
 
Symptoms: pruritus and burning/stinging 
The severity of each clinical symptom should be evaluated by the Investigator as either “none”, 
“mild”, “moderate” or “severe” using the 4-point (0-3) rating scale in Appendix A. The signs and 
symptoms of the target lesion should be evaluated for current severity per visit and not in 
comparison to any other visit or other patient. 
Wherever possible, the same Investigator should attempt to perform all clinical exams at all visits 
for an individual patient. 
To be eligible for inclusion in the study the most infected area must have a total score of at 
least 4, a minimum score of at least 2 for erythema, and a minimum score of at least 2 for either 
scaling or pruritus. 
10.6.9 Collect Sample for KOH Wet Mount 
If the signs and symptoms of tinea pedis meet the inclusion criteria at Visit 1, then samples for 
the KOH wet mount and fungal culture should be obtained from the target lesion site. After 
clinical assessments and before possible randomization, sufficient sample should be obtained to 
perform both KOH wet mount and mycological culture. The sample for the KOH wet mount 
should be placed onto a clean glass slide. The target lesion site should not be cleansed or 
sterilized before sample collection. A drop of 10% KOH should then be added to the slide and 
covered with a cover slip. The slide should be gently heated and then observed under the 
microscope. The KOH wet mount assessment will be conducted at the investigative site by the 
Investigator or appropriately trained and qualified delegated staff. The results of the KOH wet 
mount test will be entered in the patient’s source and electronic case report form (eCRF), as 
appropriate. Only those patients that have a positive KOH wet mount for tinea pedis (presence of 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
71875502  11/08/2018  Rev. 1  Encube Ethicals Pvt Ltd.  Page 30 of 45 
 
 
segmented fungal hyphae under microscopic examination) at Visit 1 will have samples sent for 
fungal culture. 
If the results of the baseline mycological culture are positive, samples for KOH will be obtained 
from the target lesion site at Visit 3. All efforts should be made to attempt valid skin scrapings for 
microscopic examinations at Visit 3, even in case of virtually healed lesions as appropriate.  
If the results of the baseline culture are negative, patient should be discontinued and no KOH wet 
mount is necessary. 
10.6.10 Inclusion/Exclusion Criteria Review 
At Visit 1, inclusion/exclusion criteria will be reviewed to ensure patients’ eligibility for 
participation in the study. 
10.6.11 Collect Sample for Mycological Culture 
If, at Visit 1, the patient meets all of the other inclusion/exclusion criteria, including a positive 
KOH wet mount test, then a sample will be sent to the centralized laboratory for fungal culture. 
As it could take up to 28 days or more for the results of the fungal cultures to be known, the 
Investigator can enroll patients into the study if they meet all of the other inclusion/exclusion 
criteria pending the results of the fungal culture. Culture must be positive for T. rubrum, T. 
mentagrophytes or E. floccosum for the patient to be included in the modified intent-to-treat 
(mITT) and per-protocol (PP) populations. 
The sample for the culture should be placed into the transport kit provided by the central 
laboratory. The kit should be sealed according to the directions on the back of the kit itself. The 
sample kit should be sent to the central laboratory as instructed in the laboratory manual provided 
by ACM-Pivotal Global Central Laboratory. 
ACM Pivotal Laboratory 
160 Elmgrove Park 
Rochester, NY 14624 
Phone: 800-525-5227 
If the results of the baseline culture are positive, patients may continue in the study and samples 
for mycological culture will be obtained from the target lesion site at Visit 3. If the results of the 
baseline culture are negative, the patient should be discontinued and early termination procedures 
should be performed. No mycological culture sample should be collected as part of the early 
termination procedures. 
Mycological culture samples will not be collected for patients with a positive KOH wet mount at 
Visit 3. 
10.6.12 Dispense Study Product 
An Independent Dispenser will dispense three tubes of study product at Visit 1 along with dosing 
instructions. The Independent Dispenser will ensure the study product logs are reported correctly. 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
71875502  11/08/2018  Rev. 1  Encube Ethicals Pvt Ltd.  Page 31 of 45 
 
 
10.6.13 Provide Patient Diary 
At Visit 1, patients will be provided with a diary to record AEs, concomitant medications and 
date and time of dosing. The patients will also receive on-site training on completing the diary. 
At Visit 2, patients will be provided with a diary to record AEs and concomitant medications. 
10.6.14 Collect and Review Patient Diary 
At Visits 2 and 3, patient diaries will be collected and reviewed for compliance with the protocol. 
10.6.15 Collecting Study Product 
The study product will be collected by the Independent Dispenser at Visit 2 (or 3 if not returned 
at Visit 2) and checked to ensure no evidence of tampering with the blind has occurred. The 
Independent Dispenser will ensure the study product logs are reported correctly. 
10.7 Adverse Events 
The patients will be monitored throughout the study for any AEs. Adverse events will be collected 
through both solicited and unsolicited means and subsequently coded in tabular form using the 
Medical Dictionary for Regulatory Activities (MedDRA) Version 21.0 or higher. The patients will be 
encouraged to report signs, symptoms, and any changes in health to the clinic staff. Signs and symptoms 
of tinea pedis will not be considered AEs unless, in the opinion of the Investigator, they have increased 
in severity to the extent that the Investigator believes it to be clinically significant. 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. Adverse events should be followed up 
until they have resolved or stabilized. 
10.7.1 Adverse Event 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 AE 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 AE is at least a reasonable 
possibility, i.e., the relationship cannot be ruled out. 
10.7.2 Severity of Adverse Event 
The severity of the AE will be graded by the Investigator using the following criteria as 
guidelines: 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
71875502  11/08/2018  Rev. 1  Encube Ethicals Pvt Ltd.  Page 32 of 45 
 
 
 
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. 
10.7.3 Relationship of Adverse Event 
Relationship to the study product: 
 
Not Related: A causal relationship between the study treatment and the AE is not a 
reasonable possibility 
 
Related: A causal relationship between the study treatment and the AE is a reasonable 
possibility. 
10.7.4 Patient’s Participation Stopping Criteria 
In the opinion of the Investigator, if the patient suffers an AE that warrants discontinuation of the 
study product because of interference with age-appropriate instrumental Activities of Daily 
Living, for example, preparing for meal, shopping for groceries or clothing, using the telephone, 
etc. the patient will be followed until the AE resolves or is considered stable. Any patient that 
discontinues the study because of an AE will be followed until resolution or stabilization of the 
AE. 
10.8 Serious Adverse Events 
10.8.1 Definition of a Serious Adverse Event 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose suggests a 
medically significant hazard, including any event that: 
 
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). 
 
Is life-threatening: in the view of the Investigator, the patient is at immediate risk of death 
at the time of the event. 
 
Results in persistent or significant disability or incapacity (substantial disruption of one’s 
ability to conduct normal life). 
 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
 
Causes congenital anomaly or birth defect. 
 
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 an SAE. 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
71875502  11/08/2018  Rev. 1  Encube Ethicals Pvt Ltd.  Page 33 of 45 
 
 
10.8.2 Reporting Serious Adverse Events 
Investigator Reporting of SAEs 
Adverse events which meet the above criteria for "Serious" will be reported to Novum within 
24 hours. Novum will report all SAEs to the Sponsor and IRB within 24 hours of notice whether 
or not they are considered expected or drug-related. All SAEs will be reported as per applicable 
regulations. All SAEs encountered during the study will be reported on the appropriate form and 
summarized in the final report. 
Following is the contact information: 
Christian P. Urrea, MD 
Medical Monitor, Clinical Trials 
Cell Phone: 412-667-1472 
Phone: 412-363-3300 Ext. 597 
Fax: 412-291-3171 
Email: cpurrea@novumprs.com 
Or 
Gail Gongas 
Vice President, Clinical Trials and Data Management 
Cell Phone 412-606-1603 
Phone: 412-363-3300 Ext. 522 
Fax: 412-291-3171 
Novum will report any SAE to Sponsor: 
Documentation of SAEs and follow-up information should be sent to the Sponsor within 24 hours 
from Novum being made aware of the SAE. Following is the contact information: 
Dr. Brijesh Wadekar 
Head- Clinical Trials 
Encube Ethicals Pvt Ltd 
Steelmade Industrial Estate, Marol Village,  
Andheri (E), Mumbai – 400059, India 
Phone: +91-22-6264-7009 
Fax: +91-22-66935230 
Email: brijesh.w@encubeethicals.com 
Novum will be responsible for notifying the FDA of any SAEs. Novum must notify FDA of fatal 
or life-threatening SAE as soon as possible, but no later than seven calendar days from reporting 
the event by the Investigator. 
Novum will inform all the participating Investigators of any SAEs reported at other study sites 
within 15 days from the initial report. 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
71875502  11/08/2018  Rev. 1  Encube Ethicals Pvt Ltd.  Page 34 of 45 
 
 
11.0 STATISTICAL METHODS 
11.1 Statistical Plan 
A Statistical Analysis Plan (SAP), detailing the intended statistical analyses of the study data, will be 
prepared as a separate document and finalized before database lock. Any deviation from the original 
SAP 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 SAP. 
All statistical analyses will be performed by Novum Pharmaceutical Research Services and 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 Analysis Dataset Model (ADaM). 
11.2 Sample Size Determination 
For the primary endpoint analysis (proportion of patients in the PP population with a Therapeutic 
Cure at the test-of-cure visit), sample size is estimated for therapeutic equivalence of the Test to the 
Reference product and superiority of each of the active treatments groups over Placebo. The sample 
size estimations are based on previous studies conducted for ketoconazole cream.1 
In the PP population, the proportion of patients with a Therapeutic Cure in the Reference group is 
expected to be 50%. Assuming that the Therapeutic Cure rate for the Test treatment group is an 
absolute difference of 5% lower than the Reference Responder rate (i.e., pT - pR = -5%), a sample size 
of 172 patients in each active group in the PP population will provide approximately 85% power to 
demonstrate therapeutic equivalence (i.e., the 90% confidence interval [Yates’ continuity-corrected] 
on the pT - pR difference is within a defined equivalence range [-20%, +20%]). 
The Therapeutic Cure rates for the Placebo and active treatment groups at the test-of-cure visit are 
anticipated to be approximately 10% and at least 40% (Test = 40%, Reference = 45%), respectively, 
in the mITT population. Using a 2:1 (Active: Placebo) randomization scheme, and assuming the 
conversion rate from mITT to PP will be approximately 80%, 216 patients in each active treatment 
group (Test and Reference) and 108 patients in the Placebo group of the mITT population will 
provide at least 99% power to demonstrate superiority of active treatments over Placebo (p < 0.05; 
using two-sided, continuity-corrected Z-test and a pooled response rate for the standard error of the 
difference in proportions). 
Under the above assumptions, the overall study power to demonstrate therapeutic equivalence and 
superiority is estimated to be at least 85% (100% × 0.85 × 0.999), assuming 100% correlation 
between the two superiority tests. 
To allow for approximately 35% of patients who may have negative fungal cultures post-
randomization, drop out from the study or are otherwise non-evaluable, approximately 830 patients 
may be randomized (332 in each active group and 166 in the Placebo group) to yield 540 patients in 
the mITT population. 
More than 50% of the patients should have baseline fungal cultures that test positive for T .rubrum. If 
fewer than 50% of enrolled patients have a positive T .rubrum culture or the number of patients with 
negative fungal cultures is more than anticipated, then additional patients may be enrolled to ensure 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
71875502  11/08/2018  Rev. 1  Encube Ethicals Pvt Ltd.  Page 35 of 45 
 
 
that at least 430 (172:172:86) patients are eligible in the PP population, of which > 50% have a 
positive T. rubrum culture at baseline. 
11.3 Study Populations 
11.3.1 Per-Protocol Population 
The PP population will include all randomized patients who: 
 
Met all inclusion and exclusion criteria. 
 
Made the final study visit within the protocol window of Day 56 ± 4 days (Day 52 to 
Day 60 inclusive) with no protocol violations that would affect the treatment evaluation. 
 
Did not have any significant protocol deviations. 
 
Were compliant with dosing between 75%-125% of the required doses. 
 
Had a positive baseline KOH and fungal culture for Trichophyton rubrum, Trichophyton 
mentagrophyties or Epidermophyton floccosum. 
Patients discontinued from the study because of lack of treatment effect after completing at least 
14 days of treatment will be included in the PP population as Therapeutic Failures provided they 
had a positive baseline KOH, positive baseline fungal culture, and did not have any significant 
protocol deviations. For these patients, there will be no mycological testing at time of 
discontinuation; therefore, they will be considered Therapeutic Failures in the primary analysis 
but the Mycological Cure data will be set to missing for the secondary endpoint. 
Patients who meet the criteria above, but who also used topical drug therapy for irritation or 
pruritus on the feet after the treatment phase of the study will be included in the PP population as 
Therapeutic Failures. If no mycological testing is performed, the patients will be considered 
Therapeutic Failures in the primary analysis but the Mycological Cure data will be set to missing 
for the secondary endpoint. 
All analyses performed using the PP population will be done on an observed case basis (i.e., no 
last observation carried forward [LOCF] will be performed). 
11.3.2 Modified Intent-to-Treat Population 
The mITT population will include: randomized patients who: 
 
Met all inclusion/exclusion criteria. 
 
Applied at least one dose of assigned product. 
 
Had at least one post-baseline evaluation. 
 
Had a positive baseline KOH and fungal culture for Trichophyton rubrum, Trichophyton 
mentagrophyties or Epidermophyton floccosum. 
Patients discontinued early for reasons other than lack of treatment effect will be excluded from 
the PP population and included in the mITT population using LOCF. Patients who qualify for 
inclusion in the mITT population with missing endpoint data who were not discontinued for lack 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
71875502  11/08/2018  Rev. 1  Encube Ethicals Pvt Ltd.  Page 36 of 45 
 
 
of treatment effect will also be evaluated using LOCF; that is, if a patient who was not 
discontinued for lack of treatment effect does not have KOH or mycological culture results at 
Visit 3, this patient will be evaluated for the primary and secondary endpoints using LOCF from 
Visit 1. Patients who discontinued because of lack of treatment will not have LOCF performed. 
Patients who meet the criteria above, but who also used topical drug therapy on the feet for the 
treatment of irritation or pruritus after the treatment phase of the study will be included in the 
mITT as Therapeutic Failures. If no mycological testing is performed, these patients will be 
considered Therapeutic Failures in the primary analysis but the Mycological Cure data will be set 
to missing for the secondary endpoint. No LOCF will be performed. 
11.3.3 Safety Populations 
The Safety population will include all patients who are randomized and received study product. 
11.4 Baseline Comparability 
Baseline characteristics will be evaluated separately for the PP, mITT and Safety populations. 
The following baseline demographics (determined from their initial study visit) will be evaluated: 
 
Age (years) 
 
Sex (Male/Female) 
 
Ethnicity (Hispanic/Non-Hispanic) 
 
Race (White, Black/African American, Native Hawaiian or Other Pacific Islander, Asian, 
American Indian or Alaska Native) 
 
Type of infection (interdigital only or interdigital with extension) 
 
Total baseline signs and symptoms score 
 
Presence or absence of onychomycosis 
 
Number of infections in the past 12 months 
 
Primary infective organism 
Summary tables by treatment group will be presented. Continuous variables will be summarized 
using descriptive statistics (number of observations, median, minimum, maximum, mean, and 
standard deviation). Categorical variables will be summarized using frequencies and percentage. 
Baseline treatment comparisons will be presented using Chi-Square or Cochran-Mantel-Haenszel 
(CMH) tests for the categorical variables, and Analysis of Variance for the continuous variables. 
All data will be listed by treatment and patient. 
11.5 Efficacy Variables 
The primary and secondary efficacy variables are the outcome of the KOH test (negative or positive), 
outcome of the mycological culture (negative or positive), and signs and symptoms scores.  


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
71875502  11/08/2018  Rev. 1  Encube Ethicals Pvt Ltd.  Page 37 of 45 
 
 
11.6 Efficacy Endpoints 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of patients in each treatment group with a 
Therapeutic Cure of tinea pedis at the test-of-cure visit two weeks after the end of treatment 
(Day 56 ± 4). 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
 
The proportion of patients in each treatment group with a Clinical Cure at Day 56 ± 4. 
 
The proportion of patients in each treatment group with a Mycological Cure at Day 56 ± 4. 
Definitions 
1. Therapeutic Cure: To be considered a Therapeutic Cure, the patient must have both Clinical and 
Mycological Cure of tinea pedis. 
2. Therapeutic Failure: A patient will be considered a Therapeutic Failure if: 
a. the patient is a Clinical or Mycological Failure 
b. the patient was considered to have an insufficient therapeutic response 
c. the patient used topical drug therapy for irritation or pruritus on the feet after the treatment 
phase of the study 
3. Clinical Cure: To be considered a clinical cure the patient’s total severity score must be ≤ 2 with 
no individual severity score > 1. 
4. Clinical Failure: A patient will be considered a Clinical Failure if the patient’s total severity score 
is > 2 or any individual score is > 1. 
5. Mycological Cure: To be considered a mycological cure the patient must have a negative KOH 
test and a negative fungal culture. 
6. Mycological Failure: A patient will be considered a Mycological Failure if the patient’s KOH test 
is positive or the patient’s fungal culture is positive. 
11.7 Efficacy Analysis 
Therapeutic Equivalence 
Therapeutic equivalence will be evaluated for the primary endpoint in the per-protocol (PP) 
population. If the 90% confidence interval (calculated using Yates’ continuity correction) on the 
absolute difference between the proportion of patients with a Therapeutic Cure in the Test and 
Reference groups (pT - pR) is contained within the range [-20%, +20%] then therapeutic equivalence 
of the Test product to the Reference product will be considered to have been demonstrated. 
The same statistical approach will be conducted for analyses of the secondary endpoints in the PP 
population. 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
71875502  11/08/2018  Rev. 1  Encube Ethicals Pvt Ltd.  Page 38 of 45 
 
 
To declare therapeutic equivalence of the Test product to the Reference product, equivalence must be 
demonstrated for only the primary endpoint in the PP population. 
Patients who are missing mycological culture data at the test-of-cure visit will not be included in the 
analysis for the secondary endpoint of Mycological Cure. 
Superiority to Placebo 
Superiority of the Test and Reference products against the Placebo product for the primary endpoint 
will be evaluated in the mITT population using, if necessary, LOCF as described in section 11.3.2. If 
the proportions of patients with a Therapeutic Cure in the Test and the Reference product groups are 
numerically and statistically superior to that of the Placebo (p < 0.05; using a two-sided Cochran-
Mantel-Haenszel [CMH] test, stratified by clinical site) then superiority of the Test and Reference 
products over Placebo will be concluded. 
The same statistical approach will be conducted for analyses of the secondary endpoints in the mITT 
population. 
To declare superiority of the Test and Reference products over Placebo, their superiority must be 
demonstrated for only the primary endpoint in the mITT population. 
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 the primary 
efficacy endpoint in the PP population for equivalence testing. The treatment-by-site interaction will 
be evaluated by the Breslow-Day test for homogeneity of the odds ratio at the 5% significance level 
(p < 0.05, 2-sided). 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 PP population at the site with the highest 
enrolling rate in the PP population. If the treatment-by-site interaction term is found to be statistically 
significant (p < 0.05) for the primary endpoint, then the interaction term will also be assessed for 
clinical relevance before pooling the data across sites. This will include examination of Therapeutic 
Cure rates at each site where sample sizes per treatment may be influential in the assessment of the 
interaction. The treatment-by-site interaction may also be evaluated for the analyses of the secondary 
endpoints in the PP population for equivalence testing if the treatment-by-site interaction is found to 
be significant in the primary analysis. 
11.8 Safety Analysis 
Adverse events (AEs) will be classified using standard Medical Dictionary for Regulatory Activities 
(MedDRA) terminology Version 21.0 or higher and summarized by treatment group. Summary tables 
comparing the type, date of onset, date of resolution, incidence, severity, relationship to the study 
product, outcome, and action taken will be prepared by treatment group. If sufficient data exist, then 
AE frequencies will be compared among the three treatments using Fisher’s exact test; if this test is 
statistically significant at the 5% significance level, then a pairwise Fisher’s exact test comparing Test 
and Reference will be conducted.  


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
71875502  11/08/2018  Rev. 1  Encube Ethicals Pvt Ltd.  Page 39 of 45 
 
 
Signs and symptoms of tinea pedis will not be considered AEs, 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 discontinued from further participation in the 
study and given alternative therapy for their condition. 
Concomitant medication use will be tabulated by patient. 
12.0 REGULATORY OBLIGATIONS 
12.1 Institutional Review Board 
The study protocol, ICF, Investigator's Brochure, or package insert (as applicable), and any specific 
advertising will be submitted to and approved by an 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. 
12.2 Study Documentation 
This study will be conducted in compliance with the protocol; 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 64th World Medical Association General 
Assembly, October 2013.10,18-20 The Investigator will permit trial-related monitoring, audits, IRB 
review, and regulatory inspections providing direct access to source data/documents. 
12.2.1 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. The Principal Investigator will sign the 
protocol signature page indicating their agreement to conduct the study according to the protocol. 
12.2.2 Informed Consent 
An ICF that includes all of the relevant elements currently required by FDA and local state 
regulations will be provided to each prospective 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. If any other language is required, 
translation will be performed by a certified translator. A copy of the ICF and Assent (when 
applicable) will be provided to the patient. 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
71875502  11/08/2018  Rev. 1  Encube Ethicals Pvt Ltd.  Page 40 of 45 
 
 
12.2.3 Protocol and Informed Consent Changes 
Sponsor approved changes to the protocol or the ICF form will be implemented as revisions to the 
original documents and will require additional review and approval by the IRB. Revisions to the 
original protocol will be documented in amendments, incorporated as a preface to the new 
version. Any revision that substantially alters the study design or increases potential risk to the 
patient requires the patient’s consent to continue in the study. 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. 
12.2.4 Source Documents and Electronic 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 eCRFs. A set of eCRFs will be completed for each patient randomized in the study. All 
data and eCRFs will be reviewed, evaluated, and signed by the Investigator. 
The original source documents and a copy of the corresponding eCRFs will be retained by the 
Investigator. Patients who terminate early from the study will have the Visit 3 (end of study) 
source/eCRF completed. 
12.2.5 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 (after the 
database has been locked) all used and unused study product will be returned to Sponsor or 
designee. 
12.2.6 Retention of Reserve Samples 
For every study product shipment received at the site, the Investigator (or designee) will 
randomly remove at least one block of study product and keep for retention. A block contains five 
patient kits (as the study is randomized in a 2:2:1 ratio). The randomization number of each 
patient kit in each block kept for retention will be noted on the drug accountability form. These 
retention samples should be stored under the appropriate storage conditions for a minimum of 
five years following the application approval or, if not approved, at least five years after the 
completion of the study.17 
12.2.7 Pregnancies 
If following initiation of study participation, it is subsequently discovered that a study patient is 
pregnant or may have been pregnant since the initiation of study participation (i.e., since the 
signing of ICF), the study product will be permanently discontinued. The Principal Investigator or 
designee must immediately notify the Medical Monitor of this event. Reporting timelines and 
Novum/Sponsor contact will be consistent with SAE reporting guidelines (i.e., pregnancies will 
be reported to the Sponsor/Novum within 24 hours to the contacts listed in Section 10.8.2). 
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. All 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
71875502  11/08/2018  Rev. 1  Encube Ethicals Pvt Ltd.  Page 41 of 45 
 
 
follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome will be communicated as per the above guidelines. Infants should be followed for a 
minimum of eight weeks after birth. 
12.2.8 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 SAEs occurring during the 
study, regardless of the assessed causality.20 
12.2.9 Record Retention 
All drug accountability records, eCRFs, source data and related regulatory documents must be 
retained for at least two years following completion of the study or Test product approval for 
marketing by the FDA. 
12.2.10 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. 
12.2.11 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. 
12.2.12 Clinical Study Report 
At the end of the study a full report per requirements of Sponsor and regulatory authorities will be 
prepared which 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. The report will be in electronic format according to eCTD ICH formatting 
standards and guidelines.21 
 
 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
71875502  11/08/2018  Rev. 1  Encube Ethicals Pvt Ltd.  Page 42 of 45 
 
 
13.0 REFERENCES 
1 
FDA. Summary Basis of Approval-Ketoconazole 2% Cream (Teva Pharmaceuticals; ANDA 75-
581).  (1999). 
2 
Weitzman, I. & Summerbell, R. C. The dermatophytes. Clinical microbiology reviews 8, 240-259 
(1995). 
3 
Drake, L. A. et al. Guidelines of care for superficial mycotic infections of the skin: tinea corporis, 
tinea cruris, tinea faciei, tinea manuum, and tinea pedis. Guidelines/Outcomes Committee. 
American Academy of Dermatology. Journal of the American Academy of Dermatology 34, 282-
286 (1996). 
4 
Joseph, W. S. A Closer Look At Topicals For Tinea Pedis. Podiatry Today 22 (2009). 
5 
Kemna, M. E. & Elewski, B. E. A U.S. epidemiologic survey of superficial fungal diseases. 
Journal of the American Academy of Dermatology 35, 539-542 (1996). 
6 
Vena, G. A. et al. Epidemiology of dermatophytoses: retrospective analysis from 2005 to 2010 
and comparison with previous data from 1975. The new microbiologica 35, 207-213 (2012). 
7 
Weinstein, A. & Berman, B. Topical treatment of common superficial tinea infections. American 
family physician 65, 2095-2102 (2002). 
8 
Del Rosso, J. Q. & Kircik, L. H. Optimizing topical antifungal therapy for superficial cutaneous 
fungal infections: focus on topical naftifine for cutaneous dermatophytosis. Journal of drugs in 
dermatology : JDD 12, s165-171 (2013). 
9 
G&W. Ketoconazole Cream 2% Prescribing Information - G&W Laboratories Inc.  (2015). 
10 
FDA. 21CFR 320 Procedures for Determining the Bioavailability or Bioequivalence of Drug 
Products. Department of Health and Human Services, Subchapter D-Drugs for Human Use 5 
(2017). 
11 
FDA. Types of evidence to establish bioavailability or bioequivalence Department of Health and 
Human Services (2013). 
12 
Havlickova, B., Czaika, V. A. & Friedrich, M. Epidemiological trends in skin mycoses 
worldwide. Mycoses 51 Suppl 4, 2-15, doi:10.1111/j.1439-0507.2008.01606.x (2008). 
13 
FDA. Draft Guidance on Ketoconazole.  (2010). 
14 
ICH. Choice of Control Group and Related Issues in Clinical Trials E10-May 2001.  (2001). 
15 
Penslar. IRB Guidebook, Office for Human Rights Protection. US Department of Health and 
Human Services (1993). 
16 
FDA. Guidance for Industry: Statistical Approaches to Establishing Bioequivalence. US 
Department of Health and Human Services, CDER (2001). 
17 
FDA. Guidance for Industry. Handling and Retention of BA and BE Testing Samples U.S. 
Department of Health and Human Services, Food and Drug Administration, Center for Drug 
Evaluation and Research (CDER). May (2004). 
18 
FDA. 21CFR Part 50 Protection of Human Subjects. Department of Health and Human Services, 
Subchapter A-General 1 (2014). 
19 
World Medical Association Declaration of Helsinki: ethical principles for medical research 
involving human subjects. Jama 310, 2191-2194, doi:10.1001/jama.2013.281053 (2013). 
20 
FDA. 21CFR Part 56 Institutional Review Boards. Department of Health and Human Services, 
Subchapter A-General 1 (2001). 
21 
ICH. Structure and Content of Clinical Study Reports E3.  Step 4 version (1995). 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
71875502  11/08/2018  Rev. 1  Encube Ethicals Pvt Ltd.  Page 43 of 45 
 
 
14.0 APPENDICES 
14.1 Appendix A: Local Signs and Symptoms 
The most severely affected area will be identified as the target lesion at the baseline visit and will be 
used for the assessments at Day 42 and Day 56 visits. 
The Clinical Signs and Symptoms of tinea pedis will be rated by the Investigator as “none”, “mild,” 
“moderate” or “severe” using the following standardized rating scale. 
0 = None (complete absence of any sign or symptom) 
1 = Mild (Slight) 
2 = Moderate (Definitely Present) 
3 = Severe (Marked, Intense) 
The following signs and symptoms will be rated at each visit: 
 
Signs: Fissuring/cracking, erythema, maceration, and scaling 
 
Symptoms: Pruritus and burning/stinging 
To be eligible for inclusion the most infected area must have a total score ≥ 4 for the clinical signs 
and symptoms at the target lesion site. In addition, the target lesion site must have a minimum score 
of at least 2 for erythema and a minimum score of at least 2 for either pruritus or scaling. 
 
 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
71875502  11/08/2018  Rev. 1  Encube Ethicals Pvt Ltd.  Page 44 of 45 
 
 
14.2 Appendix B: KOH Wet Mount Test and Mycological Culture Collection Schedule 
 
 
14.3 Appendix C: Ketoconazole Cream 2% Product Insert 
Visit 1 
KOH Wet Mount 
Test 
Positive 
Collect Baseline 
Mycological 
Culture 
Positive 
Visit 2 
Visit 3 
KOH Wet Mount 
Test 
Positive 
No Further 
Mycological 
Culture Collection 
Negative 
Collect 
Mycological 
Sample 
Negative 
Early 
Termination Visit  
Negative 
Screen Fail 


 
CONFIDENTIAL PROTOCOL 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
71875502  11/08/2018  Rev. 1  Encube Ethicals Pvt Ltd.  Page 45 of 45 
 
 
14.4 Appendix D: Amendments to the Protocol 
Amendment 
Date 
 
1 
11/08/2018 
 
The following revisions were made to the protocol dated 06/13/2018: 
 
Section 2.0, 3.0, and 10.8.2: Updated Medical Monitor information 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SAP_000.pdf: 
NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
                                            Protocol / Study No. 71875502 
 
02/28/2019 
                                  Encube Ethicals Pvt Ltd                              Page 1 of 57 
          
 
COVER PAGE 
 
STATISTICAL ANALYSIS PLAN 
 
Final Version 3.0 
 
February 28, 2019 
 
NCT03824912 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study to 
Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) to 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
Protocol Number: 71875502 
Novum Study Number: 71875502 
 
 
 
 
 
 
 
 
 
 
 
 
 


NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
                                            Protocol / Study No. 71875502 
 
02/28/2019 
                                  Encube Ethicals Pvt Ltd                              Page 2 of 57 
STATISTICAL ANALYSIS PLAN                 
 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site Clinical Study 
to Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) 
to Ketoconazole Cream 2% (G&W Laboratories Inc.) in the Treatment of Tinea Pedis 
 
 
Protocol Number: 71875502 
Novum Study Number: 71875502 
 
 
Sponsor: 
Encube Ethicals Pvt Ltd 
803, B Wing, HDIL Kaledonia, Sahar Road, 
Andheri (E), Mumbai – 400069, 
Maharashtra, India 
 
 
Contract Research Organization: 
Novum Pharmaceutical Research Services 
225 W. Station Square Drive, Suite 200 
Pittsburgh, PA 15219 
 
February 28, 2019 
Final Version 3.0 
 
 


NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
                                            Protocol / Study No. 71875502 
 
02/28/2019 
                                  Encube Ethicals Pvt Ltd                              Page 3 of 57 
 
SAP FINAL VERSION APPROVALS 
 
 
A Randomized, Double-Blind, Vehicle-Controlled, Parallel-Design, Multiple-Site  
Clinical Study to Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2%  
(Encube Ethicals Pvt Ltd) to Ketoconazole Cream 2% (G&W Laboratories Inc.) in the 
Treatment of Tinea Pedis 
 
Written By: 
 
Signature: _____________________________ 
Jianhua Liu, MSc 
Senior Biostatistician 
Novum Pharmaceutical Research Services 
 
 
 
Date:_____________________ 
Reviewed By: 
 
Signature: ____________________________ 
Pina D’Angelo, MSc 
Executive Director, Scientific Affairs (Biostatistics) 
Novum Pharmaceutical Research Services 
 
 
 
Date:_____________________ 
Approved By: 
 
Signature: ____________________________ 
Dr. Lalatendu Panigrahi 
Chief Scientific Officer 
Encube Ethicals Pvt Ltd 
 
 
 
Date:_____________________ 
Approved By: 
 
Signature: ____________________________ 
Dr. Brijesh B. Wadekar 
Head - Clinical Trials 
Encube Ethicals Pvt. Ltd. 
 
 
 
Date:_____________________ 


NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
                                            Protocol / Study No. 71875502 
 
02/28/2019 
                                  Encube Ethicals Pvt Ltd                              Page 4 of 57 
Revision History 
VERSION 
DATE 
DESCRIPTION OF REVISIONS 
REVISED BY 
Draft 1.0 
October 4, 2018 
New Document 
Jianhua Liu 
Draft 2.0 
November 08, 2018 
Incorporate client’s comments 
Jianhua Liu 
Final 1.0 
December 04, 2018 
Finalize SAP 
Jianhua Liu 
Final 2.0 
January 23, 2019 
Add missed doses to Listing L16.2.5 
Jianhua Liu 
Final 2.0 
February 05, 2019 
Add Dr. Brijesh to the approval page 
Jianhua Liu 
Final 3.0 
February 28, 2019 
1) To document that all subjects in 
the safety need to have at least one 
dose applied as per new guidance. 
2) To remove criteria of had at least 
one post-baseline evaluation from 
mITT population definition as per 
new guidance. 
Jianhua Liu 


NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
                                            Protocol / Study No. 71875502 
 
02/28/2019 
                                  Encube Ethicals Pvt Ltd                              Page 5 of 57 
List of Abbreviations and Definition of Terms 
ADaM  
 
Analysis Data Model 
AE 
 
 
Adverse Event 
CDISC 
 
Clinical Data Interchange Standards Consortium 
CMH  
 
Cochran-Mantel-Haenszel 
CRO  
 
Contract Research Organization 
eCRF  
 
electronic Case Report Form 
FDA  
 
Food and Drug Administration 
ICF 
 
 
Informed Consent Form 
ICH 
 
 
International Conference on Harmonization 
IRB 
 
 
Institutional Review Board 
KOH  
 
Potassium Hydroxide 
LOCF  
 
Last Observation Carried Forward 
MedDRA 
 
Medical Dictionary for Regulatory Activities 
mITT  
 
modified Intent-to-Treat 
mL 
 
 
Milliliter 
PP 
 
 
Per-Protocol 
SAE 
 
 
Serious Adverse Event 
SAP 
 
 
Statistical Analysis Plan 
SAS 
 
 
Statistical Analysis System 
SDTM  
 
Study Data Tabulation Model 
TEAE  
 
Treatment Emerget Advers Events 
USA  
 
United States of America 
 
 
 
 
 


NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
                                            Protocol / Study No. 71875502 
 
02/28/2019 
                                  Encube Ethicals Pvt Ltd                              Page 6 of 57 
TABLE OF CONTENTS 
1. INTRODUCTION .......................................................................................................................8 
2. OBJECTIVES ..............................................................................................................................8 
3. OVERALL STUDY DESIGN .....................................................................................................8 
4. RANDOMIZATION AND BLINDING....................................................................................11 
5. SAMPLE SIZE ..........................................................................................................................11 
6. EFFICACY VARIABLES AND EFFICACY  ENDPOINTS ..................................................12 
7. STUDY POPULATIONS ..........................................................................................................13 
8. STATISTICAL ANALYSIS METHODS .................................................................................14 
8.1 Baseline Characteristics ......................................................................................................15 
8.1.1 Patient Disposition ......................................................................................................15 
8.1.2 Demographic and Other Baseline Characteristics .......................................................15 
8.1.3 Medical History ...........................................................................................................16 
8.2 Efficacy Analyses................................................................................................................16 
8.2.1 Efficacy Analyses on Primary and Secondary Endpoints ...........................................16 
8.3 Safety Analysis ...................................................................................................................18 
8.3.1 Adverse Events ............................................................................................................18 
8.3.2 Vital Signs ...................................................................................................................18 
8.3.3 Local Signs and Symptoms .........................................................................................19 
8.3.4 Concomitant Medications ...........................................................................................19 
8.4 Multiple Comparisons .........................................................................................................19 
8.5 Methods for Handling Missing Data ...................................................................................19 
8.6 Interim Analyses .................................................................................................................20 
8.7 Changes to the Protocol Defined Statistical Analysis Plan .................................................20 
9. TABLE, LISTING AND FIGURE SHELLS ............................................................................21 
T14.1.1 Summary of Patient's Disposition ................................................................................23 
T14.1.2 Summary of Protocol Deviations.................................................................................24 
T14.1.3.1 Summary of Patients Excluded from Efficacy Analysis  (Randomized 
Population) .........................................................................................................................25 
T14.1.3.2 Summary of Patients Included in Analysis Population by Study Site ......................26 
T14.2.1 Summary of Demographic Data  (Safety Population) .................................................28 
T14.2.2 Summary of Baseline Characteristics  (Safety Population) .........................................31 
T14.2.3 Summary of Demographic Data  (modified Intent-to-Treat Population) ....................33 
T14.2.4 Summary of Baseline Characteristics (modified Intent-to-Treat Population) .............33 
T14.2.5 Summary of Demographic Data  (Per-Protocol Population) .......................................33 
T14.2.6 Summary of Baseline Characteristics (Per-Protocol Population) ................................33 
T14.2.7.1 Summary of Total Severity Score of Local Signs and Symptoms  (modified 
Intent-to-Treat Population) ................................................................................................34 
T14.2.7.2 Summary of Total Severity Score of Local Signs and Symptoms  (Per-
Protocol Population) ..........................................................................................................34 
T14.2.8.1 Summary of KOH Wet Mount and Mycological Culture  (modified Intent-
to-Treat Population) ...........................................................................................................35 


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T14.2.8.2 Summary of KOH Wet Mount and Mycological Culture  (Per-Protocol 
Population) .........................................................................................................................35 
T14.2.9 Summary of Analysis Results of Primary Efficacy Endpoint  Proportion of 
Patients in each Treatment Group with a Therapeutic Cure of Tinea Pedis  at the 
Test-of-cure Visit (Day 56 ± 4) .........................................................................................36 
T14.2.10 Summary of Analysis Results of Secondary Efficacy Endpoint  Proportion of 
Patients in each Treatment Group Who are Considered a Clinical Cure at Day 56 
± 4 ......................................................................................................................................37 
T14.2.11 Summary of Analysis Results of Secondary Efficacy Endpoint  Proportion of 
Patients in each Treatment Group Who are Considered a Mycological Cure at Day 
56 ± 4 .................................................................................................................................38 
T14.3.1 Overall Summary of Adverse Events  (Safety Population) .........................................39 
T14.3.2 Summary of Frequency of Adverse Events by Body System  (Safety 
Population) .........................................................................................................................40 
T14.3.3 Summary of Frequency of Adverse Events by Relationship  (Safety 
Population) .........................................................................................................................41 
T14.3.4 Summary of Frequency of Adverse Events by Severity  (Safety Population) ............42 
T14.3.5 Summary of Frequency of Serious Adverse Events  (Safety Population) ...................43 
T14.3.6 Summary of Vital Signs  (Safety Population) .............................................................44 
L16.2.1 Listing of Discontinued Patients ..................................................................................45 
L16.2.2 Listing of Protocol Deviations .....................................................................................46 
L16.2.3.1 Listing of Patients Excluded from the Per-Protocol Population ...............................47 
L16.2.3.2 Listing of Patients Excluded from the modified Intent-to-Treat Population ............47 
L16.2.4.1 Listing of Demographic Data ...................................................................................48 
L16.2.4.2 Listing of Medical History........................................................................................49 
L16.2.4.3 Listing of Prior and Concomitant Medication ..........................................................50 
L16.2.5 Listing of Drug Administration ...................................................................................51 
L16.2.6.1 Listing of Local Signs and Symptoms ......................................................................52 
L16.2.6.2 Listing of Mycological Culture and KOH Wet Mount Results ................................53 
L16.2.7.1 Listing of Treatment Emergent Adverse Events by Treatment ................................54 
L16.2.7.2 Listing of Pre-treatment Adverse Events ..................................................................55 
L16.2.8.1 Listing of Pregnancy Test Results ............................................................................56 
L16.2.8.2 Listing of Vital Signs ................................................................................................57 
 


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1. INTRODUCTION 
This Statistical Analysis Plan (SAP) is based on the final Clinical Study Protocol 71875502 
(Novum Study No. 71875502) Rev. 0 dated 06/13/2018. 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 71875502 (Novum Study No. 71875502) Rev. 0 dated 
06/13/2018 
 Casebook for Novum Study No. 71875502  
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 
1. Evaluate the therapeutic equivalence of a generic Ketoconazole Cream 2% (Encube 
Ethicals Pvt Ltd) to the Reference product, Ketoconazole Cream 2% (G&W Laboratories 
Inc.) in the treatment of tinea pedis. 
2. Demonstrate the superiority of the clinical effect of the Test and Reference (active) 
products over that of the Placebo (vehicle) in the treatment of tinea pedis. 
3. Compare the safety of the Test, Reference and Placebo products in the treatment of tinea 
pedis. 
3. OVERALL STUDY DESIGN 
This randomized, double-blind, vehicle-controlled, parallel-group, multiple-site study has been 
designed to evaluate the clinical (therapeutic) effect of a generic Ketoconazole Cream 2% 
(Encube Ethicals Pvt Ltd) compared to the Orange Book Reference Standard (RS) product, 
Ketoconazole Cream 2% (G&W Laboratories Inc.) in patients with tinea pedis. Additionally, both 
the Test and Reference (i.e., the RS) treatments will be tested for superiority to a Placebo. 


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Before any study-specific procedures are performed, all patients will read and sign the IRB-
approved informed consent form (ICF). 
Approximately 830 eligible patients, 18 years of age and older, will be randomized in a 2:2:1 
ratio (Test: Reference: Placebo) to one of the three study products as follows: 
 Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) 
 Reference: Ketoconazole Cream 2% (G&W Laboratories Inc.; Registrant: Teva 
Pharmaceuticals USA Inc.)) 
 Placebo: Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) 
Patients will complete three clinic visits as follows: 
 Visit 1 (Day 1): Screening/Baseline  
 Visit 2 (Day 42 ± 4): End of Treatment  
 Visit 3 (Day 56 ± 4): Test-of-Cure/End of Study 
Patients will be instructed to apply the study product to affected and immediate surrounding 
areas once daily for a total of 42 ± 4 days starting on the day of enrollment (i.e., Day 1). The last 
dose should be applied on the day of Visit 2 (Day 42 ± 4). Evaluations will be performed in 
accordance with the study schematic. Safety assessments will include monitoring of adverse 
events (AEs), vital signs measurement, and urine pregnancy tests (for females of childbearing 
potential). Clinical assessments will include the potassium hydroxide (KOH) wet mount, 
mycological culture, and rating of signs and symptoms. The Investigator should identify the most 
severe lesion (i.e., target lesion) at baseline. Although the study product should be applied to all 
infected areas (both feet), only the target lesion will be evaluated for analysis. 


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  Figure 1 Study Schematic 
 
PROCEDURE 
VISIT 1 
(Day 1) 
Screening/ 
Baseline 
VISIT 2 
(Day 42 ± 4 Days)* 
End of Treatment 
VISIT 3 
(Day 56 ± 4 Days) 
Test-of-Cure/ 
End of Study 
Informed Consent 
X 
 
 
Medical History and 
Demographics 
X 
 
 
Perform Pregnancy Test** 
X 
X 
X 
Record Vital Signs 
X 
X
X 
Review and Assessment of 
Concomitant Medications 
X 
X 
X 
Review and Assessment of 
Adverse Events 
 
X 
X 
Designate Target Lesion 
X 
 
 
Assess Local Signs and 
Symptoms 
X 
X 
X 
Collect Sample for KOH Wet 
Mount 
X 
 
X
† 
Inclusion/Exclusion Criteria 
Review 
X 
 
 
Collect Sample for Mycological 
Culture‡ 
X 
 
X 
Dispense Study Product 
X 
 
 
Provide Patient Diary 
X 
X 
 
Collect/Review Patient Diary 
 
X 
X 
Collect Study Product 
 
X 
X§ 
Discharge from Study 
 
 
X 
*Dosing regimen is once daily for 42 ± 4 days starting on the day of enrollment (Day 1) through 
the day of Visit 2 (Day 42 ± 4). 
**For females of childbearing potential 
†KOH sample will not be collected if baseline culture is negative. 
‡Mycological culture sample will not be sent if KOH is negative at baseline or positive at Visit 3. 
See Appendix B. 
§Study product will be collected at Visit 3 if it is not returned at Visit 2. 
 
 
 


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4. RANDOMIZATION AND BLINDING 
All randomized study product will be blinded and packaged in sealed boxes by an independent 
packaging company. Randomization will be pre-planned according to a computer-generated 
randomization schedule. The randomization will be generated in blocks, each containing five 
patients’ worth of study product (2 Test, 2 Reference, and 1 Placebo).  
The randomization/patient number will be a unique four-digit number.  This number will be 
assigned immediately before dispensing of study product and in ascending sequential order, 
beginning with the lowest available number at the study site. Each patient kit and each dispensed 
study tube should include the four-digit patient number on the label. 
At the end of the study, after all the clinical data have been entered and the study database has 
been locked, a copy of the randomization schedule will be sent to the statistician. 
The Investigator, staff at the study site, study monitors, and data analysis/management personnel 
will be blinded to the patient assignment.  
5. SAMPLE SIZE 
For the primary endpoint analysis (proportion of patients in the PP population with a Therapeutic 
Cure at the test-of-cure visit), sample size is estimated for therapeutic equivalence of the Test to 
the Reference product and superiority of each of the active treatments groups over Placebo. The 
sample size estimations are based on previous studies conducted for ketoconazole cream (Teva 
Pharmaceuticals; ANDA 75-581). Readers are encouraged to see the protocol reference list for 
the results of the previous studies used for sample size calculation. 
In the PP population, the proportion of patients with a Therapeutic Cure in the Reference group 
is expected to be 50%. Assuming that the Therapeutic Cure rate for the Test treatment group is 
an absolute difference of 5% lower than the Reference Responder rate (i.e., pT - pR = -5%), a 
sample size of 172 patients in each active group in the PP population will provide approximately 
85% power to demonstrate therapeutic equivalence (i.e., the 90% confidence interval [Yates’ 
continuity-corrected] on the pT - pR difference is within a defined equivalence range [-20%, 
+20%]). 
The Therapeutic Cure rates for the Placebo and active treatment groups at the test-of-cure visit 
are anticipated to be approximately 10% and at least 40% (Test = 40%, Reference = 45%), 
respectively, in the mITT population. Using a 2:1 (Active: Placebo) randomization scheme, and 
assuming the conversion rate from mITT to PP will be approximately 80%, 216 patients in each 
active treatment group (Test and Reference) and 108 patients in the Placebo group of the mITT 
population will provide at least 99% power to demonstrate superiority of active treatments over 
Placebo (p < 0.05; using two-sided, continuity-corrected Z-test and a pooled response rate for the 
standard error of the difference in proportions). 


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Under the above assumptions, the overall study power to demonstrate therapeutic equivalence 
and superiority is estimated to be at least 85% (100% × 0.85 × 0.999), assuming 100% 
correlation between the two superiority tests. 
To allow for approximately 35% of patients who may have negative fungal cultures post-
randomization, drop out from the study or are otherwise non-evaluable, approximately 830 
patients may be randomized (332 in each active group and 166 in the Placebo group) to yield 
540 patients in the mITT population. 
More than 50% of the patients should have baseline fungal cultures that test positive for 
T .rubrum. If fewer than 50% of enrolled patients have a positive T .rubrum culture or the 
number of patients with negative fungal cultures is more than anticipated, then additional 
patients may be enrolled to ensure that at least 430 (172:172:86) patients are eligible in the 
PP population, of which > 50% have a positive T. rubrum culture at baseline. 
6. EFFICACY VARIABLES AND EFFICACY  ENDPOINTS 
Efficacy Variables 
The primary and secondary efficacy variables are the outcome of the KOH test (negative or 
positive), outcome of the mycological culture (negative or positive), and signs and symptoms 
scores.  
Primary Efficacy Endpoint: 
The primary efficacy endpoint is the proportion of patients in each treatment group with a 
Therapeutic Cure of tinea pedis at the test-of-cure visit two weeks after the end of treatment 
(Day 56 ± 4). 
Secondary Efficacy Endpoints: 
The secondary efficacy endpoints are: 
 The proportion of patients in each treatment group with a Clinical Cure at Day 56 ± 4. 
 The proportion of patients in each treatment group with a Mycological Cure at Day 
56 ± 4. 
Definitions 
1. Therapeutic Cure: To be considered a Therapeutic Cure, the patient must have both 
Clinical and Mycological Cure of tinea pedis. 
2. Therapeutic Failure: A patient will be considered a Therapeutic Failure if: 


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a. the patient is a Clinical or Mycological Failure 
b. the patient was considered to have an insufficient therapeutic response 
c. the patient used topical drug therapy for irritation or pruritus on the feet between Visit 
2 (Day 42 ± 4 days) and Visit 3 ( Day 56 ± 4 days) 
3. Clinical Cure: To be considered a clinical cure the patient’s total severity score must be ≤ 
2 with no individual severity score > 1. 
4. Clinical Failure: A patient will be considered a Clinical Failure if the patient’s total 
severity score is > 2 or any individual score is > 1. 
5. Mycological Cure: To be considered a mycological cure the patient must have a negative 
KOH test and a negative fungal culture. 
6. Mycological Failure: A patient will be considered a Mycological Failure if the patient’s 
KOH test is positive or the patient’s fungal culture is positive. 
7. STUDY POPULATIONS 
Per-Protocol Population 
The PP population will include all randomized patients who: 
 Met all inclusion and exclusion criteria. 
 Made the final study visit within the protocol window of Day 56 ± 4 days (Day 52 
to Day 60 inclusive) with no protocol violations that would affect the treatment 
evaluation. 
 Did not have any significant protocol deviations. 
 Were compliant with dosing between 75%-125% of the required doses. 
 Had a positive baseline KOH and fungal culture for Trichophyton rubrum, 
Trichophyton mentagrophyties or Epidermophyton floccosum. 
Patients discontinued from the study because of lack of treatment effect after completing at least 
14 days of treatment will be included in the PP population as Therapeutic Failures provided they 
had a positive baseline KOH, positive baseline fungal culture, and did not have any significant 
protocol deviations. For these patients, there will be no mycological testing at time of 
discontinuation; therefore, they will be considered Therapeutic Failures in the primary analysis 
but the Mycological Cure data will be set to missing for the secondary endpoint. 


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Patients who meet the criteria above, but who also used topical drug therapy for irritation or 
pruritus on the feet after the treatment phase of the study will be included in the PP population as 
Therapeutic Failures. If no mycological testing is performed, the patients will be considered 
Therapeutic Failures in the primary analysis but the Mycological Cure data will be set to missing 
for the secondary endpoint. 
All analyses performed using the PP population will be done on an observed case basis (i.e., no 
last observation carried forward [LOCF] will be performed). 
Modified Intent-to-Treat Population 
The mITT population will include randomized patients who: 
 Met all inclusion/exclusion criteria. 
 Applied at least one dose of assigned product. 
 Had a positive baseline KOH and fungal culture for Trichophyton rubrum, 
Trichophyton mentagrophyties or Epidermophyton floccosum. 
Patients discontinued early for reasons other than lack of treatment effect will be excluded from 
the PP population and included in the mITT population using LOCF. Patients who qualify for 
inclusion in the mITT population with missing endpoint data who were not discontinued for lack 
of treatment effect will also be evaluated using LOCF; that is, if a patient who was not 
discontinued for lack of treatment effect does not have KOH or mycological culture results at 
Visit 3, this patient will be evaluated for the primary and secondary endpoints using LOCF from 
Visit 1. Patients who discontinued because of lack of treatment effect will not have LOCF 
performed. 
Patients who meet the criteria above, but who also used topical drug therapy on the feet for the 
treatment of irritation or pruritus after the treatment phase of the study will be included in the 
mITT as Therapeutic Failures. If no mycological testing is performed, these patients will be 
considered Therapeutic Failures in the primary analysis but the Mycological Cure data will be set 
to missing for the secondary endpoint. No LOCF will be performed. 
Safety Population 
The Safety population will include all randomized patients who use at least one dose of product. 
8. STATISTICAL ANALYSIS METHODS 
If not otherwise specified, statistical significance is defined as p < 0.05 and is two-tailed. Data 
will be summarized with respect to demographic and baseline characteristics and safety 


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variables. 
For categorical variables, the number and percent of each category within a parameter will be 
calculated. For continuous variables, statistics will include n, mean, standard deviation, median  
and range. 
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) and FDA Guidance of Technical Specifications - Comparative Clinical 
Endpoints Bioequivalence Study Analysis Datasets for Abbreviated New Drug Application 
(September 2018) . 
8.1 Baseline Characteristics 
8.1.1 Patient Disposition 
The patient disposition information will be summarized by treatment group as well as total. The 
number of patients randomized will be tabulated by treatment group and total. In addition, 
completion status and primary reason for withdrawal will be summarized by treatment group and 
total. 
8.1.2 Demographic and Other Baseline Characteristics 
Baseline comparability of all treatment groups will be evaluated separately in the PP, mITT and 
Safety populations.  
The following baseline demographics (determined from their initial study visit) will be 
evaluated: 
 Age (years) 
 Sex (male/female) 
 Ethnicity (Hispanic/non-Hispanic) 
 Race (White, Black/African American, Native Hawaiian or Other Pacific Islander, 
Asian, American Indian or Alaska Native, Other) 
 Type of infection (interdigital only or interdigital with extension) 
 Total baseline signs and symptoms score 
 Presence or absence of onychomycosis 
 Number of Tinea Pedis infections in the past 12 months 


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 Primary infective organism 
Summary tables by treatment group will be presented. Continuous variables will be summarized 
using descriptive statistics (n, mean, standard deviation, median and range). Range will have the 
same decimal places as raw values. Mean, median and standard deviation will have one decimal 
place more than that of raw values. Categorical variables will be summarized using frequencies 
and percentage.  
Baseline comparability of the treatments will be presented using Cochran-Mantel-Haenszel 
(CMH) 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 1, Patients will also be questioned about personal medical history, including tinea pedis 
history. 
Medical history data will be listed by treatment group and patient. 
8.2 Efficacy Analyses 
8.2.1 Efficacy Analyses on Primary and Secondary Endpoints 
Therapeutic Equivalence 
Therapeutic equivalence will be evaluated for the primary endpoint in the per-protocol (PP) 
population. If the 90% confidence interval (calculated using Yates’ continuity correction) on the 
absolute difference between the proportion of patients with a Therapeutic Cure in the Test and 
Reference groups (pT - pR) is contained within the range [-20%, +20%] then therapeutic 
equivalence of the Test product to the Reference product will be considered to have been 
demonstrated. 
The same statistical approach will be conducted for analyses of the secondary endpoints in the PP 
population. 
To declare therapeutic equivalence of the Test product to the Reference product, equivalence 
must be demonstrated for only the primary endpoint in the PP population. 
Patients who are missing mycological culture data at the test-of-cure visit will not be included in 
the analysis for the secondary endpoint of Mycological Cure. 
Superiority to Placebo 


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Superiority of the Test and Reference products against the Placebo product for the primary 
endpoint will be evaluated in the mITT population using, if necessary, LOCF as described in 
section 11.3.2 of the protocol.  
Patients discontinued early for reasons other than lack of treatment effect will be excluded from 
the PP population and included in the mITT population using LOCF. Patients who qualify for 
inclusion in the mITT population with missing endpoint data who were not discontinued for lack 
of treatment effect will also be evaluated using LOCF; that is, if a patient who was not 
discontinued for lack of treatment effect does not have KOH or mycological culture results at 
Visit 3, this patient will be evaluated for the primary and secondary endpoints using LOCF from 
Visit 1. Patients who discontinued because of lack of treatment will not have LOCF performed. 
 
Patients who meet the criteria above, but who also used topical drug therapy on the feet for the 
treatment of irritation or pruritus after the treatment phase of the study will be included in the 
mITT as Therapeutic Failures. If no mycological testing is performed, these patients will be 
considered Therapeutic Failures in the primary analysis but the Mycological Cure data will be set 
to missing for the secondary endpoint. No LOCF will be performed. 
If the proportions of patients with a Therapeutic Cure in the Test and the Reference product 
groups are numerically and statistically superior to that of the Placebo (p < 0.05; using a two-
sided Cochran-Mantel-Haenszel [CMH] test, stratified by clinical site) then superiority of the 
Test and Reference products over Placebo will be concluded. 
The same statistical approach will be conducted for analyses of the secondary endpoints in the 
mITT population. 
To declare superiority of the Test and Reference products over Placebo, their superiority must be 
demonstrated for only the primary endpoint in the mITT population. 
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 the 
primary efficacy endpoint in the PP population for equivalence testing. The treatment-by-site 
interaction will be evaluated by the Breslow-Day test for homogeneity of the odds ratio at the 5% 
significance level (p < 0.05, 2-sided). 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 PP 
population at the site with the highest enrolling rate in the PP population. If the treatment-by-site 
interaction term is found to be statistically significant (p < 0.05) for the primary endpoint, then 
the interaction term will also be assessed for clinical relevance before pooling the data across 
sites. This will include examination of Therapeutic Cure rates at each site where sample sizes per 
treatment may be influential in the assessment of the interaction. The treatment-by-site 


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interaction may also be evaluated for the analyses of the secondary endpoints in the PP 
population for equivalence testing if the treatment-by-site interaction is found to be significant in 
the primary analysis. 
8.3 Safety Analysis 
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 21.0 or higher).  
Treatment emergent adverse events (TEAE) are those that have a start date after the study 
treatment has been administered or the events that were present before administration of study 
treatment and worsen in severity after administration of study treatment. Treatment emergent 
adverse events will be summarized and analyzed in a summary table. Pre-treatment adverse 
events will be presented in the listing. 
A summary table of the number and percent of patients with TEAEs by system organ class, 
preferred term, and treatment will be presented. Each patient will be counted only once within 
each preferred term.  
A frequency summary table of the number of TEAEs 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 TEAEs 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”. 
If sufficient data exist, then TEAE frequencies will be compared among the three treatments 
using Fisher’s exact test; if this test is statistically significant at the 5% significance level, then a 
pairwise Fisher’s exact test comparing Test and Reference will be conducted.  
TEAEs will be listed by treatment group and patient. Pre-treatment adverse events will be listed 
by patient. 
8.3.2 Vital Signs 
The patient’s vital signs will be recorded (pulse, blood pressure, temperature and respiration 
rate) at each visit. 
Descriptive summaries (number of observations, mean, standard deviation, minimum, median 
and maximum) will be provided by treatment group and visit. 


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8.3.3 Local Signs and Symptoms 
The Clinical Signs and Symptoms of tinea pedis will be rated by the Investigator as “none”, 
“mild,” “moderate” or “severe” using the following standardized rating scale. 
0 = None (complete absence of any sign or symptom) 
1 = Mild (Slight) 
2 = Moderate (Definitely Present) 
3 = Severe (Marked, Intense) 
The following signs and symptoms will be rated at each visit: 
 Signs: Fissuring/cracking, erythema, maceration, and scaling 
 Symptoms: Pruritus and burning/stinging 
A frequency summary table comparing the signs and symptoms for each treatment group will be 
presented by visit. 
All data will be listed by treatment group and patient. 
8.3.4 Concomitant Medications 
At Visit 1, patients will be questioned about medication use over the previous six months. At all 
subsequent 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. 
8.4 Multiple Comparisons 
No multiple comparison adjustment will be made in this study. 
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 from analyses for which data are not 
available. 
Superiority of the Test and Reference products against the Placebo product for the primary 
endpoint will be evaluated in the mITT population using LOCF. 
Patients discontinued early for reasons other than lack of treatment effect will be excluded from 
the PP population and included in the mITT population using LOCF. Patients who qualify for 
inclusion in the mITT population with missing endpoint data who were not discontinued for lack 


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of treatment effect will also be evaluated using LOCF; that is, if a patient who was not 
discontinued for lack of treatment effect does not have KOH or mycological culture results at 
Visit 3, this patient will be evaluated for the primary and secondary endpoints using LOCF from 
Visit 1. Patients who discontinued because of lack of treatment will not have LOCF performed. 
 
Patients who meet the criteria above, but who also used topical drug therapy on the feet for the 
treatment of irritation or pruritus after the treatment phase of the study will be included in the 
mITT as Therapeutic Failures. If no mycological testing is performed, these patients will be 
considered Therapeutic Failures in the primary analysis but the Mycological Cure data will be set 
to missing for the secondary endpoint. No LOCF will be performed. 
8.6 Interim Analyses 
There is no interim analysis planned in this study. 
8.7 Changes to the Protocol Defined Statistical Analysis Plan 
To conform to recommendations in the recently updated Draft Guidance on Ketoconazole 
(Revised Feb 2019), the following changes to the statistical analyses described in the protocol 
will be made. 
Wordings in protocol 
Changed to 
Protocol section 11.3.3 
The Safety population will include all patients who 
are randomized and received study product. 
The Safety population will include all 
randomized patients who use at least one 
dose of product. 
Protocol section 11.3.2 
The mITT population will include randomized 
patients who: 
 Met all inclusion/exclusion criteria. 
 Applied at least one dose of assigned 
product. 
 Had at least one post-baseline 
evaluation. 
 Had a positive baseline KOH and 
fungal culture for Trichophyton 
rubrum, Trichophyton 
mentagrophyties or Epidermophyton 
floccosum. 
The mITT population will include 
randomized patients who: 
 Met all inclusion/exclusion 
criteria. 
 Applied at least one dose of 
assigned product. 
 Had a positive baseline 
KOH and fungal culture for 
Trichophyton rubrum, 
Trichophyton 
mentagrophyties or 
Epidermophyton 
floccosum. 
 


NOVUM PHARMACEUTICAL RESEARCH SERVICES 
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                                  Encube Ethicals Pvt Ltd                              Page 21 of 57 
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. 


NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
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TABLE, LISTING AND FIGURE SHELLS 


NOVUM PHARMACEUTICAL RESEARCH SERVICES 
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T14.1.1 Summary of Patient's Disposition 
(Randomized Population) 
Patients Randomized 
Test 
N = xxx 
n (%) 
Reference 
N = xxx 
n (%) 
Placebo 
N = xxx 
n (%) 
Total 
N = xxx 
n (%) 
Completed Study 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Terminated Early 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Adverse event 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Lack of efficacy 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Lost to follow-up 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Negative baseline culture result  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Noncompliance with study drug  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Patient scheduled/came in early for Visit 3 
 
 
 
 
Pregnancy 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Protocol deviation 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Significant worsening of condition requiring  
alternative or supplemental therapy  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Withdrawal by subject  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Other 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
     Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) 
     Reference: Ketoconazole Cream 2% (G&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) 
     Placebo: Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) 
                             N = number of patients randomized in that particular group; n = number of patients with data available for that particular group;   
                             total % is based on N 
 
 
 
 
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
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                                                              Encube Ethicals Pvt Ltd                                                          Page 24 of 57 
 
T14.1.2 Summary of Protocol Deviations 
(Randomized Population) 
Patients Randomized 
Test  
N = xxx 
n (%) 
Reference  
N = xxx 
n (%) 
Placebo 
N = xxx 
n (%) 
Total 
N = xxx 
n (%) 
Total Patients with Protocol Deviations 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Total Deviations 
xxx 
xxx 
xxx 
xxx 
    Lost to follow-up 
xxx 
xxx 
xxx 
xxx 
    Missed visit 
xxx 
xxx 
xxx 
xxx 
    Noncompliance with study product 
xxx 
xxx 
xxx 
xxx 
    Noncompliance with  study procedures 
xxx 
xxx 
xxx 
xxx 
    Outside visit window 
xxx 
xxx 
xxx 
xxx 
    Randomized in error 
xxx 
xxx 
xxx 
xxx 
    Restricted medication 
xxx 
xxx 
xxx 
xxx 
    Other 
xxx 
xxx 
xxx 
xxx 
     Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) 
     Reference: Ketoconazole Cream 2% (G&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) 
     Placebo: Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) 
                             N = number of patients randomized in that particular group; n = number of patients with data available for that particular group;  
                             total % is based on N 
 
 
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
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                                                              Encube Ethicals Pvt Ltd                                                          Page 25 of 57 
T14.1.3.1 Summary of Patients Excluded from Efficacy Analysis  
(Randomized Population) 
 
Test  
N = xxx 
n (%) 
Reference  
N = xxx 
n (%) 
Placebo  
N = xxx 
n (%) 
Total 
N = xxx 
n (%) 
Safety Population 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Excluded from Safety population 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
      Did not receive study product 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
mITT Population 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Excluded from mITT population 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
      Inclusion/Exclusion criteria not met 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
      Did not have at least one post-baseline evaluation 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
      Etc. 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
PP Population 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Excluded from PP population  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
      Significant protocol deviations 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
      Etc. 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
     Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) 
     Reference: Ketoconazole Cream 2% (G&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) 
     Placebo: Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) 
                             N = number of patients randomized in that particular group; n = number of patients with data available for that particular group;  
                             total % is based on N 
 
Programming note: exclusion reasons are not duplicated across the populations. 
 
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
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                                                              Encube Ethicals Pvt Ltd                                                          Page 26 of 57 
T14.1.3.2 Summary of Patients Included in Analysis Population by Study Site 
(Randomized population) 
 
Safety 
 
mITT 
 
PP 
Site 
No. 
Name 
Total 
Randomized 
Test 
Ref 
Placebo Total  Test 
Ref 
Placebo Total  Test 
Ref 
Placebo 
Total 
xx 
xxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 xxx 
xxx 
xxx 
xxx 
 xxx 
xxx 
xxx 
xxx 
xx 
xxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 xxx 
xxx 
xxx 
xxx 
 xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) 
Reference: Ketoconazole Cream 2% (G&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) 
Placebo: Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) 
 
 
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
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02/28/2019 
                                                              Encube Ethicals Pvt Ltd                                                          Page 27 of 57 
T14.1.3.3 Study Timelines (Randomized Patients) 
 
 
Trial Timelines 
Date 
First Patient First Visit (FPFV) 
mm/dd/yyyy 
Last Patient Last Visit (LPLV) 
mm/dd/yyyy 
Trial Duration (Days) 
xxx 
__________________________________________________________________________________________________________________ 
Note: Trial Duration (Days) = (Date of LPLV - Date of FPFV) + 1 
 
__________________________________________________________________________________________________________________ 
 
 
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
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                                                              Encube Ethicals Pvt Ltd                                                          Page 28 of 57 
T14.2.1 Summary of Demographic Data  
(Safety Population) 
 
 
Test 
(N = xxx) 
n (%) 
Reference 
(N = xxx) 
n (%) 
Placebo 
(N = xxx) 
n (%) 
P-value 
Age (years) 
n 
xxx 
xxx 
xxx 
x.xxxx 
 
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 
 
Age Groups 
< 18 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
x.xxxx 
 
18 – 40 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
41 – 64 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
65 – 75 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
> 75 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
Race 
American Indian or Alaska Native 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
x.xxxx 
 
Asian 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
Black/African American 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
Native Hawaiian or other Pacific Islander 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
White 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
Multiple 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) 
Reference: Ketoconazole Cream 2% (G&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) 
Placebo: Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) 
N = number of patients in the Safety Population in that particular group; n = number of patients with data available for that particular group; total % is 
based on N 
P-values are from Cochran-Mantel-Haenszel (CMH) test for the categorical variables, and Analysis of Variance for the continuous variables.  
 
 


NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
                                                                                                        Protocol / Study No. 71875502 
 
02/28/2019 
                                                              Encube Ethicals Pvt Ltd                                                          Page 29 of 57 
PROGRAM: L:\DEV\755\71875502\SAS\PGM\XXXX 
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
                                                                                                        Protocol / Study No. 71875502 
 
02/28/2019 
                                                              Encube Ethicals Pvt Ltd                                                          Page 30 of 57 
T14.2.1 Summary of Demographic Data 
 (Safety Population) 
 
 
Test 
(N = xxx) 
n (%) 
Reference 
(N = xxx) 
n (%) 
Placebo 
(N = xxx) 
n (%) 
P-value 
Sex 
Male 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
x.xxxx 
 
Female 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
Ethnicity 
Hispanic or Latino 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
x.xxxx 
 
Not Hispanic or Latino 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) 
Reference: Ketoconazole Cream 2% (G&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) 
Placebo: Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) 
N = number of patients in the Safety Population in that particular group; n = number of patients with data available for that particular group; total % is 
based on N 
P-values are from Cochran-Mantel-Haenszel (CMH) test for the categorical variables, and Analysis of Variance for the continuous variables.  
 
PROGRAM: L:\DEV\755\71875502\SAS\PGM\XXXX 
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
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02/28/2019 
                                                              Encube Ethicals Pvt Ltd                                                          Page 31 of 57 
T14.2.2 Summary of Baseline Characteristics  
(Safety Population) 
 
 
Test 
(N = xxx) 
 
Reference 
(N = xxx) 
 
Placebo 
(N = xxx) 
 
Overall 
P-value 
P-value 
Test vs. 
Reference 
Type of infection, n (%) 
Interdigital 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
x.xxxx 
x.xxxx 
 
Interdigital with extension 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
Onychomycosis, n (%) 
Presence 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
x.xxxx 
x.xxxx 
 
Absence 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
Primary infective organism, 
n (%) 
xxxxx 
xxx (x.x) 
xxx (xx.x) 
xxx (xx.x) 
 
x.xxxx 
 
xxxxx 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
Total baseline signs and 
symptom score, n (%) 
n 
xxx 
xxx 
xxx 
x.xxxx 
x.xxxx 
 
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 
 
 
Number of Tinea Pedis 
infections in the past 12 
months, n (%) 
n 
xxx 
xxx 
xxx 
x.xxxx 
x.xxxx 
 
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 
 
 
Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) 
Reference: Ketoconazole Cream 2% (G&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) 
Placebo: Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) 
N = number of patients in the Safety Population in that particular group; n = number of patients with data available for that particular group; total % is 
based on N 


NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
                                                                                                        Protocol / Study No. 71875502 
 
02/28/2019 
                                                              Encube Ethicals Pvt Ltd                                                          Page 32 of 57 
P-values are from Cochran-Mantel-Haenszel (CMH) test for the categorical variables, and Analysis of Variance for the continuous variables.  
 
Note to programmer: If the overall P-value is statistically significant among the three treatment groups at the 5% alpha level (i.e. p < 0.05), then ANOVA or 
CMH test using only the test and reference groups will be performed to identify any potential statistically significant differences that are clinically relevant 
between the two active treatment groups. 
 
 
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
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02/28/2019 
                                                              Encube Ethicals Pvt Ltd                                                          Page 33 of 57 
 
Similar tables will be created for T14.2.3, T14.2.4, T14.2.5 and T14.2.6 
 
T14.2.3 Summary of Demographic Data  
(modified Intent-to-Treat Population) 
T14.2.4 Summary of Baseline Characteristics 
(modified Intent-to-Treat Population) 
 
T14.2.5 Summary of Demographic Data  
(Per-Protocol Population) 
T14.2.6 Summary of Baseline Characteristics 
(Per-Protocol Population) 
 
 
 
 
 
 


NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
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02/28/2019 
                                                              Encube Ethicals Pvt Ltd                                                          Page 34 of 57 
T14.2.7.1 Summary of Total Severity Score of Local Signs and Symptoms  
(modified Intent-to-Treat Population) 
Visit 
Total  
Severity Score 
Test 
N = xxx 
n (%) 
Reference 
N = xxx 
n (%) 
Placebo 
N = xxx 
n (%) 
1 
<=2 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
>2 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 
2 
<=2 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
>2 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 
3/Early termination 
<=2 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
>2 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
     Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) 
     Reference: Ketoconazole Cream 2% (G&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) 
     Placebo: Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) 
 
 
PROGRAM: L:\DEV\755\71875502\SAS\PGM\XXXX 
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Similar table will be created for: 
T14.2.7.2 Summary of Total Severity Score of Local Signs and Symptoms  
(Per-Protocol Population) 
 
 


NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
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02/28/2019 
                                                              Encube Ethicals Pvt Ltd                                                          Page 35 of 57 
T14.2.8.1 Summary of KOH Wet Mount and Mycological Culture  
(modified Intent-to-Treat Population) 
 
Visit 
Result 
Test 
N = xxx 
n (%) 
Reference 
N = xxx 
n (%) 
Placebo 
N = xxx 
n (%) 
KOH Wet Mount 
1 
Positive 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
Negative 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
2 
Positive 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
Negative 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
3/Early termination 
Positive 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
Negative 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 
 
Mycological Culture 
1 
Positive 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
Negative 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
2 
Positive 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
Negative 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
3/Early termination 
Positive 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
Negative 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 
 
     Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) 
     Reference: Ketoconazole Cream 2% (G&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) 
     Placebo: Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) 
 
 
PROGRAM: L:\DEV\755\71875502\SAS\PGM\XXXX 
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Similar table will be created for: 
T14.2.8.2 Summary of KOH Wet Mount and Mycological Culture  
(Per-Protocol Population) 
 
 


NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
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02/28/2019 
                                                              Encube Ethicals Pvt Ltd                                                          Page 36 of 57 
T14.2.9 Summary of Analysis Results of Primary Efficacy Endpoint  
Proportion of Patients in each Treatment Group with a Therapeutic Cure of Tinea Pedis 
 at the Test-of-cure Visit (Day 56 ± 4) 
 
  Equivalence: Per-Protocol Population 
Number of 
Patients (N) 
 
Number of Patients with 
Therapeutic Cure (n) 
Proportion of 
Therapeutic Cure (%) 
Difference Between Treatments 
Treatment  
Group 
Difference (%) 
90% CI Evaluation 
Test 
xxx 
xxx 
xx.x 
 
 
Reference 
xxx 
xxx 
xx.x 
xx.x 
xx.x – xx.x 
 
Superiority: modified Intent-to-Treat Population 
Number of 
Patients (N) 
 
Number of Patients with 
Therapeutic Cure (n) 
Proportion of 
Therapeutic Cure (%) 
Treatment vs. Placebo 
Treatment  
Group 
Difference (%) 
P-value 
Placebo 
xxx 
xxx 
xx.x 
 
 
Test 
xxx 
xxx 
xx.x 
xx.x 
x.xxxx 
Reference 
xxx 
xxx 
xx.x 
xx.x 
x.xxxx 
          The 90% confidence interval for the difference in proportions between test and reference was calculated using Yates’ correction. 
          Superiority of Active treatments over Placebo were tested using a two-sided Cochran-Mantel-Haenszel (CMH) test, stratified by clinical site, at    
          the 5% significance level using last observation carried forward (LOCF). 
        Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) 
        Reference: Ketoconazole Cream 2% (G&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) 
        Placebo: Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) 
      
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
                                                                                                        Protocol / Study No. 71875502 
 
02/28/2019 
                                                              Encube Ethicals Pvt Ltd                                                          Page 37 of 57 
T14.2.10 Summary of Analysis Results of Secondary Efficacy Endpoint  
Proportion of Patients in each Treatment Group Who are Considered a Clinical Cure at Day 56 ± 4 
 
  Equivalence: Per-Protocol Population 
Number of 
Patients (N) 
 
Number of Patients with 
Clinical Cure (n) 
Proportion of 
Clinical Cure (%) 
Difference Between Treatments 
Treatment  
Group 
Difference (%) 
90% CI Evaluation 
Test 
xxx 
xxx 
xx.x 
 
 
Reference 
xxx 
xxx 
xx.x 
xx.x 
xx.x – xx.x 
 
Superiority: modified Intent-to-Treat Population 
Number of 
Patients (N) 
 
Number of Patients with 
Clinical Cure (n) 
Proportion of 
Clinical Cure (%) 
Treatment vs. Placebo 
Treatment  
Group 
Difference (%) 
P-value 
Placebo 
xxx 
xxx 
xx.x 
 
 
Test 
xxx 
xxx 
xx.x 
xx.x 
x.xxxx 
Reference 
xxx 
xxx 
xx.x 
xx.x 
x.xxxx 
          The 90% confidence interval for the difference in proportions between test and reference was calculated using Yates’ correction. 
          Superiority of Active treatments over Placebo were tested using a two-sided Cochran-Mantel-Haenszel (CMH) test, stratified by clinical site, at    
          the 5% significance level using last observation carried forward (LOCF). 
        Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) 
        Reference: Ketoconazole Cream 2% (G&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) 
        Placebo: Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) 
 
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
                                                                                                        Protocol / Study No. 71875502 
 
02/28/2019 
                                                              Encube Ethicals Pvt Ltd                                                          Page 38 of 57 
T14.2.11 Summary of Analysis Results of Secondary Efficacy Endpoint  
Proportion of Patients in each Treatment Group Who are Considered a Mycological Cure at Day 56 ± 4 
  Equivalence: Per-Protocol Population 
Number of 
Patients (N) 
 
Number of Patients with 
Mycological Cure (n) 
Proportion of 
Mycological Cure (%) 
Difference Between Treatments 
Treatment  
Group 
Difference (%) 
90% CI Evaluation 
Test 
xxx 
xxx 
xx.x 
 
 
Reference 
xxx 
xxx 
xx.x 
xx.x 
xx.x – xx.x 
 
Superiority: modified Intent-to-Treat Population 
Number of 
Patients (N) 
 
Number of Patients with 
Mycological Cure (n) 
Proportion of 
Mycological Cure (%) 
Treatment vs. Placebo 
Treatment  
Group 
Difference (%) 
P-value 
Placebo 
xxx 
xxx 
xx.x 
 
 
Test 
xxx 
xxx 
xx.x 
xx.x 
x.xxxx 
Reference 
xxx 
xxx 
xx.x 
xx.x 
x.xxxx 
          The 90% confidence interval for the difference in proportions between test and reference was calculated using Yates’ correction. 
          Superiority of Active treatments over Placebo were tested using a two-sided Cochran-Mantel-Haenszel (CMH) test, stratified by clinical site, at    
          the 5% significance level using last observation carried forward (LOCF). 
        Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) 
        Reference: Ketoconazole Cream 2% (G&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) 
        Placebo: Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) 
      
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
                                                                                                        Protocol / Study No. 71875502 
 
02/28/2019 
                                                              Encube Ethicals Pvt Ltd                                                          Page 39 of 57 
T14.3.1 Overall Summary of Adverse Events  
(Safety Population) 
 
Description 
 
Test  
(N = xxx) 
n (%) 
 
Reference  
(N = xxx) 
n (%) 
 
Placebo 
(N = xxx) 
n (%) 
 
Total 
(N = xxx) 
n (%) 
Patients in Safety Analysis population 
xxx 
xxx 
xxx 
xxx 
    Patients with at least one AE  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    Discontinued study product due to above AE  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 
AEs reported  
Xxx 
xxx 
xxx 
xxx 
  Mild  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Moderate  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Severe  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Not Related  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Related  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Death  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Serious AE  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
            Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) 
            Reference: Ketoconazole Cream 2% (G&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) 
            Placebo: Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) 
              MedDRA Version 21.0 
 
 
 
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
                                                                                                        Protocol / Study No. 71875502 
 
02/28/2019 
                                                              Encube Ethicals Pvt Ltd                                                          Page 40 of 57 
T14.3.2 Summary of Frequency of Adverse Events by Body System  
(Safety Population) 
 
Test  
N = xxx 
 
Reference  
N = xxx 
 
Placebo 
N = xxx 
Overall 
Fisher's 
P-value 
Fisher's 
P-value 
Test vs. 
Reference 
Body System 
Preferred Term 
Events 
Patients 
n (%) 
 
Events 
Patients 
n (%) 
 
Events 
Patients 
n (%) 
Patients with at least one 
AE 
Total 
xx 
xxx (xx.x) 
 
xx 
xxx (xx.x) 
 
xx 
xxx (xx.x) 
0.1234 
NA 
Ear and labyrinth disorders 
Ear pain 
xx 
xxx (xx.x) 
 
xx 
xxx (xx.x) 
 
xx 
xxx (xx.x) 
0.0425 
0.0372 
 
etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) 
Reference: Ketoconazole Cream 2% (G&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) 
Placebo: Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) 
N = number of patients in safety population in that particular group; n= number of patients with data available for that particular group; total % is based 
on N 
MedDRA Version 21.0 
 
Note to programmer: 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 test and reference groups will be performed to identify any potential statistically significant differences that are clinically 
relevant between the two active treatment groups. 
 
 
 
 
 
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
                                                                                                        Protocol / Study No. 71875502 
 
02/28/2019 
                                                              Encube Ethicals Pvt Ltd                                                          Page 41 of 57 
T14.3.3 Summary of Frequency of Adverse Events by Relationship  
(Safety Population) 
             
 
Test 
# of Events 
(N = xxx) 
 
Reference 
# of Events 
(N = xxx) 
 
Placebo 
# of Events 
(N = xxx) 
Body System 
MedDRA Term 
Related 
n (%) 
Not Related 
n (%) 
 
Related 
n (%) 
Not Related 
n (%) 
 
Related 
n (%) 
Not Related 
n (%) 
Total AEs 
Total 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
Ear and labyrinth 
disorders 
Ear pain 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
Hypoacusis 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) 
 Reference: Ketoconazole Cream 2% (G&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) 
Placebo: Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) 
N = Total number of events in that particular group; Percentage is based on total number of events. 
MedDRA Version 21.0 
 
 
 
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
                                                                                                        Protocol / Study No. 71875502 
 
02/28/2019 
                                                              Encube Ethicals Pvt Ltd                                                          Page 42 of 57 
T14.3.4 Summary of Frequency of Adverse Events by Severity  
(Safety Population) 
 
 
Test 
# of Events 
(N = xxx) 
 
Reference 
# of Events 
(N = xxx) 
 
Placebo 
# of Events 
(N = xxx) 
Body 
System 
MedDRA 
Term 
Mild 
n (%) 
Moderate 
n (%) 
Severe 
n (%) 
 
Mild 
n (%) 
Moderate 
n (%) 
Severe 
n (%) 
 
Mild 
n (%) 
Moderate 
n (%) 
Severe 
n (%) 
Total AEs Total 
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) 
Ear and 
labyrinth 
disorders 
Ear pain 
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) 
 
Hypoacusis 
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) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
          Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) 
          Reference: Ketoconazole Cream 2% (G&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) 
          Placebo: Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) 
N = Total number of events in that particular group; Percentage is based on total number of events. 
              MedDRA Version 21.0 
 
 
 
 
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
                                                                                                        Protocol / Study No. 71875502 
 
02/28/2019 
                                                              Encube Ethicals Pvt Ltd                                                          Page 43 of 57 
T14.3.5 Summary of Frequency of Serious Adverse Events  
(Safety Population) 
Body System 
Preferred Term 
Test  
# Events 
Reference  
# Events 
Reference  
# Events 
Injury, poisoning and procedural complications 
Alcohol poisoning 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
            Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) 
            Reference: Ketoconazole Cream 2% (G&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) 
            Placebo: Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) 
              MedDRA Version 21.0 
 
 
 
 
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
                                                                                                        Protocol / Study No. 71875502 
 
02/28/2019 
                                                              Encube Ethicals Pvt Ltd                                                          Page 44 of 57 
T14.3.6 Summary of Vital Signs  
(Safety Population) 
Vital Signs 
Visit 
Statistic 
Test  
N = xxx 
Reference  
N = xxx 
Placebo 
N = xxx 
Systolic Blood Pressure (mmHg) 
Visit 1 
n 
xxx 
xxx 
xxx 
 
 
Mean ± SD 
xxx.x ± xx.x 
xxx.x ± xx.x 
xxx.x ± xx.x 
 
 
Median 
xxx.x 
xxx.x 
xxx.x 
 
 
Range 
xxx.x – xxx.x 
xxx.x – xxx.x 
xxx.x – xxx.x 
 
 
 
 
 
 
 
Visit 2 
 
 
 
 
 
 
 
 
 
 
 
Visit 3/Early 
Termination 
 
 
 
 
 
 
 
 
 
 
Diastolic Blood Pressure (mmHg) 
 
 
 
 
 
Pulse Rate (beats/min) 
 
 
 
 
 
Respiration Rate (breaths/min) 
 
 
 
 
 
Temperature (F) 
 
 
 
 
 
 
 
 
 
 
 
           Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) 
           Reference: Ketoconazole Cream 2% (G&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) 
           Placebo: Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) 
N = Total number of events in that particular group; Percentage is based on total number of events. 
 
 
 
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
                                                                                                        Protocol / Study No. 71875502 
 
02/28/2019 
                                                              Encube Ethicals Pvt Ltd                                                          Page 45 of 57 
L16.2.1 Listing of Discontinued Patients 
Treatment 
Group 
Patient 
Screening 
Number 
Patient 
Randomization 
Number 
Discontinuation 
Reason 
Population 
Test  
xx-xxx 
xxxx 
Withdrawal by Patient 
Per-Protocol 
 
xx-xxx 
xxxx 
Lost to Follow-up 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reference  
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) 
Reference: Ketoconazole Cream 2% (G&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) 
Placebo: Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) 
 
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
                                                                                                        Protocol / Study No. 71875502 
 
02/28/2019 
                                                              Encube Ethicals Pvt Ltd                                                          Page 46 of 57 
L16.2.2 Listing of Protocol Deviations 
Treatment 
Group 
Patient 
Screening 
Number 
Patient 
Randomization 
Number 
Event Description 
Population    
Significant  
Protocol  
Deviation 
Test  
xx-xxx 
xxxx 
Outside Visit Window (Visit 3) 
Safety 
No 
 
 
 
 
 
 
Reference  
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) 
Reference: Ketoconazole Cream 2% (G&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) 
Placebo: Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) 
 
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
                                                                                                        Protocol / Study No. 71875502 
 
02/28/2019 
                                                              Encube Ethicals Pvt Ltd                                                          Page 47 of 57 
L16.2.3.1 Listing of Patients Excluded from the Per-Protocol Population 
Treatment 
Group 
Patient 
Screening 
Number 
Patient 
Randomization 
Number 
Exclusion Reason 
Test  
xx-xxx 
xxxx 
Significant protocol deviation 
 
 
 
 
 
 
 
 
Reference  
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) 
 Reference: Ketoconazole Cream 2% (G&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) 
 Placebo: Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) 
 
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L16.2.3.2 Listing of Patients Excluded from the modified Intent-to-Treat Population 
 
 


NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
                                                                                                        Protocol / Study No. 71875502 
 
02/28/2019 
                                                              Encube Ethicals Pvt Ltd                                                          Page 48 of 57 
L16.2.4.1 Listing of Demographic Data 
Treatment 
Group 
Patient 
Screening 
Number 
Patient 
Randomization 
Number 
Age 
Sex 
Ethnicity 
Race 
 
Birth  
Control 
Test  
xx-xxx 
xxxx 
30 
Female 
Not Hispanic or Latino 
Black or African American 
Double Barrier 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reference  
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) 
Reference: Ketoconazole Cream 2% (G&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) 
Placebo: Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) 
 
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
                                                                                                        Protocol / Study No. 71875502 
 
02/28/2019 
                                                              Encube Ethicals Pvt Ltd                                                          Page 49 of 57 
L16.2.4.2 Listing of Medical History 
Treatment 
Group 
Patient 
Screening 
Number 
Patient 
Randomization 
Number 
System 
Diagnosis or 
Surgical 
Procedure 
Start Date 
End Date 
Ongoing 
Number of Tinea 
Pedis infections in the 
past 12 months 
Test  
xx-xxx 
xxxx 
Gynecologic 
Menopause 
--/--/2012 
mm/dd/yyyy 
 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reference  
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) 
Reference: Ketoconazole Cream 2% (G&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) 
Placebo: Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) 
 
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
                                                                                                        Protocol / Study No. 71875502 
 
02/28/2019 
                                                              Encube Ethicals Pvt Ltd                                                          Page 50 of 57 
L16.2.4.3 Listing of Prior and Concomitant Medication 
Treatment 
Group 
Patient 
Screening 
Number 
Patient 
Randomization 
Number 
Treatment 
Area 
Medication Dosage/Unit 
Frequency* Route 
Start/End 
Date/ Ongoing Indication 
 
Prior? 
Test  
xx-xxx 
xxxx 
No 
Lisinopril 
20 MG 
QD 
PO 
--/--/2017/ 
08/12/2017 
Hypertension 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reference  
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) 
 Reference: Ketoconazole Cream 2% (G&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) 
 Placebo: Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) 
*PRN - As needed; QD – Daily (once per day); Q4H - Every 4 hours; Q8H - Every 8 hours; Q12H - 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 
 
 
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
                                                                                                        Protocol / Study No. 71875502 
 
02/28/2019 
                                                              Encube Ethicals Pvt Ltd                                                          Page 51 of 57 
L16.2.5 Listing of Drug Administration 
Treatment 
Group 
Patient 
Screening 
Number 
Patient 
Randomization 
Number 
Date of 
First Dose 
Date of 
Last Dose 
Total Doses 
Applied 
 
Missed 
 Doses 
Treatment 
Compliance 
 
Test  
xx-xxx 
xxxx 
mm/dd/yyyy 
mm/dd/yyyy 
xx 
xx 
Yes 
 
 
 
 
 
 
 
 
Reference 
Placebo  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) 
Reference: Ketoconazole Cream 2% (G&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) 
Placebo: Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) 
 
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
                                                                                                        Protocol / Study No. 71875502 
 
02/28/2019 
                                                              Encube Ethicals Pvt Ltd                                                          Page 52 of 57 
L16.2.6.1 Listing of Local Signs and Symptoms  
Treatment 
Group 
Patient 
Screening 
Number 
 
Patient 
Randomi
-zation 
Number 
Visit Evaluator 
 
Erythema  
 
 
Scaling  
 
 
 
Pruritus  
 
 
Fissuring/ 
Cracking 
 
Maceration  
 
 
Burning/ 
stinging  
 
Total 
Severity 
Score 
 
Clinical 
Cure/ 
Failure 
Test 
xx-xxx 
xxxx 
1 
xxx 
0 
0 
0 
1 
0 
0 
1 
 
 
 
2 
xxx 
0 
0 
0 
1 
0 
0 
1 
 
 
 
3 
xxx 
0 
0 
0 
1 
0 
0 
1 
Cure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reference 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) 
Reference: Ketoconazole Cream 2% (G&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) 
Placebo: Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) 
 
 
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
                                                                                                        Protocol / Study No. 71875502 
 
02/28/2019 
                                                              Encube Ethicals Pvt Ltd                                                          Page 53 of 57 
L16.2.6.2 Listing of Mycological Culture and KOH Wet Mount Results 
Treatment 
Group 
Patient 
Screening 
Number 
 
Patient 
Randomization 
Number 
Visit Mycological  
Culture 
KOH  
Wet Mount 
Mycological 
Cure/Failure 
Therapeutic 
Cure/Failure 
Test 
xx-xxx 
xxxx 
1 
T. rubrum/E. floccosum 
Positive 
 
 
 
 
 
2 
T. rubrum/E. floccosum 
Negative  
 
 
 
 
 
3 
Negative 
Negative  
Cure 
Cure 
 
 
 
 
 
 
 
 
 
 
xx-xxxx 
1 
T. rubrum 
Positive 
 
 
 
 
 
2 
T. rubrum 
Negative  
 
 
 
 
 
3 
T. rubrum 
Negative  
Failure 
Failure 
 
 
 
 
 
 
 
 
Reference 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) 
Reference: Ketoconazole Cream 2% (G&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) 
Placebo: Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) 
 
 
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NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
                                                                                                        Protocol / Study No. 71875502 
 
02/28/2019 
                                                              Encube Ethicals Pvt Ltd                                                          Page 54 of 57 
L16.2.7.1 Listing of Treatment Emergent Adverse Events by Treatment 
Treatment 
Group 
Patient 
Screening 
Number 
 
Patient 
Randomi-
zation 
Number 
Body System / 
MedDRA Term / 
AE Term 
Treatment 
Area 
Start /End 
 Date/ 
Ongoing 
Severity 
Relationship 
to Study 
Drug 
Outcome 
Action Taken/ 
Other Action 
Taken 
SAE 
Test  
xx-xxx 
 
 
 
xxxx 
Nervous system disorders / 
Headache / 
Headache 
No 
mm/dd/yyyy / 
mm/dd/yyyy 
Mild 
Related  
 
Recovered Dose Not 
Changed/ 
None 
No 
 
 
 
 
 
 
 
 
 
 
 
Reference  
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) 
Reference: Ketoconazole Cream 2% (G&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) 
Placebo: Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) 
 
 
PROGRAM: L:\DEV\755\71875502\SAS\PGM\XXXX 
OUTPUT: L:\DEV\755\71875502\SAS\OUT\XXXX 
Created on: ddmmmyy hh:mm 
Page 1 of N 
 
 


NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
                                                                                                        Protocol / Study No. 71875502 
 
02/28/2019 
                                                              Encube Ethicals Pvt Ltd                                                          Page 55 of 57 
L16.2.7.2 Listing of Pre-treatment Adverse Events 
Patient 
Screening 
Number 
 
Patient 
Randomi-
zation 
Number 
Body System / 
MedDRA Term / 
AE Term 
Treatment 
Area 
Start /End 
 Date/ 
Ongoing 
Severity 
Relationship 
to Study 
Drug 
Outcome 
Action Taken/ 
Other Action 
Taken 
SAE 
xx-xxx 
 
 
 
xxxx 
Nervous system disorders / 
Headache / 
Headache 
No 
mm/dd/yyyy / 
mm/dd/yyyy 
Mild 
Related  
 
Recovered Dose Not 
Changed/ 
None 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PROGRAM: L:\DEV\755\71875502\SAS\PGM\XXXX 
OUTPUT: L:\DEV\755\71875502\SAS\OUT\XXXX 
Created on: ddmmmyy hh:mm 
Page 1 of N 


NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
                                                                                                        Protocol / Study No. 71875502 
 
02/28/2019 
                                                              Encube Ethicals Pvt Ltd                                                          Page 56 of 57 
L16.2.8.1 Listing of Pregnancy Test Results 
Treatment 
Group 
Patient 
Screening 
Number 
 
Patient 
Randomization 
Number 
Visit 1 
Visit 2 
Visit 3 /  
Early Termination 
Test  
xx-xxx 
xxxx 
Negative 
Negative 
Negative 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reference  
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) 
Reference: Ketoconazole Cream 2% (G&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) 
Placebo: Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) 
 
 
PROGRAM: L:\DEV\755\71875502\SAS\PGM\XXXX 
OUTPUT: L:\DEV\755\71875502\SAS\OUT\XXXX 
Created on: ddmmmyy hh:mm 
Page 1 of N 
 
 


NOVUM PHARMACEUTICAL RESEARCH SERVICES 
STATISTICAL ANALYSIS PLAN 
 
Ketoconazole Cream 2% 
 
                                                                                                        Protocol / Study No. 71875502 
 
02/28/2019 
                                                              Encube Ethicals Pvt Ltd                                                          Page 57 of 57 
L16.2.8.2 Listing of Vital Signs 
Treatment 
Group 
Patient 
Screening 
Number 
 
Patient 
Randomization 
Number 
Visit 
Systolic BP 
 (mmHg) 
Diastolic BP 
 (mmHg) 
Pulse Rate 
(beats/min) 
Respiration 
Rate 
(breaths/min) 
Temperature 
(F) 
Test  
xx-xxx 
xxxx 
Visit 1 
120 
70 
84 
18 
98.6 
 
 
 
Visit 2 
140 
100 
74 
18 
97.0 
 
 
 
Visit 3 
140 
100 
74 
18 
97.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reference 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) 
Reference: Ketoconazole Cream 2% (G&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) 
Placebo: Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) 
 
PROGRAM: L:\DEV\755\71875502\SAS\PGM\XXXX 
OUTPUT: L:\DEV\755\71875502\SAS\OUT\XXXX 
Created on: ddmmmyy hh:mm 
Page 1 of N