Clinical trial NCT05550337
Conditions: Acne Vulgaris
Sponsor: Teva Pharmaceuticals USA
Start date: 2022-09-19; Completion date: 2023-05-09
Enrollment: 807 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To compare the safety and efficacy of the test (Trifarotene 0.005% cream), placebo (vehicle cream) and reference AKLIEF® (Trifarotene 0.005% cream) treatments to demonstrate clinical equivalence in subjects with acne vulgaris.

Detailed description:
To compare the safety of Test, Reference, and Placebo treatments in patients with acne vulgaris. Subjects in this randomized, double-blind, three-arm, placebo controlled, parallel-design, multi-site study will be randomly assigned in a 1:1:1 ratio to treatment with the test product, reference product or placebo control, respectively.

Arms: arm 1: Trifarotene Cream, 0.005%, Apply to the affected areas of the face once daily for 84 days. arm 2: AKLIEF® (Trifarotene Cream, 0.005%), Apply to the affected areas of the face once daily for 84 days. arm 3: Vehicle of the Test Product, Cream, Apply to the affected areas of the face once daily for 84 days.
Interventions: intervention 1: Trifarotene 0.005 % Topical Cream intervention 2: AKLIEF® intervention 3: Placebo
Intervention descriptions: intervention 1: Cream intervention 2: Cream intervention 3: Cream

Protocol documents:
Prot_000.pdf: 
 
  
 
 
 
 
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Protocol: TRIF-2101 
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PROTOCOL TITLE
A MULTI-CENTER, DOUBLE-BLIND, RANDOMIZED, THREE-ARM, PLACEBO 
CONTROLLED, PARALLEL-DESIGN GROUP STUDY TO EVALUATE THE 
THERAPEUTIC EQUIVALENCE COMPARING TRIFAROTENE CREAM, 0.005% (TEVA 
PHARMACEUTICALS, INC. TO AKLIEF ® (TRIFAROTENE 0.005% CREAM) 
(GALDERMA LABORATORIES, L.P., USA),  IN THE TREATMENT OF ACNE 
VULGARIS 
 
CLINICAL STUDY PROTOCOL 
 
Protocol Number:  TRIF-2101 
Protocol Version Number: 2.0 
Protocol Version Date: 30JUNE2022 
Study Sponsor:  Teva Pharmaceuticals, Inc. 
 
PROTOCOL APPROVAL 
 
I am aware of, and agree to comply with, all of the procedures contained within this protocol and 
requirements of applicable regulatory agencies: 
 
Sponsor Representative 
 
Nageshwar R. Thudi Ph.D.  
Vice President, Global Gx. and 
Biosimilar - Clinical Development & 
Operations 
Teva Pharmaceuticals, Inc.  
 
Signature/Date 
 
Sponsor Representative 
 
Corrine Dias  
Associate Director, Global Gx.  - 
Signature/Date 
 
 


  
 
 
 
 
 
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Clinical Development & Operations 
Teva Pharmaceuticals, Inc. 
Medical Monitor 
 
Angelo Secci, MD 
Catawba Research 
Signature/Date 
Statistical Consultant  
 
Charles Bon 
President Biostudy Solutions, LLC 
Signature/Date 
CRO Representative 
 
Chris Driskill 
Clinical Project Manager 
Catawba Research 
Signature/Date 
 
 
Chris 
Driskill
Digitally signed by 
Chris Driskill 
Date: 2022.07.20 
12:31:52 -04'00'
Angelo 
Secci
Digitally signed by 
Angelo Secci 
Date: 2022.07.20 
14:35:22 -04'00'
Charles Bon
Digitally signed by Charles 
Bon 
Date: 2022.07.20 16:34:11 
-04'00'


  
 
 
 
 
 
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CONTACT LIST 
Sponsor: 
Teva Pharmaceuticals, Inc.  
400 Interpace Parkway, Bldg. A, Parsippany NJ 
07054, USA 
 
Contract Research Organization: 
 
Chris Driskill 
Clinical Project Manager  
Catawba Research,  
5200 77 Center Drive, Suite 120  
Charlotte, NC 28217  
Office: Cell: 704-502-3007  
Fax: 980-422-0783  
Email: chris@catawbaresearch.com  
 
Statistics Data Management and Medical 
Writing: 
 
Soumitra Chowdhury 
Executive Vice-President, Data and Analytics 
Veranex 
3 Independence Way, Suite 106 
Princeton, NJ  08540 
Phone: (609) 454-3312 Ext.103 
Cell: (609) 902-9060 
Email: 
soumitra.chowdhury@veranexsolutions.com 
 
IWRS Vendor: 
 
Uma Janapareddy 
Founder & MD 
SyMetric 
No. 51, 1st Floor 
Kodihalli Main Road 
HAL 2nd Stage 
Bengaluru – 560 008, India 
Phone: +91-80-41135402 
Email: uma@symetricsystems.com 
 
Medical Monitor: 
 
Angelo Secci, MD 
7916 Flip Flop Lane, Wilmington, NC 
28409 
Phone: (484) 844-5776 
Email: ASecci@CatawbaResearch.com 
 
Drug Labeling, Packaging and 
Shipping Facility: 
 
Denis Bartle 
Associate Director, Warehouse (R&D) 
Actavis Laboratories UT, Inc. 
577 Chipeta Way 
Salt Lake City, UT 84108, USA 
Phone: 801-588-6355 
Fax: 801-588-6658 
Email: Denis.Bartle@actavis.com 
 
Retention Samples Storage Facility: 
 
Glenn Bullett 
BioRepository Resources, LLC 
755 Central Avenue, Unit 3 
New Providence, NJ 07974 
Phone: (908) 790-8890 
Fax: (908) 790-8899 
www.brr.us.com 
Email: gbullett@brr.us.com  
 
Independent Statistical Consultant: 
 
Charles Bon 
President 
Biostudy Solutions, LLC 
4008 Caesar Court,  
Wilmington, NC 28405-6444 
Phone:  (910) 352-5648 
Fax: (866) 830-3720 
Email: chuck@biostudysolutions.com  


  
 
 
 
 
 
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Institutional Review Board (IRB): 
 
Salus IRB 
2111 West Braker Lane, Suite 100 
Austin, TX 78758 
Phone: 512.380.1244  
Fax: 512.382.8902 
 
 
 


  
 
 
 
 
 
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PRINCIPAL INVESTIGATOR AGREEMENT 
 
I have carefully read and understand the foregoing protocol A MULTI-CENTER, DOUBLE-
BLIND, RANDOMIZED, THREE-ARM, PLACEBO CONTROLLED, PARALLEL-DESIGN 
GROUP STUDY, TO EVALUATE THE THERAPEUTIC EQUIVALENCE COMPARING 
TRIFAROTENE CREAM, 0.005% (TEVA PHARMACEUTICALS, INC.) TO AKLIEF® 
(TRIFAROTENE 0.005% CREAM) (GALDERMA LABORATORIES, L.P., USA) IN THE 
TREATMENT OF ACNE VULGARIS and agree it contains all the necessary information for 
conducting this study safely. I will conduct this study in strict accordance with this protocol, ICH 
guidelines for Good Clinical Practice (GCP), the Code of Federal Regulations, local regulatory 
and ethical guidelines. I will attempt to complete the study within the time designated. 
I will ensure the rights, safety and welfare, of subjects under my care are protected. I will ensure 
control of the drugs under investigation in this study. 
I will provide access to the protocol and all other study-related information supplied by the 
Sponsor to all personnel who participate in the study. I will discuss this information with them to 
assure that they are adequately informed regarding the drug and conduct of the study. 
I agree to keep records on all Subject information (case report forms, shipment and drug return 
forms and all other information collected during the study) and drug disposition in accordance 
with FDA regulations. I agree to retain and maintain strict accountability of the Investigational 
Medicinal Products supplied to the study site. 
I will not enroll any subjects into this study, until IRB/IEC (Independent Review 
Board/Institutional Ethics Committee) approval and Sponsor’s approval are obtained for 
protocol. 
 
____________________ 
__________________ 
Principal Investigator 
Signature/Date 
 


  
 
 
 
 
 
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TABLE OF CONTENTS 


PROTOCOL TITLE .............................................................................................................................. 1
PROTOCOL APPROVAL .................................................................................................................... 1
CONTACT LIST ................................................................................................................................... 3
PRINCIPAL INVESTIGATOR AGREEMENT .................................................................................. 5
TABLE OF CONTENTS ...................................................................................................................... 6
LIST OF ABBREVIATIONS ............................................................................................................. 10
STUDY SYNOPSIS ............................................................................................................................ 12
1
INTRODUCTION AND BACKGROUND ............................................................................... 23
2
STUDY OBJECTIVES .............................................................................................................. 23
3
Study Overview .......................................................................................................................... 24
4
Study Visit Schedule .................................................................................................................. 27
5
STUDY POPULATION ............................................................................................................. 28
5.1Number of Subjects .................................................................................................................... 28
5.1.1Inclusion Criteria .................................................................................................................28
5.1.2Exclusion Criteria ................................................................................................................31
5.1.3Prohibited Medications, Procedures, and Activities ...........................................................34
5.1.4Precautions ..........................................................................................................................40
5.1.5Subject Disposition and Discontinuation ............................................................................41
6
SAFETY AND TOLERABILITY EVALUATIONS ................................................................ 42
6.1General Safety Evaluations ........................................................................................................ 43
6.1.1Physical Examination ..........................................................................................................43
6.1.2Vital Signs ...........................................................................................................................44
6.1.3Pregnancy Test ....................................................................................................................44
6.2Concomitant Medications ........................................................................................................... 45
6.3Evaluation of Signs/Symptoms of Local Irritation/Application Site Reactions ......................... 45
6.4Adverse Events ........................................................................................................................... 46
6.5COVID-19 symptom screening .................................................................................................. 47


  
 
 
 
 
 
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6.6Lack of Treatment Effect (LOTE) .............................................................................................. 47
7
CLINICAL EVALUATIONS .................................................................................................... 47
7.1Investigator’s Global Assessment (IGA) ................................................................................... 48
7.2Lesion Counts ............................................................................................................................. 48
8
STUDY VISITS (See Study Visit Schedule) ............................................................................. 49
8.1Visit 1: Screening and Baseline (Day 0) .................................................................................... 49
8.2Visit 2: First Interim (Week 4; Day 28 ± 4 Days) ...................................................................... 52
8.3Visit 3: Second Interim (Week 8; Day 56 ± 4 Days) ................................................................. 53
8.4Visit 4: End of Treatment (Week 12; Day 84 ± 4 Days) ............................................................ 54
8.5Unscheduled Visits and Early Discontinuation Visit ................................................................. 55
8.6Premature Termination of Study/Study Site .............................................................................. 55
8.7Early Termination of a Subject .................................................................................................. 56
9
STUDY TREATMENT, DESCRIPTION AND ALLOCATION ............................................. 56
9.1Investigational Medicinal Products (IMP) Description .............................................................. 56
9.2Storage and Handling Conditions ............................................................................................... 57
9.2.1Packaging, Blinding and Labeling ......................................................................................57
9.2.2Randomization .....................................................................................................................58
9.2.3Subject Screening Number ..................................................................................................59
9.3Treatment Assignment ............................................................................................................... 59
9.4Administration of Investigational Medicinal Product ................................................................ 59
9.5Assessment of Compliance ........................................................................................................ 59
9.6Investigational Medicinal Product Accountability ..................................................................... 60
9.7Retention of Study Drug Samples .............................................................................................. 61
9.8Return of Clinical Supplies ........................................................................................................ 62
9.9Additional Supplies Provided by The Sponsor .......................................................................... 62
10
STATISTICAL METHODS ...................................................................................................... 63
10.1
Scientific and Statistical Considerations of the Study Design .............................................. 63
10.1.1
Sample Size Rationale ..................................................................................................63
10.1.2
Unblinding Procedures .................................................................................................64
10.1.3
Significance Level ........................................................................................................65


  
 
 
 
 
 
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10.2
Datasets to be Analyzed ........................................................................................................ 65
10.3
Measures ............................................................................................................................... 66
10.3.1
Demographics and Screening/Baseline/Randomization Characteristics ......................66
10.3.2
Safety Assessment ........................................................................................................66
10.3.3
Efficacy Assessment .....................................................................................................66
10.4
Concomitant Medication ...................................................................................................... 67
10.5
Summary of Subjects who discontinued prematurely .......................................................... 68
11
ADVERSE EVENTS ................................................................................................................. 68
11.1
Recording of Adverse Events ............................................................................................... 68
11.1.1
Assessment of Severity ................................................................................................70
11.1.2
Relationship to Study Medication ................................................................................70
11.2
Serious Adverse Events ........................................................................................................ 71
11.2.1
Expectedness ................................................................................................................72
11.3
Reporting of Serious Adverse Events (SAEs) ...................................................................... 72
11.4
Pregnancy ............................................................................................................................. 75
11.5
Follow Up of Subjects .......................................................................................................... 76
11.6
Medication Errors and Special Situations ............................................................................. 77
11.7
Reconciliation of SAEs & Pregnancy ................................................................................... 77
11.8
Safety Considerations during COVID-19 Pandemic ............................................................ 77
12
ETHICS ...................................................................................................................................... 78
12.1
IRB/Ethics Committee .......................................................................................................... 78
12.2
Ethical Conduct of the Study ................................................................................................ 78
12.3
Informed Consent/Assent ..................................................................................................... 79
12.4
Subject Confidentiality ......................................................................................................... 80
13
DOCUMENTATION ................................................................................................................. 80
13.1
Site Regulatory Documents Required for Initiation ............................................................. 80
13.2
Maintenance and Retention of Records ................................................................................ 80
13.3
Data Collection and Reporting ............................................................................................. 81
13.4
Primary Source Documents .................................................................................................. 82
13.5
Study Monitoring .................................................................................................................. 83


  
 
 
 
 
 
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13.6
Audits and Inspections .......................................................................................................... 83
13.7
Modifications to the Protocol ............................................................................................... 83
14
Completion of Study .................................................................................................................. 84
15
REFERENCES ........................................................................................................................... 84
15.1
APPENDIX I: Revision History ........................................................................................... 86
15.2
APPENDIX II: AKLIEF-trifarotene cream package insert .................................................. 87
 


 
  
 
 
 
 
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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
BA 
Bioavailability 
BE 
Bioequivalence 
CDSCO 
Central Drugs Standard Control Organization 
CFR 
Code of Federal Regulations 
COVID 19 
Coronavirus Disease 2019 
CRO 
Contract Research Organization/Clinical Research Organization  
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
hCG 
Human Chorionic Gonadotropin 
HEENT 
Head, Eyes, Ears, Nose and Throat 
HIPAA 
Health Insurance Portability and Accountability Act 
IAF 
ICF 
Informed Assent Form 
Informed Consent Form 
IGA 
Investigator’s Global Assessment 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
LOCF  
Last Observation Carried Forward 
LOTE 
Lack of Treatment Effect 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent to Treat 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
OTC 
Over the Counter 
PP 
Per Protocol 
RLD 
SMMP 
Reference Listed Drug 
Safety and Medical Monitoring Plan 
SAE 
Serious Adverse Event 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 (COVID) 
SAP 
Statistical Analysis Plan 
SOP 
Standard Operating Procedure 
U.S. 
United States 


  
 
 
 
 
 
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STUDY SYNOPSIS 
Protocol Number: TRIF-2101 
 
Version and Date of Protocol: Final Version 1.0, Dated 11-MAY-2022 
 
Title of Study:  
A MULTI-CENTER, DOUBLE-BLIND, RANDOMIZED, THREE-ARM, 
PLACEBO CONTROLLED, PARALLEL-DESIGN GROUP STUDY TO 
EVALUATE THE THERAPEUTIC EQUIVALENCE COMPARING 
TRIFAROTENE CREAM, 0.005% (TEVA PHARMACEUTICALS, INC.) 
TO AKLIEF ® (TRIFAROTENE 0.005% CREAM) (GALDERMA 
LABORATORIES, L.P., USA) IN THE TREATMENT OF ACNE 
VULGARIS 
 
Sponsor: 
Teva Pharmaceuticals, Inc.  
 
  
400 Interpace Parkway, Bldg. A, 
 
  
Parsippany NJ 07054, USA 
 
Clinical Research Organization:  Catawba Research  
 
  
 
 
    
5200 77 Center Drive Suite 120 
 
  
 
 
   
Charlotte, NC 28217 USA 
 
Treatment Duration: The study treatment period will last for 84 days (12 weeks). A window 
period of ± 4 days will be considered acceptable for each scheduled visit 
following the screening/baseline visit. 
 
Test Product:  
TRIFAROTENE CREAM, 0.005% (MANUFACTURED BY ACTAVIS 
LABORATORIES 
SALT 
LAKE 
CITY, 
UTAH 
FOR 
TEVA 
PHARMACEUTICALS, INC.) 
 
Reference Listed Product: AKLIEF® (TRIFAROTENE 0.005% CREAM) (GALDERMA 
LABORATORIES, L.P., USA)  
 
Placebo Control:  Vehicle cream (MANUFACTURED BY ACTAVIS SALT LAKE CITY, 
UTAH FOR TEVA PHARMACEUTICALS, INC.)  
 
Study Phase: Bioequivalence (BE) study with clinical endpoint  
 
Study Site(s): This study will be conducted at multiple centers in the USA and in Belize. 
 
Dose and Mode  


  
 
 
 
 
 
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of Administration:  Subjects will be instructed to apply enough investigational drug product to 
lightly cover the entire affected areas of the face once daily at bedtime for 84 
days +/-4 days. 
 
Objectives:  
To evaluate the clinical therapeutic equivalence of TRIFAROTENE 
CREAM, 0.005% (and the Reference Listed Product, AKLIEF® 
(TRIFAROTENE 0.005% CREAM) (GALDERMA LABORATORIES, 
L.P., USA) in the treatment of acne vulgaris. 
 
 
To demonstrate the superiority of the efficacy of the test and reference 
products over that of the placebo control in the treatment of acne vulgaris.  
 
Design:  
To compare the safety of Test, Reference, and Placebo treatments in patients 
with acne vulgaris. 
 
Subjects in this randomized, double-blind, three-arm, placebo controlled, 
parallel-design, multi-site study will be randomly assigned in a 1:1:1 ratio to 
treatment with the test product, reference product or placebo control, 
respectively.  
 
Clinical Evaluations will be performed at: 
Visit 1: Screening/Baseline Visit (Day 0;  
Visit 2: First Interim Visit (Week 4 / Day 28 ± 4 Days);  
Visit 3: Second Interim Visit (Week 8 / Day 56 ± 4 Days);  
Visit 4: End of Treatment Visit (Week 12 / Day 84 ± 4 Days) 
 
Subjects will be admitted into the study after informed consent/assent has 
been obtained, a medical history and physical examination (with vital signs) 
have been performed and inclusion/exclusion criteria have been met. Subjects 
must have a clinical diagnosis of acne vulgaris to qualify for inclusion in this 
study. 
Each Subject will be randomly assigned in a double-blind fashion in a 1:1:1 
ratio to treatment with either the test product, the reference product or the 
placebo control. 
The treatment area of enrolled subjects will be assessed at all clinic visits, 
including counts of the facial comedones (open and closed), papules, 
pustules, nodulocystic lesions (nodules and cysts), the Investigator’s Global 
Assessment (IGA) and the signs and symptoms of irritation (application site 
reaction) will be assessed. 
Safety will be assessed by the monitoring of all adverse events, application 
site reaction assessments; urine pregnancy test (for females of childbearing 
potential) and physical examinations including vital signs.  


  
 
 
 
 
 
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Unscheduled Visits are allowed at any time, for any reason, if in the Principal 
Investigator’s opinion, it is warranted. If the Unscheduled Visit is due to an 
adverse event (AE), the Principal Investigator will determine whether 
additional visits are needed. If a Subject is discontinued from the study during 
an Unscheduled Visit, the Unscheduled Visit will be referred to as an Early 
Discontinuation Visit and all procedures scheduled for the Early 
Discontinuation Visit will be performed.  
 
 
Study Population:  
 
 
Inclusion Criteria 
1) Male or non-pregnant, non-lactating female aged  12 and  40 years with a clinical 
diagnosis of acne vulgaris. 
2) Subjects who are 18 years of age or older (up to the age of 40) must have provided IRB/IEC 
approved written informed consent. Subjects 12 to 17 years of age inclusive must have 
provided IRB/IEC approved written assent; this written assent must be accompanied by an 
IRB/IEC approved written informed consent from the Subject’s legally acceptable 
representative (i.e., parent or guardian). In addition, all Subjects or their legally acceptable 
representatives (i.e., parent or guardian) must sign a HIPAA authorization. 
3) Subjects must have  25 non-inflammatory lesions (i.e., open and closed comedones) AND  
20 inflammatory lesions (i.e., papules and pustules) AND  2 nodulocystic lesions (i.e., 
nodules and cysts), at screening/baseline on the face.  
(a) For the purposes of study treatment and evaluation, these lesions should be 
limited to the facial treatment area. All lesions will be counted, including 
those present on the nose. Subjects may have acne lesions on other areas of 
the body which will be excluded from the count and the Investigator’s Global 
Assessment (IGA) evaluation (e.g., on the back, chest and arms). 
4) Subjects must have a definite clinical diagnosis of acne vulgaris severity grade 2, 3, or 4 as 
per the Investigator’s Global Assessment (IGA) (per Table 1 below) at screening/baseline.  
Acne vulgaris should be stable (for at least 3 months prior to screening), with minimal 
variation from day to day and within each day, in the opinion of the subject. 
 
Table 1: Investigator’s Global Assessment (IGA) Scale for Acne Vulgaris 
Grade 
Description 
0 
Clear skin with no inflammatory or non-inflammatory lesions 
1 
Almost clear; rare non-inflammatory lesions with no more 
than one small inflammatory lesion 


  
 
 
 
 
 
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2 
Mild severity; greater than Grade 1; some non-inflammatory 
lesions with no more than a few inflammatory lesions 
(papules/pustules only, no nodular lesions) 
3 
Moderate severity; greater than Grade 2; up to many non-
inflammatory lesions and may have some inflammatory 
lesions, but no more than one small nodular lesion 
4* 
Severe; greater than Grade 3; up to many non-inflammatory 
lesions and may have some inflammatory lesions, but no more 
than a few nodular lesions 
* The eCRF will allow for reporting by Investigators of lesion worsening beyond Grade 4 with 
treatment. Acne vulgaris subjects with nodulocystic acne are not to be enrolled in the study. 
Subjects who worsen beyond Grade 4 will be described in the safety evaluation. 
Note: Counts of nodules and cysts will be reported separately and not included in the 
inflammatory or non-inflammatory lesion counts. 
5) Subjects must be willing to refrain from using all other topical acne medications or 
antibiotics during the 12-week treatment period, other than the investigational product. 
6) Female subjects of childbearing potential (*WOCBP) must not be pregnant or lactating at the 
time of screening/baseline visit as documented by a negative urine pregnancy test with a 
sensitivity to at least 25 mIU/ml hCG . 
*Female subjects of childbearing potential (WOCBP) are defined as sexually mature women 
without prior hysterectomy, or who have had any evidence of menses in the past 12 months. 
However, women who have been amenorrheic for the past 12 or more months are still 
considered to be of childbearing potential, if the amenorrhea is possibly due to other causes, 
including prior chemotherapy, anti- estrogens, or ovarian suppression. Postmenopausal women 
(defined as women who have been amenorrheic for at least 12 consecutive months, in the 
appropriate age group, without other known or suspected primary cause) or women who have 
been sterilized surgically or who are otherwise proven sterile (i.e., total hysterectomy, or 
bilateral oophorectomy with surgery at least 4 weeks prior to randomization) are not considered 
WOCBP. Subjects who have undergone tubal ligation are NOT considered as surgically sterile. 
7)  Female subjects of childbearing potential must be willing to use an acceptable form of birth 
control during the study from the day of the first dose administration to 30 days after the last 
administration of study drug.     
a) For the purposes of this study the following are considered acceptable methods of birth 
control: oral or injectable contraceptives, contraceptive patches, medroxyprogesterone 
acetate (ex. Depo-Provera®) with stabilized use for at least 3 months, vaginal 
contraceptive (ex. etonogestrel/ethinyl estradiol vaginal ring (ex. NuvaRing®), 
contraceptive implant with etonogestrel or equivalent, double barrier methods, (e.g. 
condom and spermicide), intrauterine device (IUD),  true abstinence (if in line with 
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b) If a subject who was abstinent becomes sexually active during the study, a 2nd acceptable 
method of birth control should be used and documented. 
c) Subjects on hormonal contraception must be stabilized on the same type for at least three 
months prior to enrollment in the study and must not change the method during the study. 
A sterile sexual partner is not considered an adequate form of birth control. 
8) Female subjects who are premenarchal, surgically sterilized (by *hysterectomy or bilateral 
oophorectomy) or postmenopausal for at least 1 year (defined as women who have been 
amenorrheic for at least 12 consecutive months, without other known or suspected primary 
cause).  
9) All male subjects must agree to use accepted methods of birth control with their partners, from 
the day of the first dose administration to 30 days after the last administration of study drug. 
True abstinence is an acceptable method of birth control if in line with subject’s lifestyle.  
Female partners should use an acceptable method of birth control as described in the above 
criteria 7.  
10) Subjects must be willing and able to understand and comply with the requirements of the 
protocol, including attendance at all required study visits and refraining from the use of all 
other topical acne medications or antibiotics during the 12-week treatment period. 
11)  Subjects must be in good health and free from any clinically significant disease, which may 
interfere with the evaluation of acne vulgaris or the administration of the investigative product.  
12) Subjects who use make-up must have used the same brands/types of make-up for a minimum 
period of 14 days prior to study entry and must agree to not change make-up brand/type or 
frequency of use throughout the study. 
 
Exclusion Criteria 
1) Female subjects who are pregnant, lactating or planning to become pregnant during study 
participation.  
2) Subjects with a history of hypersensitivity or allergy to trifarotene, tretinoin, retinoids, or any 
of the study medication ingredients. 
3) Subjects with the presence of any skin condition that would interfere with the diagnosis or 
assessment of acne vulgaris (such conditions include but are not limited to the following on 
the face: rosacea, dermatitis, psoriasis, squamous cell carcinoma, eczema, acneiform eruptions 
caused by medications, steroid or corticosteroid-induced acne, steroid folliculitis, or bacterial 
folliculitis, auto-immune disease, perioral dermatitis, carcinoid syndrome, mastocytosis, 
acneiform eruptions caused by make-up and medication, facial psoriasis and facial eczema). 
4) Subjects with nodulocystic acne (> 2 nodules and cysts). [Nodules or cysts defined as; deep-
seated in the skin (i.e., centered in the dermis or subcutis) and an inflammatory lesion greater 
than or equal to 5 mm in diameter], acne conglobata, acne fulminans, secondary acne 
(chloracne, drug-induced acne, etc.) or acne vulgaris requiring systemic treatment. 


  
 
 
 
 
 
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5) Subjects with excessive facial hair (e.g., beards, sideburns, moustaches, etc.) that would 
interfere with diagnosis or assessment of acne vulgaris.  
6) Subjects with tattoos or excessive facial scarring that, in the Investigator’s opinion, may 
interfere with the evaluation of the patient’s acne. 
7) Subjects who have used within 6 months prior to screening/baseline oral retinoids (e.g., 
Accutane®) or therapeutic vitamin A supplements of greater than 10,000 units/day 
(multivitamins are allowed). These treatments with oral retinoids or Vitamin A supplements 
are prohibited during the study participation. 
8) Subjects who have used within 1 month prior to screening/baseline neuromuscular blocking 
agents or androgen receptor blockers (e.g., spironolactone, Flutamide etc.). 
9) Subjects who have had laser therapy, electrodessication phototherapy and or cosmetic 
procedures (e.g., ClearLight ® BOTOX, Filler, micro needling) to the facial area within 6 
months prior to study entry. 
10) Subjects who have had facial cosmetic procedures (e.g., facials) or application of cosmetic 
products (cosmetics, makeup or facial products that have a strong drying or possible 
interactive effect, particularly preparations containing spices, lime sulfur, resorcinol, or 
salicylic acid with tretinoin or other retinoids) which may affect the efficacy and safety 
profile of the investigational product within 2 weeks prior to study entry. 
11) Subjects who have received radiation therapy and/or anti-neoplastic agents within 3 months 
prior to screening/baseline. 
12) Subjects who have used for less than (<) 3 months prior to screening/baseline estrogens or oral 
contraceptives; use of such therapy must remain constant throughout the study. 
13) Subjects who have used any of the following procedures on the face within 1 month prior to 
screening/baseline or use during the study: 
a) cryodestruction or chemodestruction,  
b) dermabrasion,  
c) photodynamic therapy,  
d) acne surgery,  
e) intralesional steroids, or  
f) X-ray therapy.  
14) Subjects who have used any of the following treatments within 1 month prior to 
screening/baseline or during the study: 
a) androgen receptor blockers (e.g., spironolactone, Flutamide etc.) 
b) systemic steroids,  
c) systemic antibiotics,  


  
 
 
 
 
 
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d) systemic treatment for acne vulgaris (other than oral retinoids, which require a 6-month 
washout),   
e) systemic anti-inflammatory agents. If Subject uses a systemic anti-inflammatory product 
during the study, the Principal Investigator will judge if this protocol deviation is 
clinically significant, 
f) have taken any drugs that lower the immune system. 
g) topical immunomodulators 
 
15) Subjects who have used any of the following treatments within 2 weeks prior to 
screening/baseline or during the study:  
a)    topical steroids,  
b) 
topical retinoids,  
c) 
topical acne treatments including over-the-counter preparations 
d) 
topical anti-inflammatory agents 
e) 
topical antibiotics 
f) 
abradants,  
g) 
peels containing glycolic or other acids,  
h) 
washes or soaps, containing glycolic acid,  
i) 
Alpha-hydroxy acids,  
j) 
sulfacetamide sodium,  
k) 
non-mild facial cleansers, moisturizers that contained retinol 
l) 
topical products that contain high amounts of alcohol 
m) 
wax depilation of the face 
n) 
Use of tanning booths 
o) 
The application of alcohol-based toners or any product with high concentrations of 
alcohol, astringents, medicated topical preparations (prescription and OTC products 
including those with spices or lime ingredients).  or medicated make-up, medicated or 
harsh soaps, medicated cleansers, and cosmetics that make subject skin dry to the face 
(products that have a strong drying effect, particularly preparations containing sulfur, 
resorcinol, or salicylic acid with tretinoin or other retinoids).  
16) Subjects who have on-going malignancies requiring systemic treatment or who have any 
malignancy of the skin of the facial area. 
17) Subjects with active facial sunburn or peeling from sunburn. 
18) Subjects who engage in activities that involve excessive or prolonged exposure to sunlight or 


  
 
 
 
 
 
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weather extremes, such as wind or cold.  Exposure to excessive UV radiation within 1 week 
prior to screening/baseline. 
19) Subjects who use a sauna within 48 hours prior to screening/baseline. 
20) Subjects who have unstable medical disorders that are clinically significant or have life-
threatening diseases, or other medical condition (i.e., chronic infectious disease, system 
disorder, organ disorder, cardiovascular, gastrointestinal, hematological, hepatic, neurological, 
pancreatic, renal disease, severe psychiatric condition, etc.) that, in the Investigator's opinion, 
would place the study Subject at undue risk by participation or could jeopardize the integrity 
of the study evaluations. 
21) Subjects who consume excessive amounts of alcohol (greater than two drinks per day) or use 
drugs of abuse (including, but not limited to, cannabinoids, cocaine and barbiturates) within 
one year prior to screening. 
22) Subjects, who in the opinion of the Investigator, would be non-compliant with the requirements 
of the study protocol.  
23) Subjects who are unable or unwilling to give informed consent.  
24) Subjects who are illiterate.  
25) Subjects who have participated in an investigational drug study (i.e., Subjects have been treated 
with an investigational drug) within 30 days prior to screening/baseline or where sufficient 
washout period has not been achieved; whichever time period is longer. Subjects who are 
participating in non-treatment studies such as observational studies or registry studies can be 
considered for inclusion. 
26) Subjects who have been previously enrolled in this study. 
27) Subjects who live in the same household with subjects who are participating or have been 
previously enrolled in this study. 
28) The subject is a member of the investigational study staff or a family member of the 
investigational study staff. 
29)   Subject having symptoms* of Coronavirus Disease 2019 (COVID-19) within the 10 days 
prior to screening/baseline/visit 1 or have had close contact with someone with suspected or 
confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection within 
10 days prior to screening/baseline/visit 1 or who are at high risk of SARS-CoV-2 infection, 
defined as adults whose locations or circumstances put them at appreciable risk of acquiring  
SARS-CoV-2 infections. 
*Stuffy or runny nose, sore throat, shortness of breath (difficulty breathing), cough, low 
energy or tiredness, muscle or body aches, headache, chills or shivering, feeling hot or 
feverish, vomiting, diarrhea, loss of sense of taste and smell. 
Number of Subjects:  
 


  
 
 
 
 
 
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Approximately 807 subjects will be enrolled into the study in a 1:1:1 ratio, to obtain 765 subjects 
in the mITT (255:255:255 Test: Reference: Placebo) and 627 in the PP subjects (209:209:209 
Test: Reference: Placebo) to the following study arms: 
x TRIFAROTENE CREAM, 0.005% (Teva Pharmaceuticals, Inc.) 
x AKLIEF® 
(TRIFAROTENE 
0.005% 
CREAM) 
(GALDERMA 
LABORATORIES, L.P., USA) 
x Vehicle cream (Teva Pharmaceuticals, Inc.)  
Criteria for Evaluation:   
Primary Endpoints: 
1) 
Mean percent change from screening/baseline to week 12 in the inflammatory 
(papules and pustules) lesion counts and; 
2) 
Mean percent change from screening/baseline to week 12 in the non-
inflammatory (open and closed comedones) lesion counts.  
* Counts of nodules and cysts will be reported separately and not included in the 
inflammatory or non-inflammatory lesion counts. 
 
Measures:  
 
a) At each visit, beginning at Visit 1, an Investigator will assess the overall status of the 
Subject’s facial acne vulgaris using the Investigator’s Global Assessment (IGA) and the 
inflammatory lesion counts 
b) Proportion of patients with a clinical response of “Clinical Success” using the 
Investigator’s Global Assessment (IGA) at Week 12. Success should be defined as an IGA 
score that is at least 2 grades less than the baseline assessment. Failure should be defined 
as an IGA score that is the same, higher or one grade lower than the baseline assessment. 
c) Local irritation reactions (Application site reactions) such as erythema, dryness, 
burning/stinging, erosion, edema, pain and itching will be recorded at each visit to allow a 
comparison between treatment groups.  
 
Statistical Methods:    
Analysis of Primary Endpoint 
The evaluation of the primary endpoint will be based on the mean percent change from 
screening/baseline to week 12 in the inflammatory (papules and pustules) lesion counts and in 
the non-inflammatory (open and closed comedones) lesion counts. 
Demonstration of Bioequivalence 
Bioequivalence will be established if the 90% confidence intervals of the test/reference ratio of 
the mean percent change from screening/baseline to week 12 in the inflammatory (papules and 


  
 
 
 
 
 
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pustules) lesion counts and in the non-inflammatory (comedones) lesion counts are contained 
within [0.80, 1.25] using the per protocol (PP) population.  
Demonstration of Superiority 
The test product and RLD will be compared to placebo group to test statistical superiority at 
p<0.05 (two-sided test) with regard to: 
1) mean percent change from screening/baseline to week 12 in the inflammatory lesion 
counts and 
 2) mean percent change from screening/baseline to week 12 in the non-inflammatory 
lesion counts,  
both using the modified intent-to-treat (mITT) study population and Last Observation Carried 
Forward (LOCF).  
x An active treatment will be considered to be superior to the placebo if the difference in 
the means for the two treatment groups are statistically significant (p<0.05) and the active 
treatment’s mean percent reduction from screening/baseline is greater than that for 
placebo. 
x Analysis of local irritation reactions (application site reactions). 
x A descriptive analysis comparing the local irritation reactions (application site 
reactions) for each treatment group will be conducted to ensure that the test product is 
similar to the reference product with regard to the expected and unexpected application 
site reactions. 
x Analysis of IGA scores:  
o Descriptive statistics using categorical methods to compare IGA Scores between 
each treatment group will be conducted and presented. No inferential analyses are 
planned.  
x Summary of Subjects who terminate prematurely. 
o Reasons for premature termination will be summarized by treatment group. 
x Concomitant medication. 
o The start and stop calendar date (e.g., mm/dd/yyyy) and study day (e.g., Day X) 
of concomitant medication used prior to and during the study will be provided in 
the data set in addition to the reason for the medication use. It should clearly be 
noted whether the medication was used prior to screening/baseline visit, during 
the study, or both. 
 
Safety Analyses 
Safety analyses will be conducted on the safety population. Safety Incidence of all adverse 


  
 
 
 
 
 
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events reported during the study will be summarized using the MedDRA dictionary by treatment 
group, body system, severity and relationship to study drug. 
The report of AEs will include relatedness to treatment, date of onset, description of the AE, 
severity, action taken, outcome and date of resolution. Formal statistical evaluation(s) of the 
comparability of the two active treatment groups will be conducted with regard to the frequency 
and severity of any AE that occurs in at least 5% of the subjects in either active treatment group.  
Application site reactions such as erythema, dryness, burning/stinging, erosion, edema, pain and 
itching will be summarized for the safety population by treatment group and study visit using 
frequencies and percentages of subjects.  


 
  
 
 
 
 
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1 INTRODUCTION AND BACKGROUND 
Acne vulgaris is a disorder of the pilosebaceous unit1. Found in greatest concentrations on the 
face, upper back, shoulders and chest, a pilosebaceous unit is made up of a hair follicle lined 
with keratinocytes, a sebaceous gland, and a hair. The sebaceous gland produces a substance 
called sebum. Although sebum normally empties onto the skin’s surface through the openings of 
the follicles, the follicles may become plugged with hair, sebum and keratinocytes, resulting in 
comedones. Bacteria normally found on the skin may grow in the comedones, resulting in 
inflammation. Therefore, acne vulgaris is a multi-factorial disease, caused by the interplay of 
excess sebaceous gland secretion, bacterial growth, keratinization abnormalities, and immune 
reactivity. 
Acne is clinically characterized by the formation of open and closed comedones (non-
inflammatory lesions), papules and pustules (inflammatory lesions) and nodulo-cystic lesions. 
The highest concentration of lesions is often found on the face, shoulders, upper back, and chest. 
Although acne vulgaris is most common in adolescents and young adults, it can continue to 
occur in adults older than 50 years of age. 
Although the exact mode of action of trifarotene is unknown, current evidence suggests that topical 
trifarotene decreases cohesiveness of follicular epithelial cells with decreased microcomedo 
formation2. Additionally, trifarotene stimulates mitotic activity and increased turnover of follicular 
epithelial cells causing extrusion of the comedones.  
AKLIEF® (trifarotene) cream, for topical use was approved by the FDA in 2019 as a 
prescription product for the safe and effective topical therapy for acne vulgaris3, 4,5. Teva 
Pharmaceuticals, Inc. has developed a generic formulation of trifarotene 0.005% cream. The 
current study is designed to evaluate the safety and efficacy of this new generic formulation6. 
Acne is estimated to affect 9.4% of the global population. There is no mortality associated with 
acne, but there is often significant physical and psychological morbidity, such as permanent 
scarring, poor self-image, depression, and anxiety. 
2 STUDY OBJECTIVES 
The objectives of this study are as follows: 
x To evaluate the therapeutic equivalence of TRIFAROTENE CREAM, 0.005% (Teva 
Pharmaceuticals, Inc.) and the Reference Listed Product, AKLIEF® (TRIFAROTENE 
0.005% CREAM) (GALDERMA LABORATORIES, L.P., USA) in the treatment of acne 
vulgaris. 
x To demonstrate the superiority of the efficacy of the test and reference products over that 
of the placebo control in the treatment of acne vulgaris.  


  
 
 
 
 
 
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x Compare the safety of Test, Reference and Placebo treatments in patients with acne 
vulgaris. 
3 STUDY OVERVIEW 
Approximately 807 subjects will be assigned in a 1:1:1 ratio to treatment with the test product, 
TRIFAROTENE 0.005% CREAM, the reference product, AKLIEF® (TRIFAROTENE 0.005% 
CREAM, and placebo (vehicle cream of the test product) in this multiple-center, double-blind, 
randomized, three-arm, placebo controlled, parallel-design study.  
The duration of each Subject’s participation in the study will be 84 days. Scheduled study visits 
will include:  
x Visit 1 (Day 0) Screening/Baseline   
x Visit 2 (First Interim Visit, Day 28) 
x Visit 3 (Second Interim Visit, Day 56) 
x Visit 4 (End of Treatment/Early Discontinuation Visit, Day 84). 
 
A window period of ± 4 days will be considered acceptable for each scheduled visit following 
the screening/baseline visit. 
 At Visit 1, an informed consent/assent will be obtained from the potential study Subject prior to 
any study procedures taking place. After the Subject has been consented/assented, the Subject’s 
medical history will then be documented, including the Subject’s concomitant medications. A 
urine pregnancy test with a sensitivity to at least 25 mIU/ml hCG will be performed for female 
subjects of childbearing potential. A negative result of this test should be obtained.  
If necessary, subjects will be allowed to conduct screening procedures on two separate days in 
order to allow for enough time to complete the adequate washout period required for any 
concomitant therapy or other reasons. Subjects should sign ICF (prior to the start of any study 
procedures), complete washout, and return to the clinic to conduct the remainder of the 
screening/baseline procedures. 
The Subject will undergo a physical examination, including the recording of vital signs and 
COVID-19 symptom (such as stuffy or runny nose, sore throat, shortness of breath (difficulty 
breathing), cough, low energy or tiredness, muscle or body aches, headache, chills or shivering, 
feeling hot or feverish (temperature check), vomiting, diarrhea, loss of sense of taste and smell) 
screening. The Subject will be reviewed against the inclusion/exclusion criteria and a 
screening/baseline acne grade will be assigned to the Subject using the Investigator’s Global 
Assessment (IGA) and a screening/baseline lesion count will be performed.  
The Subject will be evaluated for signs and symptoms of local irritation. Blinded Investigational 
Medicinal Product (IMP) will be dispensed by Independent Dispenser to subjects who meet all 
of the inclusion and none of exclusion criteria. Eligible subjects will be assigned to one of the 


  
 
 
 
 
 
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three study treatment groups as per the computer-generated randomization schedule, and the 
assigned study medication will be dispensed by the Independent Dispenser. Since this is a 
double-blind study, neither the study team other than Independent Dispenser at the site nor the 
subjects will know the treatment the subject is assigned. 
Subjects will be instructed by an Independent Dispenser on the application of IMP and 
completion of Subject diaries. The Independent Dispenser will not be involved in the 
assessments/evaluations of acne lesion counts, Investigator’s Global Assessment (IGA), 
evaluation of signs and symptoms of local irritation and safety assessments.  
The Subject will also be instructed not to open the study medication pump while at the study site.  
The application of Investigational Medicinal Products will be performed by the Subject at home. 
Subjects will be instructed to apply enough study investigational drug to lightly cover the entire 
affected areas of the face for 84 consecutive days. The IMP should be applied once daily at 
bedtime after the Subject’s face has been washed with a non-medicated cleanser provided by the 
Sponsor, and gently patted dry. The subjects should wait 20 to 30 minutes before applying the 
study medication to allow the skin to be completely dry in order to minimize possible irritation. 
For the purposes of this study, the face is considered to start at the hairline and end at the jaw 
line and excludes the eyes, the lips/mouth, angles/corners of the nose, open wounds and all 
mucous membranes.  
The subject will be instructed to wash their hands before and after application of study drug.  
Subjects will be required to use diaries to document the date and time of study treatments, any 
missed treatments, any concomitant medication and the occurrence of all adverse events. 
The subjects will be instructed to bring their used IMP and their study diaries to each study visit. 
Subjects will return to the study site for Visit 2, Visit 3 and Visit 4. The Subject’s concomitant 
medications (if any), IMP compliance and any AEs will be reviewed and documented. A 
temperature check and COVID-19 symptom (such as stuffy or runny nose, sore throat, shortness 
of breath (difficulty breathing), cough, low energy or tiredness, muscle or body aches, headache, 
chills or shivering, feeling hot or feverish (temperature check), vomiting, diarrhea, loss of sense 
of taste and smell) screening will be performed. A urine pregnancy test with a sensitivity of at 
least 25 mIU/ml hCG will be performed for female subjects of childbearing potential. A negative 
result of this test should be obtained.  
The Subject will be evaluated for signs and symptoms of local irritation and any adverse events 
will be documented. The Subject’s facial acne will be assessed using the IGA, the Subject’s 
lesions will be counted, and these results will be documented.  
If the Principal Investigator determines that the Subject’s condition has worsened to the degree 
that it is unsafe for the Subject to continue in the study, the Subject may be discontinued from 
the study as a treatment failure and the Subject may be treated using the standard care or rescue 
medicines if there is exacerbation of their acne. 
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Compliance with drug applications will be assessed at each visit. Additional pumps of IMP will 
be dispensed at the visit if required, and each Subject will receive new diaries during Visit 2 and 
Visit 3. In addition, all IMP and diaries will be collected from the Subject during each scheduled 
visit or the Early Discontinuation Visit. 
At every study visit, all the procedures mentioned in the Table of events (Section 4) will be 
carried out. The treatment area of enrolled subjects will be assessed using IGA and lesion count. 
Additionally, adverse events (AEs) will be monitored, and the treatment area will be examined to 
assess application site reactions. Any change in concomitant medications will be noted. 
Unscheduled Visits are allowed at any time, for any reason, if in the Principal Investigator’s 
opinion, it is warranted. If the Unscheduled Visit is due to an AE, the Principal Investigator will 
determine whether additional visits are needed. If a Subject is discontinued from the study 
during an Unscheduled Visit, the Unscheduled Visit will be referred to as an Early 
Discontinuation Visit and all procedures scheduled for the Early Discontinuation Visit will be 
performed. If the Unscheduled Visit is not an Early Discontinuation Visit (i.e., the Subject will 
continue to take part in the study), then the reason for the unscheduled visit is documented and 
required procedures at the discretion of Investigator considering the reason for visit will be 
performed, with the exception of the collection of IMP and Subject diaries from Subjects. 
For example, if the subject has an unscheduled visit that is outside of the 4 day window for 
the study, the assessments and procedures will be documented as indicated above, however 
if the unscheduled visits is within the 4 day window for visits 1, 2 or 3 then it would be 
permissible to perform the optional procedures for the unscheduled visits as well as the 
required procedure for the scheduled visit.  
 
 
 
 
 
 
 
 
 
 
 


  
 
 
 
 
 
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4 STUDY VISIT SCHEDULE 
Visit Number 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Unscheduled / 
Early 
Discontinuation 
Visit Day 
Day 0 
Day 28 
± 4 
Day 56 
± 4 
Day 84 ± 4 
Visit Name 
Screening 
and 
Baseline 
First 
Interim 
Second 
Interim 
End of 
Treatment 
COVID-19 symptom screening 
ض 
ض 
ض 
ض 
ض 
Informed Consent 
ض 
 
 
 
 
Inclusion / Exclusion Criteria 
ض 
 
 
 
 
Demographics 
(Date of birth, gender, race and ethnicity) 
ض 
 
 
 
 
Medical History 
ض 
 
 
 
 
Physical Exam 
ض 
 
 
ض 
ض as needed 
Vital Signs 
ض 
ض3 
ض3 
ض3 
ض3 
Urine Pregnancy Test 
To be conducted for all women of child-
bearing potential1 
ض 
ض 
ض 
ض 
ض 
Clinical Assessment of Acne: Investigator’s 
Global Assessment (IGA) 
ض 
ض 
ض 
ض 
 
ض 
Investigator’s Lesion Counts Inflammatory 
and Non-Inflammatory 
ض 
ض 
ض 
ض 
 
ض 
Randomization 
ض 
 
 
 
 
Dispense IMP and Supplies 
ض 
ض4 
ض4 
 
 
Dispense Diary 
/Instructions 
ض 
ض 
ض 
 
 
IMP Review and Collection 
Finished cream pumps of IMP will be 
returned 4(as necessary) 
 
ض 
ض 
ض 
ضas needed 
Subject Compliance/ 
Diary Review and collection 
 
ض 
ض 
ض 
ضas needed 
Evaluation of Signs/Symptoms of Local 
Irritation (Application Site Reactions) 
ض 
ض 
ض 
ض 
ض 
Adverse Events Assessment2 
ض 
ض 
ض 
ض 
ض 
Concomitant Medication Review 
ض 
ض 
ض 
ض 
ض 


  
 
 
 
 
 
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1 Tubal ligation is not considered equivalent to female sterilization. Women with a history of tubal ligation are still 
considered females of childbearing potential and must have a negative urine pregnancy test with a sensitivity of at least 
25 mIU/ml hCG. 
2 Any AEs reported after signing Informed Consent should be reported. 
3 Only Temperature check at visit 2, 3, 4 and Unscheduled / Early Discontinuation as part of COVID-19 symptom 
screening. 
4Additional IMP and supplies will be provided to the Subject as required. 
5 STUDY POPULATION  
5.1 Number of Subjects  
This multi-center study will be comprised of subjects presenting with a clinical diagnosis of acne 
vulgaris who meet all inclusion and none of exclusion criteria. Approximately 807 subjects will 
be enrolled into the study in a 1:1:1 ratio, to obtain 765 subjects in the mITT (255:255:255 Test: 
Reference: Placebo) and 627 in the PP subjects (209:209:209 Test: Reference:Placebo) to the 
following study arms: 
x TEST: TRIFAROTENE CREAM, 0.005% (Teva Pharmaceuticals, Inc.) 
x REFERENCE: AKLIEF® (TRIFAROTENE 0.005% CREAM) (GALDERMA 
LABORATORIES, L.P., USA) 
x PLACEBO: Vehicle cream (Teva Pharmaceuticals, Inc.) 
Note: Number of study sites (approximately 15) may vary based on the subject recruitment rate.  
 
5.1.1 Inclusion Criteria  
1) Male or non-pregnant, non-lactating female aged  12 and  40 years with a 
clinical diagnosis of acne vulgaris. 
2) Subjects who are 18 years of age or older (up to the age of 40) must have 
provided IRB/IEC approved written informed consent. Subjects 12 to 17 years of 
age, inclusive, must have provided IRB/IEC approved written assent; this written 
assent must be accompanied by an IRB/IEC approved written informed consent 
from the Subject’s legally acceptable representative (i.e., parent or guardian). In 
addition, all Subjects or their legally acceptable representatives (i.e., parent or 
guardian) must sign a HIPAA authorization. 
3) Subjects must have  25 non-inflammatory lesions (i.e., open and closed 
comedones) AND  20 inflammatory lesions (i.e., papules and pustules) AND  2 
nodulocystic lesions (i.e., nodules and cysts), at screening/baseline on the face.  
(a)For the purposes of study treatment and evaluation, these lesions should be 
limited to the facial treatment area. All lesions will be counted, including those 
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which will be excluded from the count and the Investigator’s Global Assessment 
(IGA) evaluation (e.g., on the back, chest and arms). 
4) Subjects must have a definite clinical diagnosis of acne vulgaris severity grade 2, 
3, or 4 as per the Investigator’s Global Assessment (IGA) (per Table 2 below) at 
screening/baseline.  Acne vulgaris should be stable (for at least 3 months prior to 
screening), with minimal variation from day to day and within each day, in the 
opinion of the subject. 
Table 2: Investigator’s Global Assessment (IGA) Scale for Acne Vulgaris 
Grade  
Description  
0  
Clear skin with no inflammatory or non-inflammatory lesions  
1  
Almost clear; rare non-inflammatory lesions with no more than one small 
inflammatory lesion  
2  
Mild severity; greater than Grade 1; some non-inflammatory lesions with no 
more than a few inflammatory lesions (papules/pustules only, no nodular 
lesions)  
3  
Moderate severity; greater than Grade 2; up to many non-inflammatory lesions 
and may have some inflammatory lesions, but no more than one small nodular 
lesion  
4*  
Severe; greater than Grade 3; up to many non-inflammatory lesions and 
may have some inflammatory lesions, but no more than a few nodular 
lesions  
* The eCRF will allow for reporting by Investigators of lesion worsening beyond Grade 4 with 
treatment.  Acne vulgaris Subjects with nodulocystic acne are not to be enrolled in the study. 
Subjects who worsen beyond Grade 4 will be described in the safety evaluation.   
Note: Counts of nodules and cysts will be reported separately and not included in the 
inflammatory or non-inflammatory lesion counts. 
5) Subjects must be willing to refrain from using all other topical acne medications 
or antibiotics during the 12-week treatment period, other than the IMP. 
6) Female Subjects of childbearing potential (*WOCBP) must not be pregnant or 
lactating at the time of screening/baseline visit as documented by a negative urine 
pregnancy test. 
*Female subjects of childbearing potential (WOCBP) are defined as sexually mature women 
without prior hysterectomy, or who have had any evidence of menses in the past 12 months. 
However, women who have been amenorrheic for the past 12 or more months are still 
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including prior chemotherapy, anti- estrogens, or ovarian suppression. Postmenopausal women 
(defined as women who have been amenorrheic for at least 12 consecutive months, in the 
appropriate age group, without other known or suspected primary cause) or women who have 
been sterilized surgically or who are otherwise proven sterile (i.e., total hysterectomy, or 
bilateral oophorectomy with surgery at least 4 weeks prior to randomization) are not considered 
WOCBP. Subjects who have undergone tubal ligation are NOT considered as surgically sterile. 
7) Female subjects of childbearing potential must be willing to use an acceptable 
form of birth control during the study from the day of the first dose administration 
to 30 days after the last administration of study drug.   
(a) For the purposes of this study the following are considered acceptable 
methods of birth control: oral or injectable contraceptives, contraceptive 
patches, medroxyprogesterone acetate (ex. Depo-Provera®) with stabilized use 
for at least 3 months, vaginal contraceptive (ex. etonogestrel/ethinyl estradiol 
vaginal ring (ex. NuvaRing®), contraceptive implant with etonogestrel or 
equivalent, double barrier methods (e.g. condom and spermicide), intrauterine 
device (IUD), true abstinence (if in line with subject’s lifestyle).  
(b) If a subject who was abstinent becomes sexually active during the study, a 2nd 
acceptable method of birth control is to be used and documented. 
(c) Subjects on hormonal contraception must be stabilized on the same type for at 
least three months prior to enrollment in the study and must not change the 
method during the study. A sterile sexual partner is not considered an 
adequate form of birth control. 
8) Female subjects who are premenarchal, surgically sterilized (by *hysterectomy or 
bilateral oophorectomy) or postmenopausal for at least 1 year) (defined as women 
who have been amenorrheic for at least 12 consecutive months, without other 
known or suspected primary cause).  
9) All male Subjects must agree to use accepted methods of birth control with their 
partners, from the day of the first dose administration to 30 days after the last 
administration of study drug. True abstinence is an acceptable method of birth 
control if in line with subject’s lifestyle.  Female partners should use an 
acceptable method of birth control as described in the above criteria. 
10) Subjects must be willing and able to understand and comply with the 
requirements of the protocol, including attendance at all required study visits and 
refraining from the use of all other topical acne medications or antibiotics during 
the 12-week treatment period. 
11) Subjects must be in good health and free from any clinically significant disease, 
including but not limited to, conditions that may interfere with the evaluation of 
acne vulgaris or the administration of the investigative product. 
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a minimum period of 14 days prior to study entry and must agree to not change 
make-up brand/type or frequency of use throughout the study. 
 
5.1.2 Exclusion Criteria 
1) Female Subjects who are pregnant, lactating or planning to become pregnant during study 
participation.  
2) Subjects with a history of hypersensitivity or allergy to trifarotene, tretinoin, retinoids, or 
any of the study medication ingredients.  
3) Subjects with the presence of any skin condition that would interfere with the diagnosis or 
assessment of acne vulgaris (Such conditions include but are not limited to the following  
on the face: rosacea, dermatitis, psoriasis, squamous cell carcinoma, eczema, acneiform 
eruptions caused by medications, steroid or corticosteroid-induced acne, steroid folliculitis, 
or bacterial folliculitis, auto-immune disease, perioral dermatitis, carcinoid syndrome, 
mastocytosis, or  acneiform eruptions caused by make-up and medication, facial psoriasis 
and facial eczema). 
4) Subjects with nodulocystic acne (> 2 nodules and cysts). [Nodules or cysts defined as; 
deep-seated in the skin (i.e., centered in the dermis or subcutis) and an inflammatory 
lesion greater than or equal to 5 mm in diameter], acne conglobata, acne fulminans, 
secondary acne (chloracne, drug-induced acne, etc.), or acne vulgaris requiring systemic 
treatment. 
5) Subjects with excessive facial hair (e.g., beards, sideburns, moustaches, etc.) that would 
interfere with diagnosis or assessment of acne vulgaris.  
6) Subjects with tattoos or excessive facial scarring that, in the Investigator’s opinion, may 
interfere with the evaluation of the subject’s acne. 
7) Subjects who have used within 6 months prior to screening/baseline oral retinoids (e.g., 
Accutane®) or therapeutic vitamin A supplements of greater than 10,000 units/day 
(multivitamins are allowed).  These treatments with oral retinoids or Vitamin A 
supplements are prohibited during the study participation. 
8) Subjects who have used within 1 month prior to screening/baseline neuromuscular 
blocking agents or androgen receptor blockers (e.g., spironolactone, Flutamide etc.). 
9) Subjects who have had laser therapy, electrodessication, phototherapy and or cosmetic 
procedures (e.g., ClearLight® BOTOX, Filler, micro needling) to the facial area within 6 
months prior to study entry. 
10) Subjects who have had facial cosmetic procedures (e.g., facials) or application of cosmetic 
products (cosmetics, makeup or facial products that have a strong drying or possible 
interactive effect, particularly preparations containing spices, lime sulfur, resorcinol, or 
salicylic acid with tretinoin or other retinoids) which may affect the efficacy and safety 
profile of the IMP within 2 weeks prior to study entry. 


  
 
 
 
 
 
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11) Subjects who have received radiation therapy and/or anti-neoplastic agents within 3 
months prior to screening/baseline. 
12) Subjects who have used for less than (<) 3 months prior to screening/baseline estrogens or 
oral contraceptives; use of such therapy must remain constant throughout the study.   
13) Subjects who have used any of the following procedures on the face within 1 month prior 
to screening/baseline or use during the study: 
a. cryodestruction or chemodestruction,  
b. dermabrasion,  
c. photodynamic therapy,  
d. acne surgery,  
e. intralesional steroids, or  
f. X-ray therapy.  
14) Subjects who have used any of the following treatments within 1 month prior to 
screening/baseline or during the study: 
a. androgen receptor blockers (e.g., spironolactone, Flutamide etc.) 
b. systemic steroids,  
c. systemic antibiotics,  
d. systemic treatment for acne vulgaris (other than oral retinoids, which require a 6-
month washout),  
e. systemic anti-inflammatory agents.  If Subject uses a systemic anti-inflammatory 
product during the study, the Principal Investigator will judge if this protocol 
deviation is clinically significant, 
f. have taken any drugs that lower the immune system 
g. topical immunomodulators 
15) Subjects who have used any of the following treatments within 2 weeks prior to 
screening/baseline or during the study: 
a) topical steroids,  
b) 
topical retinoids,  
c) 
topical acne treatments including over-the-counter preparations 
d) 
topical anti-inflammatory agents 
e) 
topical antibiotics 
f) 
abradants,  
g) 
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h) 
washes or soaps, containing glycolic acid,  
i) 
Alpha-hydroxy acids,  
j) 
sulfacetamide sodium,  
k) 
non-mild facial cleansers, moisturizers that contained retinol 
l) 
topical products that contain high amounts of alcohol 
m) 
wax depilation of the face 
n) 
use of tanning booths 
o) 
application to face of alcohol-based toners, cosmetics, makeup or any product with 
high concentrations of alcohol, astringents, medicated topical preparations 
(prescription and OTC products including those with spices or lime) or medicated 
make-up, medicated or harsh soaps, medicated cleansers, and cosmetics that make 
subject skin dry to the face (products that have a strong drying effect, particularly 
preparations containing sulfur, resorcinol, or salicylic acid with tretinoin or other 
retinoids).  
16) Subjects who have on-going malignancies requiring systemic treatment or who have any 
malignancy of the skin of the facial area. 
17) Subjects with active facial sunburn or peeling from sunburn. 
18) Subjects who engage in activities that involve excessive or prolonged exposure to sunlight 
or weather extremes, such as wind or cold.  Exposure to excessive UV radiation within 1 
week prior to screening/baseline. 
19) Subjects who use a sauna within 48 hours prior to screening/baseline. 
20) Subjects who have unstable medical disorders that are clinically significant or have life-
threatening diseases, or other medical condition (i.e., chronic infectious disease, system 
disorder, organ disorder, cardiovascular, gastrointestinal, hematological, hepatic, 
neurological, pancreatic, renal disease, severe psychological conditions etc.) that, in the 
Investigator's opinion, would place the study Subject at undue risk by participation or 
could jeopardize the integrity of the study evaluations. 
21) Subjects who consume excessive amounts of alcohol (greater than two drinks per day) or 
use drugs of abuse (including, but not limited to, cannabinoids, cocaine and barbiturates) 
within one year prior to screening. 
22) Subjects, who in the opinion of the Investigator, would be non-compliant with the 
requirements of the study protocol. 
23) Subjects who are unable or unwilling to give informed consent. 
24) Subjects who are illiterate. 
25) Subjects who have participated in an investigational drug study (i.e., Subjects have been 
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sufficient washout period has not been achieved; whichever time period is longer.  
Subjects who are participating in non-treatment studies such as observational studies or 
registry studies can be considered for inclusion. 
26) Subjects who have been previously enrolled in this study. 
27) Subjects who live in the same household with subjects who are participating or have been 
previously enrolled in this study. 
28) The subject is a member of the investigational study staff or a family member of the 
investigational study staff. 
29) Subject having symptoms* of Coronavirus Disease 2019 (COVID-19) within the 10 days 
prior to screening/baseline/visit 1 or have had close contact with someone with suspected 
or confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) 
infection within 10 days prior to screening/baseline/visit 1 or who are at high risk of 
SARS-CoV-2 infection, defined as adults whose locations or circumstances put them at 
appreciable risk of acquiring SARS-CoV-2 infections. 
a) *Stuffy or runny nose, sore throat, shortness of breath (difficulty breathing), cough, low 
energy or tiredness, muscle or body aches, headache, chills or shivering, feeling hot or 
feverish, vomiting, diarrhea, loss of sense of taste and smell. 
5.1.3 Prohibited Medications, Procedures, and Activities 
Medication necessary for the health and well-being of the subject is permitted provided the 
subject has been at a stable dose for 30 days prior to screening/baseline visit. The use of any 
medication that could affect the course of acne is prohibited during the entire study period. 
Subjects should not apply creams, lotions, powders or any topical product other than the 
assigned treatment to the treatment area. See below Table 3: Restrictions and Prohibited 
Medications & also exclusion criteria.  
The following are prohibited during this study: 
1. Any topical products applied to the face, other than the assigned study treatment (e.g., 
Medicated topical products, cleanser/moisturizer/sunscreen other than those provided by 
the Independent Dispenser). 
2. Neuromuscular blocking agents. 
3. Androgen receptor blockers (e.g., spironolactone, Flutamide etc.). 
4. Systemic treatment for acne vulgaris, systemic retinoids and systemic 
steroids/corticosteroids. 
5. Systemic (e.g., oral or injectable) antibiotics known to impact on the severity of facial 
acne vulgaris, including but not limited to:  
a) tetracycline and its derivatives, erythromycin and its derivatives 
b) trimethoprim and sulfamethoxazole (Bactrim™)    


  
 
 
 
 
 
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NOTE: Subjects may take systemic antibiotics not known to impact the severity of facial acne 
vulgaris (e.g., penicillin) during this study after consultation with the Medical Monitor. 
6. Systemic anti-inflammatory agents (e.g., NSAIDs) in clinically significant doses affecting 
acne vulgaris.  
7. Immunosuppressive drugs.  
8. Antipruritic, including antihistamines, within 24 hours of study visits. 
9. Use of hormonal contraceptives should not be initiated or changed during the study. 
10. The applications of new cosmetics or new cleansers to the face are prohibited during this 
study, other than the cleanser and sunscreen provided by the Sponsor. Subjects who use 
cosmetics or make-up must have used the same brands/types of make-up for a minimum 
period of 2 weeks prior to screening/baseline visit and must agree to not change make-up 
(non-comedogenic) brand/type or frequency of use throughout the study. Facial topical 
products should not be applied within 2 hours prior to the application of the study 
treatment on each day, and within 12 hours prior to the scheduled clinic visit. 
11. All topical applications for any skin condition at all locations are to be reported during the 
course of the trial and for 2 weeks prior to randomization.  The application of alcohol-
based toners or any product with high concentrations of alcohol, astringents, medicated 
topical preparations (prescription and OTC products including those with spices or lime) 
or medicated make-up, medicated or harsh soaps, medicated cleansers, and cosmetics that 
make subject skin dry to the face (products that have a strong drying effect, particularly 
preparations containing sulfur, resorcinol, or salicylic acid with tretinoin or other 
retinoids).  
12. The use of abrasive cleansers or washes (e.g., exfoliating facial scrubs) on the face. 
13. The use of adhesive cleansing strips (e.g., Bioré® Pore Strips) on the face. 
14. Subjects must not wear make-up to any study visits, so as not to interfere with the 
evaluations. 
15. Subjects should not use a sauna during the study. 
16. Subjects should not bathe, shower, wash or swim for at least 4 hours after the application 
of the IMP. 
17. The use of moisturizer is strongly discouraged during the study but whenever necessary, 
depending upon the severity of the need, the Investigator may instruct the Subject to only 
use a non-medicated moisturizer provided by the Sponsor. The Subjects should enter the 
details of use of non-medicated moisturizer (how often it has been used) in diaries.  


 
  
 
 
 
 
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Table 3: Restrictions and Prohibited Medications 
Table 3: Restrictions and Prohibited Medications  
Treatment 
 
Restriction for entire 
study duration 
Minimum time interval from last dose or last occurrence until time of study visit.  
 
If not YES, follow 
the restrictions 
specified in the 
following columns. 
Screening/Baseline 
Visit 1  
Day 28+4 Visit 2 & 
Day 56+4 Visit 3 
Interim  
Visit 4  
Day 84+4 
 
Topical Treatments 
 
 
 
 
Topical antibiotics 
(examples: Clindamycin, 
Erythromycin)  
YES 
2 weeks 
N/A 
N/A 
Topical immunomodulators 
(examples: Pimecrolimus, 
Tacrolimus) 
YES 
1 MONTH 
N/A 
N/A 
Topical corticosteroids 
(examples: Hydrocortisone, 
Betamethasone dipropionate)   
YES 
2 weeks 
N/A 
N/A 
Topical retinoids (examples: 
Adapalene, Tretinoin) 
YES 
2 weeks 
N/A 
N/A 
Topical anti-inflammatory 
agents (example: Diclofenac 
sodium, Ibuprofen) 
YES 
2 weeks 
N/A 
N/A 
Others including products 
used for the topical treatment 
of acne (examples: azelaic 
acid, salicylic acid)  
  
YES 
2 weeks 
N/A 
N/A 


  
 
 
 
 
 
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Table 3: Restrictions and Prohibited Medications  
Treatment 
 
Restriction for entire 
study duration 
Minimum time interval from last dose or last occurrence until time of study visit.  
 
If not YES, follow 
the restrictions 
specified in the 
following columns. 
Screening/Baseline 
Visit 1  
Day 28+4 Visit 2 & 
Day 56+4 Visit 3 
Interim  
Visit 4  
Day 84+4 
 
Facial topical products 
(examples: Creams, lotions, 
facial moisturizers, make-up, 
ointments, cosmetics, 
sunscreens; (non-medicated 
facial cleanser is acceptable) 
Within 2 hours prior 
to the application of 
the study treatment on 
each day 
If used, same product 
brands/types should 
be applied throughout 
the study. 
 The same brands must 
be used from 2 weeks 
prior to Visit 1. 
Within 12 hours prior 
to the scheduled clinic 
visit. 
Within 12 hours prior to 
the scheduled clinic visit.               
Systemic Treatments 
 
 
 
 
Systemic antibiotics and 
corticosteroids (examples: 
Doxycycline, 
Hydrocortisone) 
YES 
 1 MONTH 
N/A 
N/A 
Systemic anti-inflammatory 
agents (examples: Aspirin, 
Ibuprofen) 
YES 
 1 MONTH 
N/A 
N/A 
Systemic treatments for acne 
vulgaris (examples: 
Tetracycline, isotretinoin) 
YES 
 1 MONTH 
N/A 
N/A 
Oral retinoids (example: 
ACCUTANE®) 
YES 
6 MONTHS  
N/A 
N/A 
Subjects who have used 
within 1 month prior to 
screening/baseline 
neuromuscular blocking 
agents or androgen receptor 
blockers (e.g., 
spironolactone, Flutamide 
etc.). 
YES 
1 MONTH 
NA 
NA 


  
 
 
 
 
 
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Table 3: Restrictions and Prohibited Medications  
Treatment 
 
Restriction for entire 
study duration 
Minimum time interval from last dose or last occurrence until time of study visit.  
 
If not YES, follow 
the restrictions 
specified in the 
following columns. 
Screening/Baseline 
Visit 1  
Day 28+4 Visit 2 & 
Day 56+4 Visit 3 
Interim  
Visit 4  
Day 84+4 
 
Other 
 
 
 
 
Phototherapy (examples: 
laser, light-source (e.g., 
intense pulsed light, 
photodynamic therapy) or 
other energy-based therapy), 
electrodessication 
YES 
 6 MONTHS 
N/A 
N/A 
Any dermatologic or surgical 
procedure on face 
YES 
 1 MONTH 
N/A 
N/A 
Exposure to excessive UV 
radiation 
YES 
1 week 
N/A 
N/A 
Monoamine oxidase (MAO) 
inhibitors, barbiturates, 
opiates, sedatives, systemic 
anesthetics.  
YES 
1 YEAR 
N/A 
N/A 
Application of any medicated 
or harsh soaps on face. The 
only allowable facial soaps 
should be unscented and no 
additives. 
YES 
2 WEEKS 
N/A 
N/A 
The use of antipruritic, 
including antihistamines, 
within 24 hours of the study 
visit 
Within 24 hours prior 
to visit 
Within 24 hours prior to 
visit 
Within 24 hours prior 
to visit 
Within 24 hours prior to 
visit 
The use of abrasive cleaners 
or washes (e.g., exfoliating 
facial scrubs) on the face 
YES 
2 weeks 
N/A 
N/A 


  
 
 
 
 
 
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Table 3: Restrictions and Prohibited Medications  
Treatment 
 
Restriction for entire 
study duration 
Minimum time interval from last dose or last occurrence until time of study visit.  
 
If not YES, follow 
the restrictions 
specified in the 
following columns. 
Screening/Baseline 
Visit 1  
Day 28+4 Visit 2 & 
Day 56+4 Visit 3 
Interim  
Visit 4  
Day 84+4 
 
The use of adhesive 
cleansing strips (i.e., Bioré® 
Pore Strips) on the face 
YES 
2 weeks 
N/A 
N/A 
Wax epilation on the face  
YES 
2 weeks 
Since 
Screening/Baseline 
Since Screening/Baseline 
Cosmetic procedures (e.g., facials) 
to face and  
YES 
2 weeks 
Since 
Screening/Baseline 
Since Screening/Baseline 
Cosmetic product (cosmetics that 
have a strong drying effect, 
particularly preparations 
containing sulfur, resorcinol, or 
salicylic acid with tretinoin or 
other retinoids. 
 
YES 
2 weeks 
Since 
Screening/Baseline 
Since Screening/Baseline 
The application of alcohol-based 
toners, makeup or any product 
with high concentrations of 
alcohol, astringents, medicated 
topical preparations (prescription 
and OTC products including those 
with spices or lime) or medicated 
make-up, medicated or harsh 
soaps, medicated cleansers, and 
cosmetics that make subject skin 
dry to the face (products that have 
a strong drying 
YES 
2 weeks 
Since 
Screening/Baseline 
Since Screening/Baseline 
Radiation therapy and/or 
anti-neoplastic agents 
YES 
3 MONTHS 
Since 
Screening/Baseline 
Since Screening/Baseline 


 
  
 
 
 
 
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Acceptable Medications for use throughout the study: 
1. Contraceptives – Acceptable methods of birth control as listed in the Inclusion Criteria.  
Subjects on hormonal contraception must be stabilized on the same type for at least 3 
months prior to enrollment in the study and must not change the method during the study. 
2. Acetaminophen - Acetaminophen will be allowed during the study with a maximum dose 
of 1g (i.e., 1000 mg) twice daily and for a maximum of 3 consecutive days. 
3. Non-medicated moisturizers (supplied by sponsor) or cleaning agents only, when 
necessary, as directed by investigator. 
4. Oral retinoids, therapeutic vitamin A supplements of less than 10,000 units/day (multi-
vitamins are allowed). 
Subjects will be allowed to apply the study medication to any affected area(s) of their trunk as 
needed. No other medication will be allowed to be applied to these affected area(s).  
Subjects will be questioned about all prescription and over the counter (OTC) concomitant 
medication use (including vitamins, nutritional supplements, herbal supplements, all topical 
products) at each study visit. All concomitant medications will be recorded in the Subject's 
source documents. Any Subject who violates the listed restrictions may be dropped from 
continued participation in the study by the discretion of investigator. 
 
5.1.4 Precautions  
The following precautions are to be taken during this study:  
1. To minimize exposure to sunlight and or extreme weather conditions, a wide-brimmed hat 
or other protective clothing should be worn.  The non-comedogenic sunscreen with a SPF 
15 rating or higher provided by the Sponsor may be used. 
2. The IMP should not be applied to cuts, open wounds, abrasions, sunburn or eczematous 
skin. 
3. The IMP should not be applied to the eyes, the mouth/lips, the angles/corners of the nose 
or any mucous membranes. 
4. Subjects should wash their hands before and after application of the product. 
If a reaction suggesting sensitivity or chemical irritation occurs, the Principal Investigator should 
assess the Subject’s condition as soon as possible (i.e., during an Unscheduled Visit) and 
determine whether treatment should be discontinued. If a Subject is discontinued from the study 
during an Unscheduled Visit, the Unscheduled Visit will be referred to as an Early 
Discontinuation Visit and all procedures scheduled for the Early Discontinuation Visit will be 
performed. 


  
 
 
 
 
 
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5.1.5 Subject Disposition and Discontinuation 
All Subjects are free to withdraw from participation in the study at any time, for any reason, 
specified or unspecified, and without prejudice to further treatment. The criteria for enrollment 
are to be followed explicitly. Investigators are urged to enroll only those eligible Subjects who 
are likely to complete the entire study and who are willing to comply with the protocol-specified 
procedures.  It is the right and duty of the investigator to interrupt the treatment of any Subject 
whose health or well-being may be threatened by continuation in this study, or who may be 
experiencing unmanageable factors that may interfere with the study procedures and/or the 
interpretation of study results.  Such Subjects should be withdrawn from the study rather than 
continued under a modified regimen. The reason for withdrawal or discontinuation from the 
study will be documented appropriately. 
In addition, investigational product will be stopped, and Subjects will be discontinued from the 
study for any of the following reasons:  
a. If the Subject withdraws his or her consent/assent for any reason. 
b. Subjects who are discontinued early from the study due to lack of treatment effect 
should be included in the PP population as treatment failures, using Last Observation 
Carried Forward (LOCF). 
c. If the Subject’s acne condition has worsened beyond grade 4 or to the degree that the 
Principal Investigator feels it is unsafe for the Subject to continue in the study, the 
subject should be discontinued, but included in the mITT and PP population analysis 
using LOCF and provided with effective rescue treatment for exacerbation of their 
acne. 
d. Subjects that withdraw or discontinue early for reasons other than lack of treatment 
effect should be excluded from the PP population, but included in the mITT population 
using LOCF.  
e. If the Subject has a SAE. 
f. If the Subject’s drug code is unblinded. 
g. If an adverse event occurs for which the Subject desires to discontinue treatment or the 
Principal Investigator determines that it is in the Subject’s best interest to be 
discontinued. 
h. If there is a significant protocol deviation if it affects the safety or well-being of the 
subject. 
i. If subject misses three or more consecutive doses of IMP. 
j. If a concomitant therapy is reported or required which is liable to interfere with the 
results of the study. 
k. If the Subject is lost to follow-up.  
l. If the Subject becomes pregnant. 
m. If the Subject becomes a prisoner or becomes involuntarily incarcerated.  
n. Any other reason that may affect the outcome of the study or the safety of Subjects; or 
o. Termination of the study by the Sponsor. 


  
 
 
 
 
 
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Subjects who withdraw from the study early will have Early Discontinuation procedures 
performed. Subjects who withdraw from the study will not be replaced. All subjects who are 
randomized will be included in the safety monitoring tabulating all adverse events experienced 
after dosing. 
A significant or major protocol deviation is defined as any subject or Investigator activity that 
could have possibly interfered with the therapeutic administration of the treatment, safety or 
well-being of the subject or the precise evaluation of treatment efficacy such as may affect data 
integrity. Subjects with protocol deviations are not required to be discontinued from the study 
unless, in the Investigator’s opinion, continuation in the study could be harmful to the health or 
wellbeing of the subject. Subjects that have a major protocol deviation which effects their safety 
or wellbeing should be discontinued.  
The reasons for a Subject discontinuation will be documented. If a Subject is discontinued from 
the study for any reason, Early Discontinuation Visit procedures will be completed and any 
outstanding data and study drug should be collected if possible. In addition to the reason for 
discontinuation the collected data will include the initiation of any rescue medicines, the date of 
removal and will be documented in the electronic Case Report Form (eCRF). The Sponsor will 
be notified. 
Before a subject is considered to be lost to follow-up, the Principal Investigator will document 
all attempts to reach the Subject twice by telephone and will send a certified follow-up letter. 
In the event that a subject discontinues from the study at any time due to an adverse event (AE), 
the reason for discontinuation, the nature of the event and its clinical course must be fully 
documented (see also reporting AEs and SAES, Section 11.0). For such a subject, the Principal 
Investigator must strive to follow the subject until the adverse event has resolved, becomes 
clinically insignificant, is stabilized or the subject is lost to follow-up. In case of any serious 
adverse events, procedures for reporting must be followed. 
6 SAFETY AND TOLERABILITY EVALUATIONS 
Safety will be assessed based on following:  
x Vital signs evaluation, 
x Physical Examination  
x COVID-19 symptoms screening,  
x Reported Adverse Events and Serious Adverse Events,  
x Assessment of local facial tolerability-rating of erythema, dryness, stinging/burning, 
erosion, edema, pain and itching for each treatment group will be recorded and 
reported, 
x Lack of effect of investigative products on indication.  


  
 
 
 
 
 
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6.1 General Safety Evaluations 
A complete medical history will be obtained for the Subject’s current and past medical 
conditions. Significant medical history should include, but not be limited to, evidence of 
hypertension, lipid disorders, obesity1, heart attack, stroke, congestive heart failure, kidney 
disease, auto immune disease and gestational diabetes. Significant surgical history should 
include, but not be limited to, removal of blockage from an artery and gallbladder removal. 
Concomitant medications and treatments, including the use of sunscreen, OTC products, herbal 
products, topical and systemic medicines, (non-drug treatments/therapies) etc., in addition to the 
reason for the medication use, will be assessed at screening/baseline and at each subsequent 
study visit. The start and stop calendar date (e.g., mm/dd/yyyy) and study day (e.g., Day X) and 
name of concomitant medication use during the study should be provided in the data set in 
addition to the reason for the medication use. It should clearly be noted whether the medication 
was used prior to screening/baseline visit, during the study, or both. 
Additional assessment to assess subject safety, such as physical examinations, measurements of 
vital signs are described below and included in the Schedule of Assessments for periodic 
measurements.  
All female subjects of childbearing potential will undergo a urine pregnancy test with a 
sensitivity of at least 25 mIU/ml hCG at Visit 1, Visit 2, Visit 3 and Visit 4. A negative result of 
urine pregnancy test at visit 1, 2, 3 and 4 should be obtained.  All female subjects are considered 
to be of childbearing potential unless they are premenarchal or have been surgically sterilized or 
have been postmenopausal for at least 1 year. 
 
6.1.1 Physical Examination 
A brief physical examination will be performed at screening/baseline, Visit 4 End of 
Treatment/Early Discontinuation and during an UNS visit where applicable. The physical 
examination will include, at a minimum, examination of the Subject’s general appearance, skin, 
HEENT (head, eyes, ears, nose and throat), heart, lungs, musculoskeletal system, neurological 
system, lymph nodes, abdomen and extremities. It is recommended the Subject’s body weight 
should be measured while the Subject is lightly clothed (e.g., no coat or shoes). 
The investigator, sub-investigator or appropriately delegated designee (Physician’s Assistant, 
Advanced Registered Nurse Practitioner, and Registered Nurse as per local regulations) will 
perform a brief physical examination, prior to the Subject starting study drug.  A delegation log 
will be maintained at site.  
 
 
1 Obesity = BMI 30 (as defined by Metropolitan Life Insurance Company Chart, Appendix III) 


  
 
 
 
 
 
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6.1.2 Vital Signs 
Vital signs, including blood pressure, pulse rate, respiratory rate and body temperature will be 
documented at Visit 1, Visit 2, Visit 3 and Visit 4. Vital signs will be measured after the subject 
has rested in a seated position for about 5 minutes.  
Blood pressure (millimeters of mercury [mmHg]) and heart rate (beats per minute [bpm]) will be 
measured during the physical examination after 5 minutes rest in sitting position. Blood pressure 
and heart rate will be obtained preferably using the same arm and same equipment each time. If 
one arm has higher blood pressure than the other, that arm should be used for further blood 
pressure measurements (all further blood pressure measurements should be done in the same 
arm). 
Body temperature will be measured using FDA approved tympanic or infrared thermometer with 
digital display and recorded in the eCRF in degree Celsius (°C). Preferably the same method will 
be used each time. 
Vital signs, including blood pressure, pulse rate, respiratory rate and body temperature will be 
documented at visit 1. Vital signs will be measured after the Subject has rested in a seated 
position for at least 5 minutes. Additionally, temperature will also be documented at Visit 2, 3, 4 
and Unscheduled / Early Discontinuation as part of COVID-19 symptom screening. 
 
6.1.3 Pregnancy Test 
All female Subjects of childbearing potential will undergo a urine pregnancy test with a 
sensitivity of at least 25 mIU/ml hCG during Visit 1 and at each subsequent study visit.  
All female Subjects are considered to be of childbearing potential unless they are premenarchal, 
have been surgically sterilized (by *hysterectomy or bilateral oophorectomy) or have been 
postmenopausal for at least 1 year. Tubal ligation is not considered equivalent to female 
sterilization.  Women with a history of tubal ligation are still considered females able to become 
pregnant and must complete a urine pregnancy test.  
*Female subjects of childbearing potential (WOCBP) are defined as sexually mature women 
without prior hysterectomy, or who have had any evidence of menses in the past 12 months. 
However, women who have been amenorrheic for the past 12 or more months are still 
considered to be of childbearing potential, if the amenorrhea is possibly due to other causes, 
including prior chemotherapy, anti- estrogens, or ovarian suppression. Postmenopausal women 
(defined as women who have been amenorrheic for at least 12 consecutive months, in the 
appropriate age group, without other known or suspected primary cause) or women who have 
been sterilized surgically or who are otherwise proven sterile (i.e., total hysterectomy, or 
bilateral oophorectomy with surgery at least 4 weeks prior to randomization) are not considered 
WOCBP. Subjects who have undergone tubal ligation are NOT considered as surgically sterile. 
Women of childbearing potential, in addition to having a negative urine pregnancy test, must be 
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administration to 30 days after the last administration of study drug.  
Female subjects who are premenarchal, surgically sterilized (by hysterectomy or bilateral 
oophorectomy) or postmenopausal for at least 1 year, do not require a urine pregnancy test and 
are not required to use an acceptable form of birth control. 
Full hysterectomy or bilateral oophorectomy are considered surgically sterile. Tubal ligation is 
not considered equivalent to female sterilization. 
For the purpose of this study the following are considered acceptable methods of birth control: 
oral or injectable contraceptives, contraceptive patches, medroxyprogesterone acetate (ex. Depo-
Provera®) with stabilized use for at least 3 months, vaginal contraceptive (ex. 
etonogestrel/ethinyl estradiol vaginal ring (ex. NuvaRing®), contraceptive implant with 
etonogestrel or equivalent, double barrier methods (e.g., condom and spermicide), IUD, 
abstinence. If a subject who was abstinent becomes sexually active during the study, a 2nd 
acceptable method of birth control should be used and documented.  
A sterile sexual partner is NOT considered an adequate form of birth control. Subjects on 
hormonal contraception must be stabilized on the same type for at least three months prior to 
enrollment in the study and must not change the method during the study.   
 
6.2 Concomitant Medications 
Concomitant medications and therapeutic treatments, including the use of sunscreen, OTC 
products, herbal products, topical and systemic medicines, dietary supplements and any current 
non-drug treatments/therapies will be assessed at the screening/baseline visit and at each 
subsequent study visit. The start and stop calendar date (e.g., dd/mmm/yyyy and study day (e.g., 
Day X) of concomitant medication use during the study should be provided in the data set in 
addition to the reason for the medication or treatment use. It should clearly be noted whether the 
medication was used prior to screening/baseline visit, during the study, or both. 
A record of concomitant medications taken by the Subject is to be obtained using generic name, 
if known, with the corresponding indication. The medications to be recorded will include 
prescription and over-the-counter (OTC) medications and dietary supplements. Any therapeutic 
treatments during the trial should also be recorded. All medications taken on a regular basis, 
including acetaminophen, should be recorded. 
 
6.3 Evaluation of Signs/Symptoms of Local Irritation/Application Site 
Reactions 
At each study visit, beginning at Visit 1, Subjects will be evaluated for any signs and symptoms 
of local irritation such as erythema, dryness, burning/stinging, erosion, edema, pain and itching. 
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The following scale will be used for the signs and symptoms of local irritation:  
 
Score 
Assessment 
Description 
0 
Absent 
None 
1 
Mild 
Slight, barely perceptible 
2 
Moderate 
Distinct presence 
3 
Severe 
Marked, intense 
Subjects with a screening/baseline irritation score of 3 (severe, marked/intense) will not be 
enrolled. 
Signs and symptoms of local irritation are to be recorded only as AEs if they significantly 
worsen, require any medical intervention or result in subject discontinuation (eg. after 
screening/baseline, severe irritation (i.e., grade 3, described as severe or marked/intense) that 
requires treatment will be reported as an adverse event). 
Local irritation reactions in the treatment area are common and the Investigator may instruct 
Subjects to stop the application of treatment (“rest period”) to reduce Subject discomfort and to 
allow local skin reactions to subside based upon the Investigator’s clinical assessment. The 
Investigator may advise the subject to use the Sponsor provided moisturizer at this time. 
Treatment should resume as soon as the reaction subsides sufficiently to allow reapplication. The 
Subject should not miss the scheduled application for more than three (3) consecutive doses. The 
Subject should not modify or resume the treatment regimen without consultation with the 
Investigator. The Investigator may make this decision based upon a documented phone 
consultation or at an unscheduled visit. All dose modifications must be reported on the 
appropriate Study Medication Log & Dosing Compliance eCRF, along with Subject 
documenting in the subject diary. 
The treatment period should not be extended beyond 12 weeks due to missed doses or rest 
periods. Subjects whose condition worsens or lesions do not respond to treatment following at 
least 28 days (or in the opinion of the Investigator) should be re-evaluated by the Investigator 
and management reconsidered. 
6.4 Adverse Events  
An adverse event (AE) is defined as any untoward medical occurrence (sign, symptom or 
abnormal laboratory finding) regardless of severity in a Subject or clinical-trial Subject 
administered a medicinal product and which does not necessarily have to have a causal 
relationship with this treatment. All adverse events, whether observed by an Investigator or 
Study Coordinator or reported by the Subject, whether related to study drug or not related to 
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description of the AE, the duration and intensity of each episode, the action taken, the 
relationship to the IMP and the degree of severity, the seriousness, date of resolution and the 
outcome.  
All reported adverse events and serious adverse events will be recorded and reported as per 
section 11.0 Adverse Events. 
6.5 COVID-19 symptom screening 
Temperature check and COVID-19 symptom (such as Stuffy or runny nose, Sore throat, 
Shortness of breath (difficulty breathing), Cough, Low energy or tiredness, Muscle or body 
aches, Headache, Chills or shivering, feeling hot or feverish (temperature check), vomiting, 
diarrhea, loss of sense of taste and smell) screening will be done for each subject at visit 1, 2, 3, 
4 and Unscheduled / Early Discontinuation visit. During the screening, if the subject found to 
have any one of the above said symptoms, then it will be judged by the investigator whether it is 
related or not-related to COVID-19 and appropriate procedures will be followed by the 
investigator and site10. 
6.6 Lack of Treatment Effect (LOTE) 
After completion of at least 4 weeks of the treatment period, if the subject comes to the 
Investigator and informs about not observing the desired treatment effect, then Investigator will 
evaluate the lesion counts and IGA scores and judge the lack of treatment effect. If the subject 
makes the decision to withdraw or discontinue from the study, then the reason for 
withdrawal/discontinuation will be coded as “lack of treatment effect (LOTE).”  The subject 
would be included in the PP population as a treatment failure using Last Observation Carried 
Forward (LOCF).  
7 CLINICAL EVALUATIONS 
An examination of the Subject’s face will be performed at screening/baseline and at each 
subsequent visit.  During the dermatologic examination, evaluations to determine efficacy of 
treatment will be conducted, including grading of the Subject’s facial acne using the criteria 
outlined in the IGA and lesion counts. The IGA should be done before lesion counts. 
Preferably a single Investigator (i.e., Principal Investigator or Sub-Investigator) or qualified staff 
will perform evaluations of efficacy (i.e., lesion counts and IGA) for each Subject at each visit 
from the beginning to the end of the Subject’s participation to maintain consistency and lessen 
interrater variability; however, only up to two Investigators or qualified staff may perform 
evaluations of efficacy for a single Subject if necessary. All efforts should be made to have the 
same evaluator at Visit 4 as Visit 1.  
All Investigators or qualified staff who will perform evaluations of efficacy must attend study-
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7.1 Investigator’s Global Assessment (IGA) 
At each study visit, beginning at Visit 1, an Investigator will assess the overall status of the 
Subject’s face for acne vulgaris using the IGA. To be included in the study, subjects must have a 
definite clinical diagnosis of acne vulgaris of severity grade 2, 3, or 4 at screening/baseline.  
The following scale will be used for the IGA: 
 
Grade  
Definition  
0 
Clear skin with no inflammatory or non-inflammatory lesions 
1 
Almost clear; rare non-inflammatory lesions with no more than one 
small inflammatory lesion 
2 
Mild severity; greater than Grade 1; some non-inflammatory lesions 
with no 
more than a few inflammatory lesions (papules/pustules only, no 
nodular 
lesions)  
3 
Moderate severity; greater than Grade 2; up to many non-
inflammatory lesions 
and may have some inflammatory lesions, but no more than one 
small nodular 
lesion 
4* 
Severe; greater than Grade 3; up to many non-inflammatory lesions 
and may 
have some inflammatory lesions, but no more than a few nodular 
lesions 
* The eCRF will allow for reporting by Investigators of lesion worsening beyond 
Grade 4 with treatment. Subjects with nodulocystic acne vulgaris are not to be 
enrolled in the study. Subjects who worsen beyond Grade 4 will be described in the 
safety evaluation. 
Please note that counts of nodules and cysts will be reported separately and not included in the 
inflammatory or non-inflammatory lesion counts. 
7.2 Lesion Counts 
At each study visit, beginning at Visit 1, an Investigator will assess by counting the number of 
open and closed comedones (non-inflammatory lesions), pustules and papules (inflammatory 
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including those present on the nose. Counts of nodules and cysts should be reported separately 
and not included in the inflammatory or non-inflammatory lesion counts. A papule with a 
pustule on its apex will be counted as a pustule.  Lesions involving the eyes, lips/mouth and 
scalp should be excluded from the count. Identity of the evaluator will be recorded in the source 
and the eCRF. 
To be included in the study, subjects must have  25 non-inflammatory lesions (i.e., open and 
closed comedones) AND  20 inflammatory lesions (i.e., papules and pustules) AND  2 
nodulocystic lesions (i.e., nodules and cysts), at screening/baseline on the face.  
 
Lesion Type  
Definition 
Closed Comedone 
Non-inflammatory lesion; whitehead, skin-colored or 
slightly inflamed “bump” in the skin 
Open Comedone 
Non-inflammatory lesion: blackhead, surface of the 
plugged sebaceous follicle has a blackish appearance 
Papule 
Inflammatory lesion: a small ( 5mm in diameter), 
solid palpable lesion, usually with inflamed elevation 
of the skin that does not contain pus 
Pustule 
Inflammatory lesion: a small ( 5mm in diameter), 
inflamed skin swelling that is filled with pus 
Nodules 
Large, hard bumps under the skin's surface 
Cysts 
Similar to a nodule, but is pus-filled, and  5mm in 
diameter 
8 STUDY VISITS (SEE STUDY VISIT SCHEDULE) 
8.1 Visit 1: Screening and Baseline (Day 0)  
The following procedures will be performed at Visit 1:  
1. Written informed consent/assent will be obtained. Subjects who are 18 years of age or 
older (up to the age of 40) must have provided IRB/IEC approved written informed 
consent. Subjects 12 to 17 years of age, inclusive, must have provided IRB/IEC approved 
written assent. Written assent must be accompanied by an IRB/IEC approved written 
informed consent from the Subject’s legally acceptable representative (i.e., parent or 
guardian). Prior to initiating screening for the study, Subjects will be given the approved 
ICF/informed assent form (IAF) describing the study and any risks associated with 
participation. The Subject will be allowed as much time as needed to read and understand 
the information presented in the consent/assent form. Appropriate study personnel will be 
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related procedures. If the Subject chooses to participate in the study, he or she will be 
asked to sign and date the consent/assent form and will be provided with a copy for his or 
her records. Both the ICF and assent (if applicable) must be signed by the Subject or the 
Subject’s legally acceptable representative (i.e., parent or guardian) before any protocol 
assessments can be undertaken. 
 
2. Screening/Baseline Demographics: Demographics will be collected, including date of 
birth, gender, race and ethnicity. 
3. COVID-19 symptom screening.  
4. Medical History: A complete medical history will be obtained for the Subject’s current 
and past medical conditions. Significant medical history should include, but not be 
limited to, evidence of hypertension, lipid disorders, obesity*, heart attack, stroke, 
congestive heart failure, kidney disease, and auto immune disease and gestational 
diabetes. Significant surgical history should include, but not be limited to, removal of 
blockage from an artery and gallbladder removal. 
* Obesity = BMI 30 (as defined by Metropolitan Life Insurance Company Chart) 
5. Vitals: Vital signs (blood pressure, pulse, respiratory rate and body temperature) will be 
documented. Subjects must remain in a seated position for at least 5 minutes before vital 
signs are obtained. 
6. Physical Examination: A brief physical examination, including height (measured in 
inches) and weight (measured in pounds), will be performed. At a minimum, the physical 
examination will include the following: assessment of general appearance, skin, Head, 
Eyes, Ears, Nose and Throat (HEENT), heart, lungs, musculoskeletal system, lymph 
nodes, neurological systems, abdomen, and extremities. 
7. Concomitant Medications: A complete list of current and past (within the previous 6-
months) concomitant medications will be obtained for each Subject.  
8. Pregnancy Test: A urine pregnancy test will be conducted for all females of 
childbearing potential.  
9. Clinical Assessment:   An evaluation of the patient’s acne will be performed by an 
Investigator to determine the severity of the acne and confirm the diagnosis of acne 
vulgaris. 
10. Investigator Global Assessment: The overall status of the Subject’s facial acne vulgaris 
(from the jaw line to the hairline) will be assessed using the IGA.  
11. Lesion Count: Lesion counts will be done by counting the number of facial open and 
closed comedones, pustules, papules and nodulo-cystic lesions from the jaw line to the 
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12. Application Site Reaction: Subjects will be evaluated for any signs and symptoms such 
as erythema, dryness, burning/stinging, erosion, edema, pain and itching.  
13. Inclusion/Exclusion Criteria: When the Subject has completed all screening procedures, 
compliance with the inclusion and exclusion criteria will be reviewed. After the inclusion 
and exclusion criteria have been confirmed, the Subject will be randomized to a treatment 
group. The Subject will be assigned a randomization number.  
14. Adverse Events: The occurrence of all AEs will be assessed and documented following 
procedures.  
15. Randomization: Subjects will be randomly assigned in a treatment allocation ratio of 
1:1:1 to receive the Test product or the Reference Product or the Placebo control, 
respectively. The Independent Dispenser will dispense IMP using the IWRS system.  
16. Investigational Medicinal Product and Supplies: The following will be dispensed 
during Visit 1 post randomization by the Independent Dispenser:  
• 
The investigational product (1 pump) 
• 
Non-medicated cleanser  
• 
Sunscreen with SPF 15 or greater 
• 
Two packs Towels 
• 
A diary card to record product use from Visit 1 to Visit 2 
Depending upon the severity of the need, the Investigator may instruct the Subject to use a non-
medicated, non-comedogenic moisturizer. A non-medicated moisturizer may be dispensed for 
use at the instruction of the Investigator. 
Randomized Subjects will be instructed by the Independent Dispenser on the correct method for 
the application of the IMP. The application of the IMP will be performed by the Subject at home, 
instructed to apply the first dose in the evening. The study restrictions will also be reviewed with 
the Subject and an instruction sheet will be issued to the Subject.  
Randomized Subjects will be provided with a diary and instructed how and when to complete the 
diary. They will be told that they are to document all treatments administered, including the date 
and time and all treatments missed. In addition, Subjects will be instructed to document all AEs. 
Subjects will also be instructed to call the study site if they experience any severe intolerability 
(i.e., local skin reactions) to IMP. 
17. Visit 2 (Day 28 ± 4 days from the date of Visit 1): will be scheduled and the Subject will 
be instructed to bring all IMP (used, unused, and partially used) and the Subject diary 
with him or her to this visit. Subjects will be reminded not to use any facial topical 
products within 12 hours prior to the next scheduled clinic visit. 
 


  
 
 
 
 
 
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8.2 Visit 2: First Interim (Week 4; Day 28 ± 4 Days) 
The following procedures will be performed at Visit 2: 
1. Initial Check: Temperature check and COVID-19 symptom screening.  
2. Pregnancy Test: A urine pregnancy test will be conducted for all females of 
childbearing potential.  
3. Subject Compliance: The Subject’s compliance with the study protocol, including use, 
application and compliance of IMP, will be assessed. The Subject’s diary will be 
collected and reviewed for completion.  
4. Investigational Medicinal Product: The Subject’s IMP dispensed at Visit 1 will be 
returned to the Independent Dispenser for review and re-dispensed if IMP remains.  
5. Concomitant Medication: The use of concomitant medications since the previous study 
visit will be documented and assessed for each Subject.  
6. Adverse Events: The occurrence of all AEs will be assessed and documented following 
procedures.  
7. Investigator Global Assessment: The overall status of the Subject’s facial acne vulgaris 
(from the jaw line to the hairline) will be assessed using the IGA by the Investigator or 
qualified staff member.  
8. Lesion Count: Lesion counts will be done by counting the number of facial open and 
closed comedones, pustules, papules and nodulo-cystic lesions from the jaw line to the 
hairline. All lesions will be counted, including those present on the nose.  
9. Application Site Reaction: Subjects will be evaluated for any signs and symptoms such 
as erythema, dryness, burning/stinging, erosion, edema, pain and itching.  
10. Investigational Medicinal Product and Supplies:  
The following will be dispensed during Visit 2:  
x The investigational product (1 pump) (new pump assigned through the 
randomization system and or pump from screening/baseline visit re-dispensed if 
sufficient IMP remains) 
x One pack of Towels  
x Cleanser (as required) 
x A diary card will be dispensed to record product use from Visit 2 to Visit 3 
Depending upon the severity of the need, the Investigator may instruct the Subject to use a non-
medicated, noncomedogenic moisturizer provided by the Sponsor. If the moisturizer was not 
dispensed at Visit 1, one bottle of non-medicated moisturizing cream or lotion may be dispensed, 
only if necessary. It is not anticipated that Subjects will require additional supplies during this 
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11. Study instructions will be reviewed with the Subject, including the procedure for 
application of the IMP.  
12. Visit 3 (Day 56 ± 4 days from the date of Visit 1): will be scheduled and the Subject will 
be instructed to bring all IMP (used, unused, and partially used) and the Subject diary 
with him or her to this visit. Subjects will be reminded not to use any facial topical 
products within 12 hours prior to the next scheduled clinic visit. 
8.3 Visit 3: Second Interim (Week 8; Day 56 ± 4 Days)  
The following procedures will be performed at Visit 3: 
 
1. Initial Check: Temperature check and COVID-19 symptom screening.  
2. Pregnancy Test: A urine pregnancy test will be conducted for all females of 
childbearing potential.  
3. Subject Compliance: The Subject’s compliance with the study protocol, including use, 
application and compliance of IMP, will be assessed. The Subject’s diary will be 
collected and reviewed for completion.  
4. Investigational Medicinal Product: The Subject’s IMP dispensed at the previous 
visit(s) will be returned to the Independent Dispenser for review, collection and or re-
dispensed if IMP remains.  
5. Concomitant Medication: The use of concomitant medications since the previous study 
visit will be documented and assessed for each Subject. 
6. Adverse Events: The occurrence of all AEs will be assessed and documented following 
procedures.  
7. Investigator Global Assessment: The overall status of the Subject’s facial acne vulgaris 
(from the jaw line to the hairline) will be assessed using the IGA.  
8. Lesion Count: Lesion counts will be done by counting the number of facial open and 
closed comedones, pustules, papules and nodulo-cystic lesions from the jaw line to the 
hairline. All lesions will be counted, including those present on the nose.  
9. Application Site Reaction: Subjects will be evaluated for any signs and symptoms of 
signs and symptoms of facial irritation such as erythema, dryness, burning/stinging, 
erosion, edema, pain and itching.  
10. Investigational Medicinal Product: 
The following will be dispensed during Visit 3:  
x The investigational product (1 pump) (new pump assigned through the 
randomization system if required and or pump dispensed at Visit 2 re-
dispensed if IMP still remains). 
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x Cleanser (as required) 
x A diary card will be dispensed to record product use from Visit 3 to Visit 
4. 
Depending upon the severity of the need, the Investigator may instruct the Subject to use a non-
medicated, noncomedogenic moisturizer provided by the Sponsor, only if necessary. If the 
moisturizer was not dispensed at the previous study visits, one bottle of non-medicated 
moisturizing cream or lotion may be dispensed. It is not anticipated that Subjects will require 
additional supplies during this visit; additional supplies will be dispensed if required. 
11. Study instructions will be reviewed with the Subject, including the procedure for 
application of the IMP.  
12. Visit 4 (Day 84 ± 4 days from the date of Visit 1): will be scheduled and the Subject will 
be instructed to bring all IMP (used, unused, and partially used) and the Subject diary 
with him or her to this visit. Subjects will be reminded not to use any facial topical 
products within 12 hours prior to the next scheduled clinic visit. 
8.4 Visit 4: End of Treatment (Week 12; Day 84 ± 4 Days)  
The following procedures will be performed at Visit 4: 
1. Initial Check: Temperature check and COVID-19 symptom screening.  
2. Pregnancy Test: A urine pregnancy test will be conducted for all females of 
childbearing potential.  
3. Subject Compliance: The Subject’s compliance with the study protocol, including use, 
application and compliance of IMP, will be assessed. The Subject’s diary will be 
collected and reviewed for completion.  
4. Investigational Medicinal Product: The Subject’s IMP dispensed at the previous 
visit(s) will be returned to the Independent Dispenser.  
5. Concomitant Medication: The use of concomitant medications since the previous study 
visit will be documented and assessed for each Subject.  
6. Adverse Events: The occurrence of all AEs will be assessed and documented following 
procedures. 
7. Investigator Global Assessment: The overall status of the Subject’s facial acne vulgaris 
(from the jaw line to the hairline) will be assessed using the IGA.  
8. Lesion Count: Lesion counts will be done by counting the number of facial open and 
closed comedones, pustules, papules and nodulo-cystic lesions from the jaw line to the 
hairline. All lesions will be counted, including those present on the nose.  
9. Physical Examination: A brief physical examination, including height (measured in 
inches) and weight (measured in pounds), will be performed. At a minimum, the physical 
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Eyes, Ears, Nose and Throat (HEENT), heart, lungs, musculoskeletal system, lymph 
nodes, neurological systems, abdomen, and extremities. 
10. Application Site Reaction: Subjects will be evaluated for any signs and symptoms of 
erythema, dryness, burning/stinging, erosion, edema, pain and itching.  
8.5 Unscheduled Visits and Early Discontinuation Visit 
An Unscheduled Visit is allowed at any time, for any reason, if in the Principal Investigator’s 
opinion, it is warranted. If the Unscheduled Visit is due to an AE, the Principal Investigator will 
determine whether additional visits are needed.  
If a Subject is discontinued from the study during an Unscheduled Visit, the Unscheduled Visit 
will be referred to as an Early Discontinuation Visit and all procedures scheduled for the Early 
Discontinuation Visit will be performed. If the Unscheduled Visit is not an Early 
Discontinuation Visit (i.e., the Subject will continue to take part in the study), then the reason for 
the unscheduled visit is documented and required procedures at the discretion of Investigator 
considering the reason for visit will be performed apart from the collection of IMP and Subject 
diaries from Subjects.   
If the Subject’s condition has worsened to the degree that it is unsafe for the Subject to continue 
in the study, the Subject may be discontinued from the study as treatment failure and a standard 
of care treatment may be advised at the Principal Investigator’s discretion. 
   
8.6 Premature Termination of Study/Study Site 
The Sponsor reserves the right to discontinue the study at any time. The reasons will be 
discussed with the Investigator. A study site may also be discontinued by the Sponsor for 
significant deviations from the protocol or due to difficulties experienced in running the study at 
that center. 
The Sponsor may terminate this study in one particular or several study center(s) for one (or 
other) of the following reasons: 
a. Non-compliance with GCP and/or regulatory requirements 
b. Centre cannot recruit an adequate number of subjects 
c. False data captured in the eCRF due to carelessness or deliberately 
d. Inadequate co-operation with the Sponsor or its representatives 
e. The Investigator requests closure of his/her study center. 
If the study is prematurely terminated in one or more study centers, all Investigators have to 
inform their subjects and take care of appropriate follow-up and further treatment of the subjects. 
Ethics Committees and regulatory authorities will be informed about the reason and time of 
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The CRO should inform Teva Pharmacovigilance if the whole study is early discontinued due to 
safety reasons and should provide Teva Pharmacovigilance with the Early Termination Report. 
8.7 Early Termination of a Subject 
 A subject may terminate from the study early for any reason at any time without any 
disadvantages. In this case, the Investigator should make every effort to have the subject return 
to the next scheduled visit to perform all required Early Termination (Early Discontinuation) 
visit activities and to collect and reconcile all study IMP.  If the subject does not return for the 
Early Termination (Early Discontinuation) visit, the site should fully document the reason for 
early termination. All data, including the date and primary reason for termination, must be 
recorded on the Early Termination (Early Discontinuation) case report form (CRF), and source 
document. 
Any subject who experiences an adverse event may be terminated from the study or from study 
treatment at any time at the discretion of the Investigator. In this case, the subject should be 
followed at the discretion of the Investigator until the resolution or stabilization of the AE. All 
applicable data should be recorded in the adverse events section of the case report form (CRF). If 
a subject terminates from the study early for multiple reasons that include adverse events, the 
Early Termination (Early Discontinuation) case report form should indicate that early 
termination was related to an adverse event.  
An exception to this requirement will be the occurrence of an adverse event that in the opinion of 
the investigator is not severe enough to warrant early termination but that requires the use of a 
prohibited medication, thereby requiring discontinuation of the subject. In such a case, the reason 
for discontinuation would be needed to take a prohibited medication, not the adverse event. 
The Investigator must inform the Medical Monitor and CRO as soon as possible of all subjects 
who are being considered for early termination due to adverse events. Additional reports must be 
provided when requested. The CRO will inform the Sponsor of this event.  
9 STUDY TREATMENT, DESCRIPTION AND ALLOCATION  
9.1 Investigational Medicinal Products (IMP) Description 
All study medications will be dispensed by and returned to a qualified Independent Dispenser 
designated by the Principal Investigator. The Independent Dispenser will not be involved in 
performing any of the clinical assessments (IGA, lesion count, evaluation of signs and symptoms 
of local irritation, or evaluation of safety). 
The IMP will be dispensed only from the institution(s) approved by an Institutional Review 
Board. 
The following treatments will be self-administered or administered by the Subject's caregiver 
during this study. 
The IMP supplied in 45 gm pumps, by the Sponsor will consist of the following: 


  
 
 
 
 
 
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Test Product: 
TRIFAROTENE CREAM, 0.005% (Manufactured by 
Actavis Laboratories, Salt Lake City, UT for Teva 
Pharmaceuticals, Inc.) 
Reference 
Product: 
AKLIEF® (TRIFAROTENE 0.005% CREAM) 
(GALDERMA LABORATORIES, L.P., USA) 
Placebo Control: 
Placebo (Vehicle) topical cream (Manufactured by Actavis 
Laboratories, Salt Lake City, UT for Teva Pharmaceuticals, 
Inc.) 
9.2 Storage and Handling Conditions  
x Store at 20 to 25ÛC (68 to 77ÛF) with excursions permitted to 15°to 30°C (59° to 86°F) 
in a secured, authorized access area at the investigative site. 
x Keep away from heat. 
x Keep out of reach of children. 
9.2.1 Packaging, Blinding and Labeling  
The IMP will be randomized, packaged and blinded by an independent packaging team (Actavis 
Laboratories, Salt Lake City, UT). The labeling and packaging scheme will be outlined in a 
separate document by the Sponsor. The label content of IMP products will meet the requirements 
of ICH GCP guidelines, country specific guidelines and study protocol. 
The randomization will be pre-planned according to a computer-generated randomization 
schedule so that the test product, reference product and placebo are assigned in a 1:1:1 ratio. The 
study product will be packaged identically; an individual pump of study product (i.e., either Test, 
Reference or Placebo) will be packaged, as a “subject kit”. Each subject will be assigned to one 
kit.  
Using SyMetric System’s Interactive Web Response Technology system (i.e., IWRS), all 
subjects consented and screened into the study will be assigned a “Subject Number.” The 
Subject Number is the only subject identifier for subjects who are screened into the study (i.e., 
after being consented). The Subject Number is assigned, when a subject is screened into the 
study (i.e., after being consented). The study subject numbers will be assigned to study subjects 
sequentially in the order in which study subjects are enrolled into the study. The Subject Number 
will be an 8-digit number: comprised of a 2-digit Country number 3-digit Site number and 3-
digit Sequence number.  
The system will also assign a study product kit number (based on the randomization schedule 
created by an independent biostatistician). The study product kit number is the identifying 
number listed on the study product dispensed to eligible (i.e., at each dispensing point in the 
study, at Visit 1, and 2 or 3 as required) subjects. The study product kit number is a 5-digit 
number. This will be the identifier used for randomized patients (i.e., randomization number). 


  
 
 
 
 
 
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Both the subject number and randomization number will be entered into the subject's eCRF. 
Each time a subject is dispensed study product (i.e., at Visit 1, and 2 or 3 as required, and when 
applicable unscheduled visit), the subject will receive a new study product kit number. The 
Subject Number and study product kit numbers will be recorded in the Subject Source and 
eCRF. Each subject will maintain the same subject number and treatment assignment throughout 
the study. 
A label will be attached to each of the pumps of study product.  The label will include at least the 
following information: Protocol number, subject number, study product kit number, space for 
subject’s initials, statement that the study product is for Investigational Use only, space for 
dispensing date and the Sponsor’s name. In addition, all subjects will be provided with written 
instructions on how to use the study product. . 
The study product will be blinded, packaged and delivered to the Investigative Site in bulk. The 
study medications will be shipped to the Investigator’s site from a centralized location.  
This is a double-blind clinical endpoint bioequivalence study. The IMP will be labeled and 
packaged such that neither the Subject nor any Investigator or study can identify the treatment. 
The Investigator, staff at the study site, study monitors, and data analysis/management personnel 
will be blinded to the treatment assigned to the subject. The study site will have at least one 
Independent Dispenser. The role of the unblinded Independent Dispenser will be to randomize, 
dispense and collect study medication to/from the subjects, maintain dispensing records, and 
ensure the study medication logs are complete and accurate. The subject will be requested not to 
discuss the appearance of the study medication with the Investigator or study staff outside of the 
Independent Dispenser. Independent dispenser should not participate in any activities other than 
the activities defined in this section. 
The Principal Investigator will be responsible for ensuring that all study products are stored in a 
locked, secure location, with access limited to the Investigator and his/her designee(s). An 
accurate inventory of the study medication will be maintained in accordance with federal 
regulations. 
To ensure that information that could potentially bias handling of data is not disclosed, the 
packaging team will hold the randomization scheme until after database lock. At the end of the 
study, after all the clinical data has been entered and the study database has been locked, a copy 
of the randomization schedule will be sent to the statistician by SyMetric. In addition, after the 
database has been locked, the packaging site will send each Investigative Site a sealed envelope 
containing the full study randomization scheme that should be retained with the study documents 
in the event of an FDA Inspection. 
9.2.2 Randomization 
The randomization schedule for this study will be generated by SyMetric, a third-party vendor of 
Catawba Research such that a non-study-assigned independent expert will allocate the subjects 
to one of the three treatment arms using a computer-generated automated process, i.e., Integrated 
Web Response System (IWRS). A copy of the randomization scheme (respective to that site) 
will be retained at the study site following the completion of the study and should be available to 


  
 
 
 
 
 
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regulatory authority inspectors at the time of site inspection to allow for verification of the 
treatment identity of each subject.  
 
9.2.3 Subject Screening Number 
Once a subject has signed the ICF, the subject will be assigned with a screening number, starting 
with three-digit site numbers followed by three-digit number starting from 001 in chronological 
order of screening in each site (e.g., 01001 for the first subject who signed ICF and screened at 
site 01).  The sites will assign the subject the screening number and the number will be 
maintained outside SyMetric’s IWRS until a subject is randomized. 
9.3 Treatment Assignment  
The subject study identification number will correspond to a computer-generated randomization 
schedule assigning that number to one of the three study treatment groups. The randomization 
scheme will be generated so that the test product, the reference product and the vehicle (placebo) 
control are assigned in a 1:1:1 ratio. The subject numbers at the site will correspond to the order 
in which subjects are enrolled into the study. 
 
9.4 Administration of Investigational Medicinal Product  
At Visit 1, IMP will be dispensed by the Independent Dispenser to randomized Subjects along 
with a diary. Each Subject will also receive written study instructions, which detail the proper 
application method of the IMP and general study instructions. Before each application, Subject 
should wash their face with a non-medicated cleanser (provided by the Sponsor), and pat dry.
Skin should be allowed to dry for 20-30 minutes before applying study medication. The skin 
should be completely dry in order to minimize possible irritation. The Independent Dispenser 
will instruct the Subject not to open the IMP containers at the study center and to apply enough 
product to lightly cover the entire affected areas of the face once daily in the evening, preferably 
at bedtime.  
Contact with the eyes, lips/mouth, angles/corners of the nose, open wounds and other mucous 
membranes should be avoided. Hands should be washed before and after applying the study 
medication. IMP should be applied in this manner daily for 84 days. 
Subjects will be required to use diaries to document the date and time of application of study 
treatments, any missed treatments and the occurrence of all adverse events. 
Subjects will be instructed not to bathe, shower, wash or swim for at least 4 hours after the 
application of the IMP.  
 
9.5 Assessment of Compliance  
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Subject will be instructed to use the diary to document all doses taken by checking the yes or no 
box for the appropriate date. In addition, Subjects will be instructed to document all concomitant 
medication and AEs on the diary. Used IMP will be returned to the study site at each scheduled 
visit or Early Discontinuation Visit or as applicable. If the subject does not return the Diary, 
compliance cannot be determined. Subjects taking fewer than 75% or more than 125% of the 
required doses, or who miss the scheduled applications for more than 3 consecutive days will be 
considered non-compliant and will be excluded from PP population. 
Compliance criteria are as outlined in the table below: 
For subjects who have completed the study: 
 
  
Compliance Criteria 
Study 
Period 
Duration 
Scheduled 
Doses 
Not 
more 
than 
125% 
(doses) 
Not 
less 
than 
75% 
(doses) 
Randomized 
Treatment 
84 Days 
84 
105 
63 
 
  
9.6 Investigational Medicinal Product Accountability  
It is the responsibility of the Principal Investigator to ensure that the current disposition of the 
IMP is maintained at each study site where IMP is inventoried and dispensed. When a drug 
shipment is received at a study site, the Principal Investigator or the Principal Investigator’s 
Designee (for the purposes of this study the Independent Dispenser) must inventory the drug and 
sign the receipt form provided with the shipment. The receipt form should be emailed as per 
instructions provided on the receipt.  A copy of the receipt should remain at the site. 
The Principal Investigator at each site is responsible for ensuring that all investigational products 
are stored in a locked, secure location, with access limited to the Investigator and his/her 
designee(s). The Investigator will not supply study test articles to any person not enrolled in this 
study, or to any physician or scientist except those named as sub-investigators. 
A Drug Accountability Log will assist study site staff in maintaining inventory records of study 
drug and is necessary for monitoring. An accurate inventory of the IMP will be maintained by 
the Independent Dispenser, in accordance with federal regulations. Subject’s must return used, 
partially used or unused IMP to the Independent Dispenser, at the end of the study, (Visit 4) so 
that any remaining drug supplies can be accounted for and noted in the Drug Accountability Log.  
The certified copy of Drug Accountability Log must be provided to the study monitor at the 
conclusion of the study and the original should remain at the study site.  


  
 
 
 
 
 
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Once the site has been notified that they may do so, all unused investigational product and empty 
or partially used pumps of investigational product, other than the randomly selected for retention 
samples, will be returned to the Drug Labeling, Packaging and Shipping Facility (Actavis 
Laboratories UT, Inc.)  or be destroyed at the site after study close-out following approval from 
the Sponsor, and final drug accountability is reconciled.  
 
9.7 Retention of Study Drug Samples  
Enough of the study drug will be retained amongst the sites participating in the study to meet the 
sample retention requirements of the US-FDA 21 CFR 320.38, 320.63, Guidance for Industry 
“Compliance Policy for the Quantity of Bioavailability and Bioequivalence Samples Retained 
Under 21 CFR 320.38(c)” and the Guidance for Industry "Handling and Retention of BA and BE 
Testing Samples”. 
Samples of study drug will be randomly selected at the investigational site, in accordance with 
21 CFR 320.38, 320.63, Guidance for Industry “Compliance Policy for the Quantity of 
Bioavailability and Bioequivalence Samples Retained Under 21 CFR 320.38(c)” and the 
Guidance for Industry, “Handling and Retention of BA and BE Testing Samples”, regarding 
retention of study drug samples. and 21 CFR 320.36 for requirements for maintenance of records 
of bioequivalence testing. In addition, the Investigators should follow the procedures of 21 CFR 
58 and ICH E6, “Good Clinical Practice: Consolidated Guideline”, for retention of study records 
and data in order to conduct their studies in compliance with Good Laboratory Practices (GLP) 
and Good Clinical Practices (GCP).  
Each reserve sample will be stored under conditions consistent with product labeling [Store at 
room temperature between 20°C - 25°C (68°F to 77°F)] and with access limited to authorized 
personnel. Each reserve sample will be retained for a period of at least 5 years following the 
date on which the application or supplemental application is approved, or, if application is not 
approved, at least 5 years following the date of completion of the study. 
Upon receipt of the investigational products, designated site personnel will randomly select 9 
kits (ensuring 3 are test, 3 are reference and 3 are placebo) from each shipment prior to 
dispensing to subjects and document on the Retention Sample Checklist. The selection process 
will ensure a sufficient amount of retention samples are retained as per Sponsor requirement. 
The number of subject kits kept for retention will be noted on the study product accountability 
form, as a retention sample, in addition to the retention sample log. The study site PI is 
responsible for storage of retention samples while at the site, until shipment to a third-party 
repository.  
To ensure samples are not confused with investigational product for subject use and to ease the 
storage burden at a site, the randomly selected retention samples of investigational product will 
be transferred by the sites to an independent biorepository vendor, an independent third-party 
storage facility for long term storage. To ensure compliance with product specific storage 
requirements, the original label should not be covered with a new shipping label. If the retention 
samples are remaining at a site (eg. Belize sites), the Standard Operating Procedure (SOPs) will 


  
 
 
 
 
 
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be followed in order to comply with the regulations. 
The samples can be retrieved from the storage facility at any time upon FDA notification of the 
visit or during a pre-approval inspection conducted by authorized FDA personnel. The samples 
can be returned to the investigational site or submitted to the place identified in the agency's 
request. The request has to be sent directly to an independent biorepository vendor by email or 
fax from the site. The Sponsor (Teva Pharmaceuticals, Inc.) and CRO (Catawba Research) must 
be notified, and copies of documentation should be sent to the individuals listed below: 
 
Retention Samples 
Storage Facility  
 
BioRepository 
Resources, LLC 
755 Central Avenue, 
Unit 3 
New Providence, NJ 
07974 
 
Glenn Bullett  
President  
Email: 
gbullett@brr.us.com   
Phone: (908) 790-8890  
Fax: (908) 790-8899  
Cell: (908) 635.3777 
Sponsor  
 
Teva Pharmaceuticals, Inc,  
400 Interpace Parkway, 
Bldg. A  
Parsippany NJ 07054, USA 
 
Corrine Dias 
Associate Director, Global 
Gx. - Clinical Development 
& Operations 
Cell: 416-903-5489 
Email: 
corrine.dias@tevapharm.com 
Clinical Research 
Organization:  
 
Catawba Research 
5200 77 Center Drive, Suite 
120 
Charlotte, NC 28217 
 
Chris Driskill 
Clinical Project Manager 
Office: Cell: 704-502-3007  
Fax: (980) 422-0783 
Email: 
chris@catawbaresearch.com  
9.8 Return of Clinical Supplies  
Except for the retention samples, all used and unused pumps of IMP may be returned to the Drug 
Labeling, Packaging and Shipping Facility (Actavis Laboratories UT, Inc.) for destruction or be 
destroyed at the site after study close-out following approval from the Sponsor, and final drug 
accountability is reconciled. 
It is important that retention samples and all used and unused pumps of IMP not be returned to 
CRO (Catawba Research) or the Sponsor (Teva) at the end of the study.  
9.9 Additional Supplies Provided by The Sponsor 
Subjects will be provided with a non-medicated cleanser to cleanse the face, paper towels to pat 
the face dry before applying the study medication, and sunscreen for use when sun exposure 
cannot be avoided.  A non-medicated, non-comedogenic moisturizer will also be provided. 
Depending upon the severity of the need, the Investigator may instruct the Subject to use the 
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For the purpose of this study, the following items will be provided by the Sponsor: 
x Non-medicated cleanser  
x Sunscreen with SPF 15 or greater 
x Soft towels  
x Non-medicated moisturizing cream or lotion.   
10 STATISTICAL METHODS  
10.1 Scientific and Statistical Considerations of the Study Design 
The study was designed following FDA Draft Guidance on Trifarotene Recommended May 
20216 and FDA Draft Guidance on Adapalene; Benzoyl peroxide Gel; topical, Recommended 
Dec 2016; Revised Nov 2018, Nov 20197 and Guidance for Industry -Acne Vulgaris: 
Establishing Effectiveness of Drugs Intended for Treatment, May 20184. 
 
10.1.1 Sample Size Rationale  
Sample size calculations are based on information from a Medical Review11 for developing a 
bioequivalence study comparing Trifarotene cream 0.005% after 12 weeks of treatment.  It 
appears that an appropriate estimate for the percent reduction for inflammatory lesions for active 
treatments is 60% with that for vehicle treatment 12.3% lower, at 48.7% reduction.  For non-
inflammatory lesions an appropriate estimate for percent reduction for active treatment is 53.5% 
with vehicle treatment at 39.6%.  The standard deviation for both inflammatory and non-
inflammatory percent lesion reductions should be no more than 33% and 38% for active and 
vehicle treatments, respectively. 
The following assumptions were used in computer simulations to determine the sample size. 
 
Lesion 
Type 
Active  
% Reduction 
Active  
Std. Dev. 
(%) 
Vehicle  
% Reduction 
Vehicle  
Std. Dev. 
(%) 
Inflammatory 
60.0 
33 
48.7 
38 
Non-
Inflammatory 
53.5 
33 
39.6 
38 
 
It is assumed that the Test and Reference products have equivalent efficacy and that 
approximately 82% of mITT subjects in a study will qualify for the PP population. 
Randomizing 765 subjects in the mITT (255:255:255 Test:Reference:Placebo) and 627 in the PP 
(209:209:209 Test:Reference:Placebo) should provide at least an 85% probability of showing 
that the 90% confidence intervals on the Test/Reference ratio of mean percent reduction from 
baseline, for both lesion types, are contained within the interval 0.800 to 1.250 in the PP 


  
 
 
 
 
 
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population and at the same time demonstrating that the Test and Reference products are 
statistically superior (p<0.05) to the placebo in the mITT population. 
10.1.2 Unblinding Procedures  
This is a Randomized, Double-blind, Three-Arm, Placebo Controlled, Parallel design, multi-
centre study. Subjects will be randomly assigned in a 1:1:1 ratio to receive the test product, the 
reference product and the vehicle (placebo) control. The randomization assignment will be 
generated using SAS® by an independent statistician (SyMetric), not involved with the study. The 
treatment each subject will receive will not be disclosed to the Investigators, study center 
personnel, subject, sponsor, or CRO involved in the study conduct, monitoring, data review or 
analysis. 
SyMetric will hold the randomization code throughout the conduct of the study in order to 
minimize bias. If necessary, for the safety and proper treatment of the subjects, the Investigator 
can unblind the subject’s treatment assignment to conduct appropriate follow-up care. Whenever 
possible, the Sponsor or medical monitor will be notified before unblinding the study 
medication. The date and signature of the person breaking the code as well as the reason for 
breaking the code and any associated AEs will be recorded in the subject’s source 
documentation. 
The Investigator, staff at the study site, study monitors, and data analysis/management personnel 
will be blinded to the treatment assigned to the subject, with the exception of the Independent 
Dispenser. The study site will have at least one Independent Dispenser. The role of the unblinded 
Independent Dispenser will be to dispense and collect study medication to/from the subjects, 
maintain dispensing records, and ensure the study medication logs are complete and accurate. 
The subject will be requested not to discuss the appearance of the study medication with the 
Investigator or study staff outside of the Independent Dispenser. Independent dispenser should 
not participate in any activities other than the activities defined in this section.  
In case of an emergency, if the details of the study drug are required for management of an 
emergency as per the opinion of Investigator, the Investigator can unblind the product that is 
received by the subject during the study. In case of non-emergency condition that requires study 
drug information for management of condition as per Investigator’s opinion, the Investigator 
should obtain Sponsor or medical monitor approval in writing prior to breaking of the blind. The 
unblinding can be performed through a computer-generated automated process, i.e., Interactive 
Web Response System (IWRS). It is recommended that all attempts should be made to maintain 
the study blind. However, in case that unblinding is performed, the reason for breaking the blind 
must be clearly documented in the source documentation and Case Report Form (CRF) and the 
subject must be discontinued from the study. 
The date on which the code was broken together with the identity of the person responsible must 
also be documented. 
The treatment assignments will remain blinded until the final database is locked. 
 


  
 
 
 
 
 
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10.1.3 Significance Level  
All statistical tests will be two-sided at a significance level of Į = 0.05, unless otherwise 
indicated. No adjustment will be made for multiplicity. 
 
10.2 Datasets to be Analyzed  
Three analysis populations will be used in the analysis of the clinical data: 
a. The mITT and safety populations include all randomized subjects who use at least one 
dose of product (compliance review from Subject diary). 
b. The Per Protocol (PP) population includes all mITT Subjects who: 
1.  meet all inclusion/exclusion criteria,  
2. apply 75% to 125% of the scheduled applications of the assigned product, did not 
miss more than three consecutive scheduled applications,  
3. return for the 12-week evaluation within the visit window (± 4 days; i.e., study 
Day 80-88), 
4.  and have no protocol deviations that affect proper administration of the treatment 
or accurate evaluation of its effectiveness. 
Subjects who are discontinued early from the study due to lack of treatment effect (LOTE) after 
completing minimum four (4) weeks of treatment will be included in the PP population as 
treatment failures (i.e., non-responders) using the Last Observation Carried Forward (LOCF) 
approach. In addition, subjects whose condition or symptoms worsens and require alternate or 
supplemental or rescue therapy for the treatment of their condition during the treatment phase of 
the study should be discontinued, included in the mITT and PP population analysis using LOCF, 
and provided with effective treatment. The use of supplemental medicines and rescue medicine 
will be per standard of care (SOC) per medical judgement of the Investigator.  All supplemental 
and rescue medicines will include name, dose, frequency of administration, start and end dates, 
which is supplied to discontinued subjects for worsening of conditions.   
Subjects discontinued early for other reasons should be excluded from the PP population, but 
included in the mITT population, using the Last Observation Carried Forward (LOCF) approach.  
Lack of treatment effect (LOTE): After completion of at least 4 weeks of the treatment period, if 
the subject comes to the Investigator and informs about not observing the desired treatment 
effect, then Investigator will evaluate the lesion counts and IGA scores and judge the lack of 
treatment effect. If subject makes the decision to withdraw or discontinue from the study, then 
the reason for withdrawal/discontinuation will be coded as “lack of treatment effect” (LOTE). 
The subject would be included in the PP population as a treatment failure using Last Observation 
Carried Forward (LOCF).  
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of treatment effect to show changes from screening/baseline to time of discontinuation (last 
observation).  
10.3 Measures 
At each visit, beginning at Visit 1, an Investigator will assess the overall status of the Subject’s 
facial acne vulgaris using the Investigator’s Global Assessment (IGA) and the Lesion Counts. 
Local irritation/application site reactions such as erythema, dryness, burning/stinging, erosion, 
edema, pain and itching will be recorded at each visit to allow a comparison between treatment 
groups. A detailed scale is presented. 
10.3.1 Demographics and Screening/Baseline/Randomization Characteristics   
Demographic and screening/baseline/randomization characteristics will be evaluated for 
comparability across treatment groups for the mITT, PP, and safety populations.  Continuous 
variables will be analyzed with an analysis of variance with factors of treatment and 
investigational site.  Categorical variables such as gender, ethnicity, and race will be analyzed 
with a Cochran-Mantel-Haenszel test, stratified by investigational site.  
10.3.2 Safety Assessment  
The extent of exposure will be summarized using descriptive statistics. No inferential analyses 
are planned. 
Incidence of all adverse events reported during the study will be summarized using the MedDRA 
dictionary by treatment group, body system, severity, and relationship to study drug. The 
comparability of the Test and Reference treatment groups for the frequency and severity of any 
adverse event that occurs in at least 5% of the subjects in either treatment group will be 
evaluated using categorical methods. 
The concomitant medications used will be summarized by treatment group. 
Application site reactions such as erythema, dryness, burning/stinging, erosion, edema, pain and 
itching will be summarized for the safety population by treatment group and study visit using 
frequencies and percentages of subjects. 
Safety analyses will be performed on the safety population. All safety data will be listed by 
treatment and Subject in data listings. 
10.3.3 Efficacy Assessment  
10.3.3.1 Primary Endpoints  
The primary efficacy endpoints are the mean percent change from screening/baseline to week 12 
in the inflammatory (papules and pustules) and in the non-inflammatory (open and closed 
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10.3.3.2 Test of Clinical Equivalence 
The evaluations of clinical equivalence will be performed for the PP population.  
For the primary efficacy assessment, the two-sided, 90% confidence interval on the 
test/reference ratio of the mean percent change from screening/baseline to week 12 in each lesion 
type will be calculated using Fieller’s method and the pooled variance estimate (MSE) obtained 
from a two-way Analysis of Variance (ANOVA) of the Test and Reference results. The 
statistical model for the ANOVA will contain terms for treatment and center. If the skewness of 
the residuals from the ANOVA is outside of -2 to 2, then a nonparametric approach will be used 
to obtain the confidence intervals. Bioequivalence will be established if the 90% confidence 
intervals for the ratio of test/reference means, for both inflammatory and non-inflammatory 
lesion counts, are contained within the interval [0.80, 1.25] using the per protocol (PP) 
population. 
10.3.3.3 Test of Superiority 
The evaluations of superiority will be performed using the mITT population.  
Superiority of the Test treatment versus the Vehicle and for the Reference treatment versus the 
Vehicle will be conducted separately. 
The test product and RLD will each be compared to that of the placebo group separately using 
ANOVA to evaluate if they are statistically superior at p<0.05 (two-sided test) to the placebo. 
Superiority will be established If the mean percent change (reduction) from screening/baseline to 
week 12 for each active treatment, for both inflammatory and non-inflammatory lesion counts, is 
greater than, and statistically different from (p<0.05), that for the vehicle (placebo) Control.The 
statistical model for the ANOVA will contain terms for treatment and center. If the skewness of 
the residuals from the ANOVA is outside of -2 to 2, then a nonparametric approach will be used. 
10.3.3.4 Analysis of IGA scores 
Descriptive statistics using categorical methods to compare IGA Scores between each treatment 
group will be conducted and presented. No inferential analyses are planned. 
10.3.3.5 Analysis of Application Site Reactions 
Descriptive statistics using categorical methods to compare application site reactions between 
each treatment group will be conducted.  
 
10.4 Concomitant Medication 
The start and stop calendar date (e.g., dd/mmm/yyyy) and study day (e.g., Day X) of 
concomitant medication use should be provided in the data set in addition to the reason for the 
medication use. It should clearly be noted whether the medication was used prior to 
screening/baseline visit, during the study, or both. 


  
 
 
 
 
 
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10.5 Summary of Subjects who discontinued prematurely 
Reasons for early discontinuation will be summarized by treatment group. 
11 ADVERSE EVENTS  
11.1 Recording of Adverse Events  
An adverse event is any untoward medical occurrence in a Subject administered a medicinal 
product regardless of whether it has a causal relationship with this treatment. An adverse event 
can therefore be any unfavorable and unintended physical sign, symptom, or laboratory 
parameter that develops or worsens in severity during the course of this study, or significant 
worsening of the disease under study or of any concurrent disease, whether or not considered 
related to the medicinal product. A new condition or the worsening of a pre-existing condition 
will be considered an adverse event. Stable chronic conditions (such as arthritis) that are present 
before study entry and do not worsen during this study will not be considered adverse events. 
Accordingly, an adverse event can include any of the following: 
1. intercurrent illnesses 
2. physical injuries 
3. events possibly related to concomitant medication 
4. significant worsening (change in nature, severity, or frequency) of the disease under 
study or other preexisting conditions  
5. events occurring during diagnostic procedures or during any washout phase of this study 
6. laboratory or diagnostic test abnormalities that result in the withdrawal of the patient 
from the study, are associated with clinical signs and symptoms or a serious adverse 
event, or require medical treatment or further diagnostic work up, or are considered by 
the investigator to be clinically significant (Note: Abnormal laboratory test results at the 
screening visit that preclude a patient from entering the study or receiving study 
treatment are not considered adverse events). 
7. side effects caused by drug interaction.  
 The potential adverse reactions of TRIFAROTENE CREAM, 0.005% (Teva Pharmaceuticals, 
Inc.) are anticipated to be similar to those observed with the use of AKLIEF® (TRIFAROTENE 
0.005% CREAM) (GALDERMA LABORATORIES, L.P., USA). The skin of certain sensitive 
individuals may become excessively red, edematous, swollen, blistered or crusted, local 
erythema, peeling at the site of application. Temporary hyper- or hypopigmentation has been 
reported with repeated application of tretinoin. Trifarotene, like other retinoids, has been 
reported to cause severe irritation on eczematous skin and should be used with utmost 


  
 
 
 
 
 
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caution in patients with this condition. 
Worsening of the disease under study will be measured by an increase in the IGA score by one 
or more grades, and should be recorded as an adverse event only if the presentation and/or 
outcome is more severe than would normally be expected from the normal course of the disease 
in a particular subject. 
In this study, any adverse event occurring after the subject has signed the informed 
consent/assent form until the end of follow-up period should be recorded and reported as an 
adverse event. 
A treatment-emergent AE (TEAE) is any AE that occurs after initiation of study medication, or 
any event already present that worsens in either intensity or frequency following exposure to 
study medication.  
For adverse event recording, the study period is defined for each subject as that time period from 
signature of the informed consent/assent form through the end of the study (including the follow 
up period). All adverse events that occur during the defined study period must be recorded on the 
source documentation and CRF, regardless of the severity of the event or judged relationship to 
the study drug. For serious adverse events, the Serious Adverse Event Form must also be 
completed, and the serious adverse event must be reported immediately (see Section on 
Reporting below).  
At each contact with the subject, the Investigator or designee must question the subject about 
adverse events by asking an open-ended question such as, “Have you had any unusual symptoms 
or medical problems since the last visit? If yes, please describe.” All reported or observed signs 
and symptoms will be recorded individually, except when considered manifestations of a 
medical condition or disease state. A precise diagnosis will be recorded whenever possible. 
When such a diagnosis is made, all related signs, symptoms, and any test findings may be 
recorded collectively as a single diagnosis on the CRF and, if it is a serious adverse event, also 
on the Serious Adverse Event Form. 
The onset and end dates and times, action taken regarding study drug, treatment administered, 
and outcome for each adverse event must be recorded on the source documentation. 
The relationship of each adverse event to study drug treatment, and the severity and seriousness 
of each adverse event, as judged by the Investigator, must be recorded as described below. 
The clinical course of each adverse event will be monitored at suitable intervals until resolved or 
stabilized or returned to screening/baseline, until the subject is referred for continued care to a 
health care professional or until a determination of a cause unrelated to the study drug or study 
procedure[1] is made. 
Adverse events will be coded according to MedDRA (Medical Dictionary for Regulatory 
Activities) and reported with respect to severity, duration, relationship to study medication(s), 
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11.1.1 Assessment of Severity  
The severity of each adverse event must be recorded as 1 of the choices on the following scales: 
x Mild: No limitation of usual activities 
x Moderate: Some limitation of usual activities 
x Severe: Inability to carry out usual activities  
 
11.1.2 Relationship to Study Medication  
Adverse events will be assessed for the relationship to the study drug (causality) according to the 
following scale: 
 
TERM 
DEFINITION 
CLARIFICATION 
No 
Reasonable 
Possibility 
(not related) 
This category applies 
to 
those adverse events 
which, after careful 
consideration, are 
clearly due to 
extraneous causes 
(disease, environment, 
etc.) or to those 
adverse events, which 
after careful medical 
consideration at the 
time they are 
evaluated, are judged 
to be unrelated to the 
test drug. 
x An adverse experience may be 
considered 
x No Reasonable Possibility if it is 
clearly due to extraneous causes or 
when (must have two): 
x It does not follow a reasonable 
temporal sequence from the 
administration of the test drug. 
x It could readily have been produced 
by the subject’s clinical state, 
environmental or toxic factors, or 
other modes of therapy administered 
to the subject. 
x It does not follow a known pattern of 
response to the test drug. 
x It does not reappear or worsen when 
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Reasonable 
Possibility 
(related) 
This category applies 
to those adverse events 
for which, after careful 
medical consideration 
at the time they are 
evaluated, a connection 
with the test drug 
administration cannot 
be ruled out with 
certainty or felt with a 
high degree of 
certainty to be related 
to the test drug. 
x An adverse experience may be 
considered Reasonable Possibility 
related if or when (at least two of the 
following): 
x It follows a reasonable temporal 
sequence from administration of the 
drug. 
x It could not be reasonably explained 
by the known characteristics of the 
subject’s clinical state, environmental 
or toxic factors, or other modes of 
therapy administered to the subject. 
x It disappears or decreases on 
cessation or reduction in dose. There 
are important exceptions when an 
adverse event does not disappear 
upon discontinuation of the drug, yet 
drug relatedness clearly exists. 
x It follows a known pattern of 
response to the test drug. 
 
11.2 Serious Adverse Events  
An Adverse Event or Suspected Adverse Reaction is considered ‘‘serious’’ if, in the view of 
either the investigator or sponsor, it results in any of the following outcomes: 
x Results in death  
x A life-threatening adverse event; (Note: the term “life-threatening” as used here refers 
to an event in which the Subject was at risk of death at the time of the event; it does 
not refer to an event which hypothetically might have caused death if it was more 
severe.)  
x Requires in-Subject hospitalization or prolongation of existing hospitalization; This 
means that hospital inpatient admission and/or prolongation of hospital stay were 
required for treatment of an AE, or that they occurred as a consequence of the event. 
Hospitalizations scheduled prior to study entry will not be considered SAEs, unless 
there was worsening of the pre-existing condition during the subject’s participation in 
this study. 
x Results in persistent or significant disability/incapacity (substantial disruption of the 
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x Is a congenital anomaly/birth defect. 
x Any “other” important medical event.  
Important medical events that may not result in death, be life-threatening or require 
hospitalization may be considered Serious Adverse Events when, based on appropriate medical 
judgment, they may jeopardize the Subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or the 
development of drug dependency or drug abuse. Note: Any suspected transmission of an 
infectious agent via a medicinal product is considered an important medical event. 
An adverse event that does not meet any of the criteria for seriousness listed above will be 
regarded as a non-serious adverse event. 
Regardless of the above, any additional adverse events, which the Principal Investigator 
considers significant, should be immediately reported to the CRO (Catawba Research). 
11.2.1 Expectedness 
The sponsor’s Pharmacovigilance Department will determine the expectedness for all serious 
adverse events. CRO and Investigators will not determine the expectedness. 
An AE which is not included in the adverse events section of the relevant Safety Information 
Reference by its specificity, severity, outcome or frequency is considered an unexpected adverse 
event. 
The reference safety information for this study is AKLIEF® (TRIFAROTENE 0.005% 
CREAM) (GALDERMA LABORATORIES, L.P., USA, Prescribing Information to use as 
reference for safety information is to be found in Appendix II. 
 
11.3 Reporting of Serious Adverse Events (SAEs) 
To satisfy regulatory requirements, all serious adverse events (as described in Section 11.3) that 
occur during the study period (including the protocol defined follow up period) regardless of 
judged relationship to treatment with the study drug, must be reported to Teva’s Lead Safety 
Officer (LSO) on their PV team and CRO in parallel, by the Investigator. The event must be 
reported within 24 hours of when the Investigator learns about it. Completing the serious adverse 
event form (preferably in English) and reporting the event must not be delayed, even if not all 
the information is available. Subsequently, the CRO will communicate this information with the 
Teva Clinical Manager (Sponsor) and Medical Monitor (MM) in parallel (and any other contacts 
identified in the Safety and Medical Monitoring Plan (SMMP)) within 1 business day (in some 
studies an SAE email distribution list may be used). If there is no LSO, then according to the 
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PLEASE NOTE THAT EMAIL IS THE PREFERRED MEANS OF COMMUNICATION. 
 
All SAEs must be reported in parallel to the following persons: 
1. Appropriate Pharmacovigilance (PhV) unit: 
Email:  us.clinops.sae@tevapharm.com 
2. Catawba Research Safety Group: 
Email: safety@catawbaresearch.com 
Catawba Research will communicate the details of the SAE with the Sponsor: 
Sponsor’s Contact person for this study (copy of the SAE details for information purposes only) 
Name: Corrine Dias  
Phone: 416-903-5489 
E-mail: Corrine.Dias@tevapharm.com 
 
 
Name: Amy Alexander 
Phone: (647) 625-0118 
Email: Amy.Alexander@tevapharm.com 
 
The SAE form should be completed, preferably in English. The SAE form completion and 
reporting must not be delayed even if all of the information is not available at the time of the 
initial contact. Additional information (follow-up) about any SAE unavailable at the initial 
reporting should be forwarded within 24 hours of the information becoming available to the 
same address as the initial report.  
It should be considered that Day 0 is the day a Teva employee, or an employee of a company 
which Teva has a contractual arrangement with, becomes aware of a case which fulfils the 
minimum criteria for reporting. Note: If the investigator calls a Teva representative or CRO 
representative, this will count as Day 0 and the contacted person must inform Teva immediately. 
For sites in Belize, the Investigator is also required to inform the Director of Health Services of 
the Ministry of Health Belize of any SAEs within 24 hours of the identification of an event.  
Once the Belize sites have informed the Director of Health Services of the Ministry of Health 
Belize, then they will follow the same procedures as the US sites. 
The reporting timelines for reporting of SAE’s by the Investigator to the CRO and LSO (if 
applicable) (depending on the type of study) is within 24 hours. If the Investigator exceeds 24 
hours to report the SAE, this should be identified as a protocol deviation and documented 
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In case, the Investigator fails to report any serious adverse event within the stipulated period, 
he/she shall have to furnish the reason for the delay to the satisfaction of the IRB along with the 
report of the serious adverse event. The report of the serious adverse event, after due analysis, 
shall be forwarded by the Investigator to IRB, Sponsor (Teva) and CRO (Catawba Research) 
within fourteen days of the occurrence of the serious adverse event as referred in clause (ix)-
section 35 of Part-B of Chapter-V of New Drugs & Clinical Trial Rules; 2019. The study site 
must transmit the SAE form through an email to safety@catawbaresearch.com, and Teva 
contacts listed above.   
 
These SAE reports must contain the following information, preferably using the template 
provided by the Sponsor: 
A. Study name/number 
B. Study Drug 
C. Investigator details (name, phone, fax, e-mail) 
D. Subject Number 
E. Subject Initials when appropriate 
F. Subject Demographics 
G. Clinical Event 
1) Description 
2) Date of onset 
3) Treatment (drug, dose, dosage form) 
4) AE Relationship to study drug 
5) Action taken regarding study drug in direct relationship to the AE 
H. If the AE was Fatal: 
1) Cause of death (whether or not the death was related to study drug) 
2) Autopsy findings (if available) 
Each report of a serious adverse event will be reviewed and evaluated by the Investigator and the 
sponsor pharmacovigilance to assess the nature of the event and the relationship of the event to 
the study drug, study procedures, and to underlying disease. 
 For studies conducted in USA: It is the responsibility of the CRO to report a Serious Adverse 
Event (SAE) to the FDA within proper time constraints as per the Guidance for Industry and 
Investigators Safety Reporting Requirements for INDs and BA/BE Studies – please refer to the 
most current version. Confirmation of submission of this report must then be provided to Teva’s 
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The timeliness for submission of expedite reports should be 15 days or 7 days (death cases) or as 
otherwise specified in local regulations. 
The CRO will take on the responsibility of reporting SAEs to the Investigators and/or to the 
Ethic Committee. 
Any serious adverse event will be reported to competent authority and ethics committee 
according to the country specific requirements and the responsibilities defined above. All AEs 
will be reported in the Clinical Study Report with the complete information named above 
according to the requirements of the Note for Guidance on Structure and Content of Clinical 
Study Reports (CPMP/ICH/137/95). 
 Subjects who have had an SAE during the study must be followed clinically until all parameters 
(including laboratory) have either returned to normal or have stabilized or are otherwise 
explained. The Investigator does not need to actively monitor subjects for new serious adverse 
events once the study has ended. However, serious adverse events occurring after a subject 
ended the study should be reported to the Sponsor if the Investigator becomes aware of them. 
  
 
11.4 Pregnancy 
Female subjects of childbearing potential must have been using and must agree to continue to 
use accepted methods of birth control, throughout the study and demonstrate negative pregnancy 
tests.  
All female subjects are considered to be of childbearing potential unless they are premenarchal, 
have been surgically sterilized (by *hysterectomy or bilateral oophorectomy) or have been 
postmenopausal for at least 1 year. Tubal ligation is not considered equivalent to female 
sterilization.  Women with a history of tubal ligation are still considered females able to become 
pregnant and must complete a urine pregnancy test.  
Alternatively, any of the following methods of birth control are acceptable: oral or injectable 
contraceptives, contraceptive patches, medroxyprogesterone acetate (ex. Depo-Provera®) with 
stabilized use for at least 3 months), vaginal contraceptive (etonogestrel/ethinyl estradiol vaginal 
ring (ex. NuvaRing®)) contraceptive implant with etonogestrel or equivalent, double barrier 
methods (e.g., condom and spermicide), IUD, abstinence.  
If a subject who was abstinent becomes sexually active during the study, a 2nd acceptable method 
of birth control should be used and documented. Prior to study enrollment women of 
childbearing potential must be advised of the importance of avoiding pregnancy during study 
participation.  
*Full hysterectomy or bilateral oophorectomy considered surgically sterile. Tubal ligation is not considered 
equivalent to female sterilization. 
A negative result of a pregnancy test having a minimum sensitivity of at least 25 mIU/ml for 
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Pregnancy testing will also be performed at every study visit and the results of all pregnancy 
tests (positive or negative) will be documented. Subjects must have a negative urine pregnancy 
to continue in the study. 
  
All pregnancies of women participating in the study that occur during the study, or within at least 
5 half-lives, or 30 days for unknown half-lives days of completion of the study, are to be 
reported immediately to the individual identified in the clinical study personnel contact 
information section of this protocol, and the Investigator must provide the Sponsor with the 
completed pregnancy form. The process for reporting a pregnancy to the Sponsor is the same as 
that for reporting a serious adverse event but using the pregnancy form as provided by the 
Sponsor.  
Any female subject/patient becoming pregnant during the screening period (i.e., before study 
drug administration) will be considered a screen failure and will not be allowed to rescreen. The 
Investigator is not required to report such pregnancies, provided no protocol-related procedures 
with known risk on pregnancy were applied. 
Any female subject becoming pregnant during the study will discontinue treatment. All subjects 
who become pregnant will be monitored for the outcome of the pregnancy (including 
spontaneous or voluntary termination). If the pregnancy continues to term, the outcome (health 
of the infant up to 8 weeks of age), including details of birth and presence or absence of any birth 
defect, congenital abnormalities, or maternal and newborn complications, will be reported to the 
Sponsor. Any complication of pregnancy during the study and any complication of pregnancy 
that the Investigator becomes aware of after termination from the study will be reported as an 
adverse event or serious adverse event, as appropriate. 
11.5 Follow Up of Subjects 
The staff of the clinical facility/site has to monitor the clinical trial subject's safety from the 
occurrence of an AE until satisfactory recovery. 
The clinical course of each adverse event will be monitored at suitable intervals until resolved or 
stabilized or returned to screening/baseline, until the subject is referred for continued care to a 
health care professional or until a determination of a cause unrelated to the study drug or study 
procedure is made. 
Any AE which remains unresolved at the time point of subject’s last visit requires detailed 
evaluation and follow-up until the AE has been resolved or a reasonable explanation for its 
persistence is found; in case of AEs related to the IMPs every effort has to be made to follow-up 
clinical trial subjects to determine the final outcome. If follow-up cannot be completed until 
release of CRF by the investigator the individual CRF will be released and transferred to the 
Clinical Data Management. In this case, follow-up information will be documented separately in 
the subjects’ record and outcome including a short description on follow-up procedures 
performed must be sent to the sponsor. 
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receive definitive treatment for any adverse reaction, if required. Details of follow-up care are to 
be provided (i.e., if treatment or hospitalization is required). The responsibility to provide 
adequate follow-up for AEs includes periodically repeating laboratory tests yielding clinically 
abnormal results at the end of study evaluation. 
11.6 Medication Errors and Special Situations 
Any administration of study drug that is not in accordance with the study protocol should be 
reported in the subject's source documents (and in the eCRF), regardless of whether or not an 
adverse event occurs as a result.  
The following are types of medication errors and special situations:  
1. Medication error: Any unintentional error in the prescribing, dispensing, or 
administration of a medicinal product while in the control of the healthcare professional, 
patient, or consumer. 
2. Overdose: Administration of a quantity of a medicinal product given per administration 
or cumulatively which is above the maximum recommended dose according to the 
authorized product information. Clinical judgment should always be applied. 
3. Misuse: Situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the authorized product information or the study protocol. 
4. Abuse: Persistent or sporadic, intentional excessive use of medicinal products which is 
accompanied by harmful physical or psychological effects. 
5. Occupational exposure: Exposure to a medicinal product, as a result of one’s professional 
or non-professional occupation. 
6. Lack of efficacy. 
11.7 Reconciliation of SAEs & Pregnancy 
It is the CRO responsibility throughout the course of the study, to maintain a listing of all SAEs 
and pregnancy reports. At the conclusion of the study, in the case that NO SAE/pregnancy 
occurred, the CRO should send an email to Teva Global PV to indicate that no SAE/pregnancy 
occurred during the study. In the case that a SAE/pregnancy did occur, the CRO should send an 
email to PV requesting the reconciliation line listing. The CRO should perform a reconciliation 
of the SAEs in the study with those in the Teva Global PV database. 
All communication regarding Safety Data Reconciliation should be directed to the Teva Global 
PV email address: PV-DMU-Studies.Programs-Management@tevapharm.com
 
11.8 Safety Considerations during COVID-19 Pandemic 
The safety of site staff and study subjects are to be protected against possible transmission of 
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to the virus as well as protect participants and study staff while maintaining study integrity. 
SOPs/site specific plan should include methods to reduce the amount of time spent by the study 
participant at study site and any interactions with site staff and study subjects. 
At each visit, temperature check and COVID-19 symptom (such as tuffy or runny nose, sore 
throat, shortness of breath (difficulty breathing), cough, low energy or tiredness, muscle or body 
aches, headache, chills or shivering, feeling hot or feverish, vomiting, diarrhea, loss of sense of 
taste and smell) screening for study subjects and site staff will be performed. At each visit, site 
should also ensure, subject exposure to others with suspected or confirmed SARS-CoV-2 
infection.  
Study subjects and site staff should wear appropriate personal protective equipment/masks and 
practice hand sanitization methods. Site should ensure physical distancing (maintaining at least 6 
feet between people) and take appropriate action to prevent possible infection from the COVID 
viruses as an important strategy where possible. Sites should assign only one participant per 
room, while performing any general safety evaluations or assessments and should disinfect the 
room once the participant leaves. 
Care should be taken to ensure study integrity and scientific validity of the data generated due to 
modifications to study conduct or design. Subject that has tested positive for COVID-19 during 
the trial may be discontinued from the study as per investigator’s discretion.  
12 ETHICS  
12.1 IRB/Ethics Committee 
IRB/Ethic committee (IRB/EC) approval will be obtained from an EC registered with FDA. PI 
will provide the Sponsor or Catawba Research with documentation of IRB/EC approval of the 
protocol, ICF, advertising material and all documents required as per applicable regulations 
before the study may begin at the study sites. Site shall maintain all the study records for no less 
than 5 years from the date of study completion or termination of the trial. PI will supply 
documentation for IRB/EC’s annual renewal to the Sponsor or Catawba Research and provide 
any IRB/EC approvals of revisions to the informed consent or protocol amendments.  
The PI will report promptly to the IRB/EC, any new information that may adversely affect the 
safety of subjects or the conduct of the study. Similarly, the PI will submit written summaries of 
the study status to the IRB/EC annually, or more frequently if requested by the IRB/EC. Upon 
completion of the study, the PI will provide the IRB/EC with a brief report of the outcome of the 
study, if required.   
12.2 Ethical Conduct of the Study 
This study will be conducted, and the informed consent will be obtained according to the ethical 
principles stated in the Declaration of Helsinki (2013), FDA regulations, the applicable 
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The study will be conducted in compliance with the protocol. 
The rights, safety and well-being of the study subjects are the most important considerations and 
should prevail over interests of society and science. 
 
12.3 Informed Consent/Assent 
The Principal Investigator must ensure that subjects and/or their legally acceptable representative 
(i.e., parent or guardian) are clearly and fully informed about the purpose, potential risks and 
other critical issues regarding clinical studies in which they volunteer to participate. The 
principles of Informed Consent/Assent, according to FDA Regulations and ICH GCP will be 
followed. A copy of the proposed consent/assent form must be submitted to the IRB/IEC, 
together with the protocol, for approval. Prior to beginning of the study, the Principal 
Investigator must have the IRB/IEC’s written approval of the written informed consent/assent 
form and any other information to be provided to Subjects. 
• The Investigator or the Investigator’s representative will explain the nature of the study, 
including the risks and benefits, to the potential participant [or their legally authorized 
representative and answer all questions regarding the study. 
• Potential participants must be informed that their participation is voluntary. They [or their 
legally authorized representatives] will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, privacy and 
data protection requirements, where applicable, and the IRB/IEC or study center. 
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study. 
• A copy of the ICF(s) must be provided to the participant [or their legally authorized 
representative]. 
Informed consent/assent will be obtained from all subjects using the following procedure: 
Subjects who are 18 years of age or older (up to the age of 40) must have provided IRB/IEC 
approved written informed consent. Subjects 12 to 17 years of age, inclusive, must have 
provided IRB/IEC approved written assent. Written assent must be accompanied by an IRB/IEC 
approved written informed consent from the Subject’s legally acceptable representative (i.e., 
parent or guardian). Prior to initiating screening for the study, Subjects will be given the 
approved ICF/assent describing the study and any risks associated with participation. The 
Subject will be allowed as much time as needed to read and understand the information 
presented in the consent/assent form. Appropriate study personnel will be available to answer 
any questions the Subject might have regarding the study or study-related procedures. If the 
Subject chooses to participate in the study, he or she will be asked to sign and date the 
consent/assent form and will be provided with a copy for his or her records. Both the ICF and 


  
 
 
 
 
 
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assent (if applicable) must be signed by the Subject or the Subject’s legally acceptable 
representative (i.e., parent or guardian) before any protocol assessments can be undertaken. 
 
12.4 Subject Confidentiality  
The monitor(s), the auditor(s), IRB/IEC, and the regulatory authority(ies), will be granted direct 
access to the Subject’s original medical records for verification of the clinical trial procedures 
and/or data, without violating the confidentiality, to the extent permitted by the applicable laws 
and regulations and that by signing a written informed consent form, the Subject or the Subject’s 
legally acceptable representative is authorizing such access. 
The identity of the Subject will not be made publicly available and will be kept confidential and, 
to the extent permitted by the applicable laws and regulations and meets the requirements of 21 
CFR 50, local regulations, ICH guidelines, HIPPA privacy and data protection requirement. If 
the results of the trial are published, the Subject’s identity will remain confidential. 
13 DOCUMENTATION  
13.1 Site Regulatory Documents Required for Initiation  
At a minimum, the following documents will be received by the CRO prior to the initiation of 
the study:  
1. Completed and signed FDA Form 1572 
2. Current curricula vitae, signed and dated for the Principal Investigator and each Sub-
Investigators named in the FDA form 1572 (current within 2 years) 
3. Current medical licenses of the Principal Investigator and each Sub-Investigator named in 
FDA form 1572 
4. Documentation of IRB/IEC approval of this study protocol, Principal Investigator and 
informed consent/assent forms  
5. Current IRB/IEC membership list or roster  
6. Fully executed protocol, and a copy of the protocol agreement page and any applicable 
amendments signed by the Principal Investigator  
7. Documentation of “No Objection” to proceed from the local regulatory agency, wherever 
applicable. 
8. Non-disclosure Agreements for the investigator site named in FDA form 1572 
9. Financial Disclosure Statement for the Principal Investigator and each Sub-Investigator 
named in FDA form 1572. 
10. Statement of Non-Debarment 
 
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filing system of all relevant documentation8, 9. 
Copies of all pertinent records will be retained by the Principal Investigator for at least two years 
following final approval of the drug and/or notification from the Sponsor. These regulatory 
documents should be retained for a longer period if required by local regulatory authorities. 
These records include documents pertaining to the receipt and return of drug supplies, IRB/IEC, 
informed consent, source documents. No documents shall be transferred from the site or 
destroyed without first notifying the Sponsor. If the Principal Investigator withdraws from the 
study, the records shall be transferred to a mutually agreed upon designee in agreement with 
Catawba Research and Sponsor. Notice of such transfer will be given in writing to the Sponsor. 
The Principal Investigator is required to prepare and maintain adequate and accurate case 
histories designed to document all observations and other data pertinent to the investigation on 
each individual treated with the IMP or entered as a control in the investigation. Data reported on 
the CRF, which are derived from source documents, must be consistent with the source 
documents.  
   
13.3 Data Collection and Reporting  
Data for individual subjects will be collected on eCRF. The data management system will be 
Electronic Data Capture (EDC). The Investigator and his/her study site personnel will be 
responsible for completing the eCRFs. The Investigator is required to verify that all of the 
requested information is accurately recorded in the eCRFs. All information requested in the 
eCRFs needs to be supplied, including subject identification, date(s), assessment values, etc., and 
any omission or discrepancy will require explanation. All information on eCRFs must be 
traceable to source documents.  
Source documents such as the clinic chart (medical records specifically collected for the study 
information) are to be maintained separately from the eCRF in order to allow data verification. 
Because of the potential for errors, inaccuracies and illegibility in transcribing data into eCRFs, 
originals of laboratory and other test results must be kept on file. Source documents and copies 
of test results must be available at all times for inspection by the study monitor or any applicable 
auditors. The following should also be available for review:   
1. Subject Screening Log – documenting all subjects screened for participation in the study 
and reflecting their eligibility status. If ineligible, the reason the subject was ineligible 
should be documented 
2. Delegation of Authority / Study Personnel Signature Log – all site personnel will be 
listed along with their responsibilities and signatures; to be maintained at the site 
throughout the study 
3. Monitoring Log – the date and purpose of all monitoring visits by the CRO 
representative/Sponsor/Designee will be documented 
4. Enrollment Log – documenting Subject initials and start and end dates for all subjects 
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5. Drug Inventory/Packing Slip – reflecting the total amount of drug shipped to the site 
and received and signed by the Principal Investigator 
6. Drug Accountability Log – reflecting the total amount of IMP dispensed to and returned 
by each Subject 
7. Informed Consent Form and Assent Form – which must be available for each Subject 
and be verified for proper documentation 
The study monitor will be responsible for reviewing and verifying the data recorded in the 
eCRFs, utilizing the original source documentation and will query discrepant findings. The 
Investigator and study site personnel will be responsible for answering all queries. All queries 
issued by the data management personnel will be answered by site personnel and verified by the 
monitor. 
 
13.4 Primary Source Documents  
The Principal Investigator must maintain primary source documents supporting significant data 
for each Subject’s medical notes. These documents, which are considered “source data”, should 
include documentation of:  
1. Demographic information  
2. Evidence supporting the diagnosis/condition for which the Subject is being studied  
3. General information supporting the Subject’s participation in the study  
4. General history and physical findings  
5. Hospitalization or Emergency Room records (if applicable)  
6. Each study visits by date, including any evaluations, relevant findings/notes by the 
Principal Investigator(s), occurrence (or lack) of adverse events and changes in 
medication usage, including the date the study drug commenced and completed.  
7. Any additional visits during the study  
8. Any relevant telephone conversations with the Subject regarding the study or possible 
adverse events  
9. An original, signed informed consent form/assent form (as applicable) for study 
participation  
10. Subject Diary 
The Principal Investigator must also retain all Subject specific printouts/reports of 
tests/procedures performed as a requirement of the study. During monitoring visits, the monitor 
will need to validate data in the eCRFs against these sources of data.  
 


  
 
 
 
 
 
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13.5 Study Monitoring  
The study will be monitored by a representative of the CRO/sponsor (as applicable) to assess 
compliance with the protocol, ICH-GCP and applicable regulations. The Principal Investigator 
will be visited by a monitor prior to the study and at regular intervals during the course of the 
study. These visits are for the purposes of verifying adherence to the protocol. 
The study monitor will review the Informed Consent/Assent Forms and verify eCRF entries by 
comparing them with the source documents (hospital/clinic/office records) that will be made 
available for this purpose. The monitor will review the maintenance of regulatory documentation 
and drug accountability. The monitor will review on a regular basis the progress of the study 
with the Principal Investigator and other site personnel.  
eCRF sections may be monitored during these visits. At the end of the study, a closeout 
monitoring visit will be performed. Monitoring visits will be arranged in advance at a mutually 
acceptable time with site personnel. Sufficient time must be allowed by the site personnel for the 
monitoring of eCRFs and relevant source documents. The Study Coordinator and/or Principal 
Investigator should be available to answer questions or resolve data clarifications. Adequate time 
and space for these visits should be made available by the Principal Investigator. 
13.6 Audits and Inspections  
During the study and/or after it has been completed, one or more site visits may be undertaken 
by auditors as authorized representatives of the Sponsor. The purpose of the audit is to determine 
whether or not the study is being conducted and monitored in compliance with the protocol, 
recognized GCP guidelines and all applicable regulations. 
Additionally, the study may be inspected by regulatory agencies. These inspections may take 
place at any time during the study and/or after it has been completed.  
THE INVESTIGATOR MUST NOTIFY THE CLINICAL RESEARCH ORGANIZATION 
AND/OR SPONSOR PROMPTLY OF ANY INSPECTIONS SCHEDULED BY 
REGULATORY AUTHORITIES, AND PROMPTLY FORWARD COPIES OF INSPECTION 
REPORTS TO THE SPONSOR. 
 
13.7 Modifications to the Protocol  
The procedures defined in the protocol will be carefully reviewed to ensure that all parties 
involved with the study fully understand the protocol. In order to ensure the validity of the data, 
no deviations from the protocol, with minimal exceptions, may be made unless the issue is broad 
enough to warrant revision of the protocol. Such revisions must be submitted to and have 
documented approval from the Sponsor and the IRB/IEC prior to implementation.  
The only circumstance in which an amendment may be initiated without prior IRB/IEC approval 
is to eliminate apparent immediate hazards to a Subject or Subjects. However, the Principal 


  
 
 
 
 
 
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Investigator must notify the Sponsor immediately and the IRB/IEC within 5 working days after 
implementation.  
All protocol deviations will be reported on the Protocol Deviation Log and included in the study 
reports. A protocol deviation  is defined as any change, deviation from the study design or 
procedures of research project that is NOT approved by the IRB/IEC prior to its initiation or 
implementation, OR deviation from standard operating procedures, Good Clinical Practices 
(GCPs), federal, state or local regulations. 
14 COMPLETION OF STUDY  
The Principal Investigator is required to sign the eCRFs and forward all other relevant data and 
records to the CRO.  
The Principal Investigator is expected to submit a final report to the IRB/IEC and the Sponsor 
within one (1) month of study completion or discontinuation.  CRO must submit a final report as 
agreed in the Study Agreement for this study between Sponsor and CRO. 
15 REFERENCES  
1. Kurokawa I, Layton AM, Ogawa R. Updated Treatment for Acne: Targeted Therapy Based 
on Pathogenesis. Dermatol Ther (Heidelb). 2021 Aug;11(4):1129-1139 
2. Baldwin H, Webster G, Stein Gold L, Callender V, Cook-Bolden FE, Guenin E. 50 Years 
of Topical Retinoids for Acne: Evolution of Treatment. Am J Clin Dermatol. 2021 
May;22(3):315-327. 
3. Bell KA, Brumfiel CM, Haidari W, Boger L. Trifarotene for the Treatment of Facial and 
Truncal Acne. Ann Pharmacother. 2021 Jan;55(1):111-116 
4. FDA Guidance for Industry. Acne Vulgaris: Establishing Effectiveness of Drugs Intended 
for Treatment. Food and Drug Administration. May 2018. 
5. FDA Label (DailyMed) for Trifarotene Revised: Oct 2019 
6. FDA’s Draft Guidance on Trifarotene (May 2021) 
7. FDA’s Draft Guidance on Adapalene; Benzoyl peroxide (gel, 0.3%; 2.5%), 
Recommended Dec 2016; Revised Nov 2018, Nov 2019. 
8. Guidance for Industry. Handling and Retention of BA and BE Testing Samples. Office of 
Generic Drugs. FDA. May 2004. 
9.  Guidance for Industry “Compliance Policy for the Quantity of Bioavailability and 
Bioequivalence Samples Retained Under 21 CFR 320.38(c) 
10. FDA Guidance for Industry. Protecting Participants in Bioequivalence Studies for 
Abbreviated New Drug Applications During the COVID-19 Public Health Emergency. 
January 2021.   


  
 
 
 
 
 
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11. FDA Summary Basis of Approval. Alkief # 211527 October 2019  
 


  
 
 
 
 
 
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15.1 APPENDIX I: Revision History 
Version #  
Affected Sections 
Final 1.0 
(13May2022) 
N/A (new) 
Final 2.0 
1. Section 9.2.1 Packaging, Blinding and Labeling: 
Revisions made to account for change in IMP pump 
label to not use 2-part scratch off label 
2. Study Population - Inclusion Criteria #3 (Page 14): 
Removed the word “treatment” 
3. Section 5.1.1 – Inclusion Criteria #3 (Page 29): 
Removed the word “treatment” 
4. Section 9.2.3 – Subject Screening Number (Page 59) 
Revised Screening Number to include a three-digit Site 
Number, instead of a two-digit Site Number 
5. Section 10.1.2 - Unblinding Procedures (Page 64): 
Removed scratching off the tear off blinding label on 
IMP as a way to perform unblinding 
In addition, administrative and editorial changes have been 
made throughout the version 2 protocol to improve 
readability and syntax 
 


  
 
 
 
 
 
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15.2 APPENDIX II: AKLIEF-trifarotene cream package insert 
 
 


  
 
 
 
 
 
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Certificate Of Completion
Envelope Id: 0D9D795CDE6B46F79AE5D83DDB6190BA
Status: Completed
Subject: Please DocuSign: TRIF-2101_Protocol_Version 2.0_30Jun2022_FINAL_Med Monitor Signed_AS_Stats Sig...
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Rhiannon Twentyman
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Time Zone: (UTC) Dublin, Edinburgh, Lisbon, London
Teva Pharmaceutical Industries Ltd
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Rhiannon.Twentyman@tevapharm.com
IP Address: 162.251.104.10 
Record Tracking
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Electronic Record and Signature Disclosure: 
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VP-Global GX PD/CE and BioS
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PRIVACY NOTICE 
This privacy (“Notice”) is provided by Teva Pharmaceutical Industries Ltd. and the Teva entity with which 
you communicate in relation to signed documents ("Teva”).You can view a list of all the Teva affiliates at 
the following website:  http://www.tevapharm.com. Teva is referred to in this Notice as “we”, “us” and 
“our.” 
1. Scope of this Notice 
This Notice describes how we use your personal data when we ask you to sign a certain document 
electronically in the system of our service provider, DocuSign, and when we deliver signed documents to 
you. In this way, we can exchange communication electronically, which is faster than exchanging paper 
documents. 
You may also decide to register in the DocuSign system, which is a separate service provided by 
DocuSign as a separate controller and is governed by separate rules. Teva is not responsible for the 
privacy policies or practices of DocuSign related to such registration. 
The Notice applies to our staff (including employees and external consultants), to our vendors/partners 
and their staff, and to healthcare professionals to whom we may deliver documents via DocuSign with a 
request for them to sign the documents electronically. 
2. Scope of data we process 
In order to use DocuSign, and in particular, in order to invite you to sign documents, guarantee security 
and accountability, and manage documents after they have been signed, we may need to use some of 
your personal data, e.g. name, surname, email address and phone number, or a token and details 
regarding the document signed and when it is signed.   
If we do not have all the information necessary in order to use DocuSign (e.g. your email), we will ask you 
to share such information with us. If you decline, documents will be signed and circulated traditionally in 
paper form (which may take longer). 
3. How We Use Your Information 
We generally process your data for the purposes described in our general website privacy 
policy https://www.tevapharm.com/our-company/corporate-governance/data-privacy/ or in other polices 
you may have received from us (e.g. employee privacy policy). 
We may want or need to communicate with you for a number of legitimate purposes described in such 
privacy policies (e.g. to respond to your queries or other correspondence, to meet legal, regulatory, 
pharmacovigilance and compliance requirements, or to perform our contract with you or your employer). 
Instead of doing so in traditional paper form, we offer a tool that allows us and you to communicate and 
sign documents safely via electronic means and to guarantee accountability (the availability of signed 
documents).  You may print out a document signed and delivered via DocuSign for a limited period 
(usually 30 days) after such documents are first sent to you. Afterwards, you may ask us to send you 
paper copies of such signed documents. 
We process such data for our legitimate business purposes to assure safe and accountable electronic 
communication and electronic signing and delivering of documents. 
Legitimate Interests 
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You can find more information regarding Teva&apos;s legitimate interest balancing test by contacting us 
at the addresses specified in "Your Rights" section below. 
Sharing Your Personal Data 
Teva discloses your personal data to the following categories of recipients: 
x 
our staff (including employees and external consultants), professional advisors and agents. 
x 
DocuSign, the provider of the electronic signature system, which acts as a third-party service 
provider that processes your personal data on behalf of Teva and which is bound by contractual 
obligations to keep your personal data confidential and appropriately secure, but which also acts 
as a separate and independent controller (if you use their other services, e.g. if you register with 
them); 
x 
other functions and companies in the Teva group of companies worldwide. 
x 
other third-party service providers that process your personal data on behalf of Teva and which 
are bound by contractual obligations to keep your personal data confidential and appropriately 
secure, such as IT support. 
Cookies and Related Tracking Technologies 
For information on cookies and related tracking technologies, please visit the cookie notice of DocuSign 
at https://www.docusign.com/company/cookie-policy. 
How We Store Your Information 
Confidentiality and Security of your personal data 
Teva maintains data integrity by using the relevant appropriate technical and organizational security 
measures to protect against unauthorized or unlawful processing of personal data and/or against 
accidental loss, disclosure, access or accidental or unlawful destruction or misuse of personal data.  
Teva’s employees and data processors who act on behalf and under the instructions of Teva are 
contractually bound to use these data only for purposes regarding the performance of their contractual 
obligations and therefore are bound to keep your personal data in confidence. 
Your Rights – for Europe only 
You may be entitled under applicable law to ask Teva for a copy of your information, to correct it, erase or 
restrict its processing, or to ask us to transfer some of this information to other organizations. You may 
also have rights to object to some processing. These rights may be limited in some situations – for 
example, where we can demonstrate we have a legal requirement to process your personal data. 
You are not required to provide your personal data, unless you wish to do so. However, if you decide not 
to provide your personal data, we may not be able to perform the activities described under section “How 
we use your information”. 
You have an absolute right to opt-out of processing for direct marketing purposes at any time. You can do 
this by following the instructions in the communication where this is an electronic message or by 
contacting us using the details set out below. 
If you have any concerns about how we process your personal data or wish to exercise any of your rights 
or wish to obtain other information, such as a copy of a legitimate interests balancing test, you can get in 
touch with Teva’s Data Protection Office by contacting us. If you live in Europe, you can contact us 


at EUPrivacy@tevaeu.com.  For all other regions, please contact us at IL_Privacy.Tevail@teva.co.il.  We 
hope that we can satisfy any queries you may have about the way in which we process your personal 
data. However, if you have unresolved concerns you also have the right to complain to the data protection 
authority in the location in which you live, work or believe a data protection breach has occurred. 
International Transfers 
Teva operates internationally and will transfer your information to the recipients set out in the ‘Sharing 
Your Personal Data’ section in countries outside your own country and outside the European Economic 
Area, including to the UK, Israel and the United States. When transferring your information to Israel, Teva 
relies on the European Commission’s adequacy decision with respect to the transfer of data from the 
European Union to Israel; when transferring to other countries outside the EEA that are not subject to an 
"adequacy decision" by the EU Commission or equivalent, Teva generally relies on EU Commission 
approved standard contractual clauses.  Information on the relevant mechanism can be provided upon 
request to EUprivacy@tevaeu.com. 
Electronic Records and Electronic Signatures 
Specifically, these electronic systems must comply with Title 21 of the Code of Federal Regulations 
(21CFR Part 11) relating to electronic records and electronic signatures. This affidavit is required for each 
employee using an electronic signature and must be signed prior to his/her use of electronic signatures. 
Please read this affidavit and sign below to signify that you have read and understood this affidavit. 
Pursuant to Section 11.100 of Title 21 of the Code of Federal Regulations, the undersigned hereby 
certifies that his/her electronic signature is the legally binding equivalent of his/her traditional 
handwritten signature. 
  
Changes to this Notice 
This Notice may change from time to time. Teva will place an updated version of the Notice on this page 
and may otherwise communicate changes as appropriate. 
Updated: May 2021 

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