Clinical trial NCT02320149
Conditions: Acne Vulgaris
Keywords: acne
Sponsor: Almirall, S.A.
Start date: 2014-12-18; Completion date: 2017-02-01
Enrollment: 968 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the efficacy and safety of an approximate 1.5mg/kg/day dose of oral sarecycline compared to placebo in the treatment of moderate to severe facial acne vulgaris

Detailed description:

Arms: arm 1: Sarecycline tablets, 1.5 milligram(mg)/kilogram(kg)/day, taken orally once daily for 12 weeks. arm 2: Placebo-matching sarecycline tablets, taken orally once daily for 12 weeks.
Interventions: intervention 1: Sarecycline intervention 2: Placebo
Intervention descriptions: intervention 1: 1.5 mg/kg/day taken orally at the same time each day, intervention 2: Placebo-matching sarecycline tablets taken orally at the same time each day.

Protocol documents:
Prot_000.pdf: 
 
 
NCT02320149 
 
 
 
Study SC1401 
 
Title: A Randomized, Multicenter, Double-blind, Placebo-controlled Study to 
Evaluate the Efficacy and Safety of 1.5 mg/kg per Day of Sarecycline Compared to 
Placebo in the Treatment of Acne Vulgaris. 
 
 
 
Protocol Date: December 16, 2015 
Statistical Analysis Plan (SAP) Date: March 3, 2017 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 1 of 66 
1  TITLE PAGE 
Clinical Trial Protocol: SC1401 
Study Title: 
A Randomized, Multicenter, Double-blind, Placebo-controlled Study 
to Evaluate the Efficacy and Safety of 1.5 mg/kg per Day of 
Sarecycline Compared to Placebo in the Treatment of Acne Vulgaris 
Study Number: 
SC1401 
Study Phase: 
3 
Study Drug: 
Sarecycline tablets 
IND Number: 
107,645 
Indication: 
Treatment of inflammatory lesions of moderate to severe acne vulgaris 
in subjects 9 years and older 
 
 
Sponsor: 
Warner Chilcott (US), LLC, US Regulatory Agent of Warner Chilcott 
Company, LLC, an Allergan Affiliate  
 
 
Date 
Original Protocol: 
15-Aug-2014 
Amendment 1 
15-Sep-2014 
Amendment 2 
13-Mar-2015 
Amendment 3 
16-Dec-2015 
 
 
 
 
 
 
Confidentiality Statement 
This document is a confidential communication of Warner Chilcott.  Acceptance of this document signifies 
agreement by the recipient that no unpublished information contained within will be published or disclosed to a 
third party without prior written approval, except that this document may be disclosed to an Institutional 
Review Board under the same confidentiality conditions.  


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 2 of 66 
2  SYNOPSIS 
Warner Chilcott (US), LLC, US Regulatory Agent of Warner Chilcott Company, LLC, an 
Allergan Affiliate  
Name of Finished Product: 
Sarecycline tablets 
Study Title: 
A Randomized, Multicenter, Double-blind, Placebo-controlled Study to Evaluate the 
Efficacy and Safety of 1.5 mg/kg per Day of Sarecycline Compared to Placebo in the 
Treatment of Acne Vulgaris 
Study Number: 
SC1401 
Study Phase: 3 
Primary Objective:  
The primary objective is to evaluate the efficacy of oral sarecycline 1.5 mg/kg/day 
compared to placebo in treating inflammatory acne lesions in subjects with moderate to 
severe facial acne vulgaris based on Investigator’s Global Assessment (IGA) score and 
inflammatory lesion counts. 
Secondary Objectives: 
The secondary objectives are to evaluate the safety of oral sarecycline 1.5 mg/kg/day based 
on adverse events, vital signs, electrocardiograms, physical examinations and clinical 
laboratory tests. 
Study Design: 
Randomized, double-blind, placebo-controlled, parallel group 
Study Population:  
Males and females, 9 to 45 years of age (inclusive) with moderate to severe facial acne 
vulgaris 
Number of Subjects:  Approximately 1000 subjects enrolled at approximately 50 sites 
Study drug; Dose; and Mode of Administration: 
Sarecycline tablets; 60 mg, 100 mg and 150 mg, providing a dose of 1.5 mg/kg/day; oral 
Reference Therapy; Dose; and Mode of Administration: 
Matching placebo tablets; oral 
Duration of Treatment:  
12 weeks 
Efficacy Assessments: 
IGA scores and lesion counts at baseline and following 3, 6, 9, and 12 weeks of treatment. 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 3 of 66 
The co-primary efficacy endpoints will be the change from baseline (CFB) in inflammatory 
facial lesion counts at Week 12 and IGA success at Week 12. 
Safety Assessments: 
Adverse events, vital signs, electrocardiograms, physical examinations and clinical 
laboratory tests. 
Pharmacokinetic Assessments: 
Subjects will have the ability to participate in one of two PK sampling options: PK 
Schedule 1 or PK Schedule 2 (see below).  Additionally, subjects who are 9 to 11 years 
of age have the ability to participate in PK Schedule 3 (see below).  Subjects that do not 
participate in PK sampling are still eligible for study participation.  For some of the sites, 
the only choices will be PK Schedule 2 or no PK sampling.   
PK Schedule 1 
Visit 
Sample Time 
Visit 1 (Week 3 ± 3 days) 
(1) Predose:  Within 0.5 hours before dose administration 
(2) Postdose:  Between 0.5 hours and 1 hour after dose administration 
(3) Postdose:  Between 1.5 hours and 3 hours after dose 
administration 
Visit 4 (Week 12 ± 3 days) 
(1) Postdose:  Between 4 hours and 5 hours after dose administration 
(2) Postdose:  Between 6 hours and 8 hours after dose administration 
PK Schedule 2 
Visit 
Sample Time 
Visit 1 (Week 3 ± 3 days) 
At any time during the visit 
Visit 4 (Week 12 ± 3 days) 
At any time during the visit 
PK Schedule 3 (only for 9-11 year old subjects) 
Subjects who participate in PK Schedule 3 will receive one dose of active study 
treatment at Visit 4 (Week 12) after all visit assessments are completed regardless of 
randomized study treatment (active or placebo).
 
Visit 
Sample Time 
Visit 1 (Week 3 ± 3 days) 
At any time during the visit 
Visit 4 (Week 12 ± 3 days) 
(1) Postdose:  Between 0.5 hours and 1 hour after dose 
administration 
(2) Postdose:  Between 1.5 hours and 2 hours after dose 
administration 
(3) Postdose:  Between 3 hours and 4 hours after dose 
administration 
 
Statistical Methods: 
Continuous variables will be summarized by visit and treatment, as applicable, using 
descriptive statistics (mean, median, 25th percentile, 75th percentile, standard deviation, 
standard error of mean, minimum, maximum, and number of subjects).  Categorical 
variables will be summarized using frequency distributions (counts and percentages). 
The co-primary efficacy endpoints, the change from baseline in inflammatory lesion counts 
and IGA success (defined as at least a 2-point decrease from baseline in the IGA 
assessment and a score of clear [0] or almost clear [1] on the IGA assessment) at Week 12 
will be analyzed at α=0.05 for no difference between treatments using the Intent-to-Treat 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 4 of 66 
population.  The absolute change from baseline in inflammatory lesion counts will be 
analyzed using an analysis of covariance (ANCOVA) model with factors for treatment and 
(pooled) site and the baseline value as a covariate.  The adjusted means with associated 
95% confidence intervals (CIs) from the ANCOVA model will also be presented for each 
treatment and for the difference between the treatments at Week 12.  IGA success will be 
analyzed using a Cochran-Mantel-Haenszel (CMH) test with adjustment for (pooled) site 
at Week 12.  The risk difference and the 95% CIs for the risk difference and the relative 
risk and the 95% CIs for the relative risk will be presented as well.  A hierarchical testing 
approach will be used for the secondary efficacy endpoints, percent change from baseline 
in inflammatory lesion counts at Week 12, and absolute and percent CFB in 
inflammatory lesion counts at Weeks 9, 6, and 3 (using ANCOVA), such that statistical 
testing will only be performed if both co-primary efficacy endpoints are statistically 
superior to placebo at α=0.05.  Statistical testing of the secondary endpoints will be 
conducted in the following order, with all tests proceeding at the 0.05 level if and only 
if the previous tests were all significant at the 0.05 level: (1) Percent CFB for 
inflammatory lesion counts at Week 12 (must be significant at the 0.05 level to 
proceed to the next analyses), (2) Absolute and percent CFB for inflammatory lesion 
counts at Week 9 (both endpoints must be significant at the 0.05 level to proceed to 
the next analyses), (3) Absolute and percent CFB for inflammatory lesion counts at 
Week 6 (both endpoints must be significant at the 0.05 level to proceed to the next 
analyses), (4) Absolute and percent CFB for inflammatory lesion counts at Week 3 
(both endpoints must meet the 0.05 level for Week 3 to meet statistical significance).  
The secondary endpoints listed above will all be analyzed using an analysis of 
covariance model with factors for treatment and (pooled) site and the baseline value as a 
covariate for the ITT population.  Missing data for the co-primary and secondary 
endpoints will be handled using a multiple imputation approach. 
Plasma concentration data of sarecycline will be analyzed by nonlinear mixed effects 
modeling approach. 
Date of Original Protocol: 15-Aug-2014 
Date of Protocol Amendment 1: 15-Sep-2014 
Date of Protocol Amendment 2: 13-Mar-2015 
Date of Protocol Amendment 3: DD-Dec-2015 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 5 of 66 
3 TABLE OF CONTENTS 
1 TITLE PAGE 
................................
................................
.....................................................1 
2 SYNOPSIS 
.......................................................................................................................2 
3 TABLE OF CONTENTS 
.................................................................................................5 
4 LIST OF ABBREVIATIONS 
...........................................................................................9 
5 ETHICS............................................................................................................................11
 
5.1 
Ethical Conduct of Study 
................................
.......................................................11 
5.2 
Institutional Review Board 
................................
....................................................11 
5.3 
Subject Information and Consent...........................................................................11
 
5.4 
Subject Confidentiality 
................................
..........................................................12 
5.5 
Authorization to Disclose Protected Health Information.......................................12
 
6 INVESTIGATOR AND STUDY ADMINISTRATIVE STRUCTURE 
.........................13
 
7 INTRODUCTION 
................................
................................
...........................................14 
8 STUDY OBJECTIVES 
..................................................................................................15 
9 INVESTIGATIONAL PLAN 
.........................................................................................16 
9.1 
Overall Study Design and Plan 
................................
..............................................16 
9.2 
Rationale for Study Design and Control Group 
.....................................................16 
9.3 
Selection of Study Population 
...............................................................................17 
9.3.1 
Inclusion Criteria .........................................................................................17 
9.3.2 
Exclusion Criteria 
................................
........................................................17 
9.3.3 
Subject Identification 
................................
...................................................18 
9.3.4 
Removal of Subjects from Treatment or Assessment 
..................................18
 
9.4 
Study Treatments 
................................
................................
...................................20 
9.4.1 
Treatments Administered 
............................................................................20 
9.4.1.1 
Subjects Participating in PK Schedule 3 .......................................20
 
9.4.2 
Identity of Study drugs.................................................................................20 
9.4.2.1 
Description of Study drugs 
................................
................................20 
9.4.2.2 
Packaging, Labeling and Dispensing 
.................................................20
 
9.4.2.3 
Storage and Accountability 
...............................................................21 
9.4.3 
Method of Assigning Subjects to Treatment ...............................................22 
9.4.3.1 
Subjects Participating in PK Schedule 3 .......................................22
 
9.4.4 
Selection of Doses and Timing of Administration in the Study 
..................22 
9.4.4.1 
Subjects Participating in PK Schedule 3 .......................................23
 
9.4.5 
Blinding........................................................................................................23 
9.4.6 
Prior and Concomitant Therapy 
..................................................................23 
9.4.6.1 
Excluded Medications and Therapies 
................................................24 
9.4.6.2 
Medication Washout Prior to Study Randomization 
.........................24 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 6 of 66 
9.4.6.3 
Use of Contraception 
................................
.........................................25 
9.4.7 
Treatment Compliance 
................................................................................26 
9.5 
Study Activities 
....................................................................................................26 
9.5.1 
Screening Period 
................................
..........................................................26 
9.5.1.1 
Screen Visit 1 (SV1) 
................................
..........................................27 
9.5.1.2 
Screen Visit 2 (SV2)/Baseline 
...........................................................27
 
9.5.2 
Treatment Period 
.........................................................................................28 
9.5.2.1 
Telephone Contact (Week 1 ± 3 days) 
...............................................28 
9.5.2.2 
Visit 1 (Week 3 ± 3 days) 
................................
..................................28 
9.5.2.3 
Visit 2 (Week 6 ± 3 days) 
................................
..................................29 
9.5.2.4 
Visit 3 (Week 9 ± 3 days) 
................................
..................................30 
9.5.2.5 
Visit 4 (Week 12 ± 3 days) 
................................
................................30 
9.5.2.6 
Visit 5 (Week 13 ± 3 days) (for subjects participating in PK 
Schedule 3) 
.......................................................................................31 
9.5.2.7 
Early Termination Visit 
................................
.....................................31 
9.6 
Study Assessments 
...............................................................................................32 
9.6.1 
Efficacy Assessments...................................................................................32
 
9.6.1.1 
Facial Investigator’s Global Assessment 
...........................................32
 
9.6.1.2 
Non-facial Investigator’s Global Assessment 
....................................32
 
9.6.1.3 
Facial Lesion Counts..........................................................................33 
9.6.2 
Safety Assessments 
.....................................................................................33 
9.6.2.1 
Adverse Events 
................................
..................................................33 
9.6.2.2 
Clinical Laboratory Evaluations 
........................................................36 
9.6.2.3 
Physical Examinations 
................................
.......................................36 
9.6.2.4 
Height and Body Weight ...................................................................37 
9.6.2.5 
Vital Signs 
.........................................................................................37 
9.6.2.6 
Electrocardiograms 
................................
............................................37 
9.6.2.7 
Pregnancy 
..........................................................................................37 
9.6.3 
Other Evaluations.........................................................................................37 
9.6.3.1 
Photography 
................................
.......................................................38 
9.6.3.2 
Skindex-16 Questionnaire 
.................................................................38 
9.6.3.3 
Concomitant Medication Use ............................................................38 
9.6.3.4 
Pharmacokinetic Sampling 
................................
................................38 
10 QUALITY CONTROL AND ASSURANCE .................................................................41 
11 PLANNED STATISTICAL METHODS 
................................
........................................42 
11.1 Determination of Sample Size 
................................
...............................................42 
11.2 Analysis Populations and Datasets 
................................
........................................43 
11.3 General Statistical Procedures 
................................
...............................................44 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 7 of 66 
11.3.1 Overview 
....................................................................................................44 
11.3.2 Summary Statistics.......................................................................................44
 
11.3.3 Site Pooling Algorithm 
................................
................................................44 
11.4 Efficacy Parameters 
................................
...............................................................44 
11.4.1 Co-primary Efficacy Endpoints 
................................
...................................44 
11.4.2 Secondary Efficacy Endpoint ......................................................................45 
11.4.3 Missing Data Handling 
................................
..............................................45 
11.4.4 Other Efficacy Endpoints 
............................................................................46 
11.5 Analysis of Efficacy Variables 
................................
..............................................46 
11.5.1 CFB in Inflammatory Lesion Counts 
...........................................................46 
11.5.2 IGA Success 
...............................................................................................47 
11.5.3 Percent CFB in Inflammatory Lesion Counts 
..............................................47 
11.5.4 Decrease in IGA Assessment of at Least 2 Points 
.......................................48
 
11.5.5 Additional Analyses 
....................................................................................49 
11.5.6 Sensitivity Analyses 
....................................................................................49 
11.5.7 Subgroup Analyses 
................................
......................................................50 
11.6 Safety Analyses 
....................................................................................................50 
11.6.1 Adverse Events 
................................
............................................................50 
11.6.2 Extent of Exposure 
......................................................................................51 
11.6.3 Clinical Laboratory Evaluations 
................................
..................................51 
11.6.4 Electrocardiograms 
................................
......................................................52 
11.6.5 Vital Signs 
..................................................................................................52 
11.7 Other Assessments or Analyses 
................................
.............................................52 
11.7.1 Demographics and Baseline Characteristics 
................................................52
 
11.7.2 Medications 
................................................................................................52 
11.7.3 Compliance 
................................
................................
..................................53 
11.7.4 IGA for Non-facial Sites 
.............................................................................53 
11.7.5 Noninflammatory Lesion Counts 
................................................................53 
11.7.6 Skindex Questionnaire 
................................
.................................................53 
11.7.7 Photographs..................................................................................................54 
11.7.8 Pharmacokinetics 
................................
.........................................................54 
12 DOCUMENTATION REQUIREMENTS AND RECORDKEEPING 
...........................55
 
12.1 Source Documentation 
..........................................................................................55 
12.2 Data Capture and Discrepancy Management 
.........................................................55
 
13 OTHER INFORMATION 
................................
...............................................................56 
13.1 Financing and Insurance 
................................
........................................................56 
13.2 Publication and Disclosure Policy 
................................
.........................................56 
13.3 Termination of the Study 
................................
.......................................................56 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 8 of 66 
14 REFERENCE LIST 
................................
................................
.........................................57 
15 APPENDICES 
................................
................................
.................................................58 
 
 
LIST OF IN-TEXT TABLES 
Table 9-1: 
Study drug Quantity and Dispensing Schedule .........................................21 
Table 9-2: 
Study drug Dose Selection 
........................................................................22 
Table 9-3: 
Medication Washout Requirements 
...........................................................25 
Table 9-4: 
Investigator’s Global Assessment of Inflammatory Acne 
.........................32 
Table 9-5 
Sampling Times for PK Schedule 1 
...........................................................39 
Table 9-6 
Sampling Times for PK Schedule 2 
...........................................................39 
Table 9-7 
Sampling Times for PK Schedule 3 
...........................................................40 
 
LIST OF APPENDICES 
Appendix 1 Study Schedule of Events 
................................
..........................................59 
Appendix 2 Clinical Laboratory Evaluations 
................................
................................61 
Appendix 3 Collection, Processing, Storage and Shipment Instructions for PK 
Samples  62
 
Appendix 4 Skindex Questionnaire 
................................
...............................................63 
Appendix 5 Investigator Signature 
................................
................................................65 
Appendix 6 Sponsor Signatures.....................................................................................66 
 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 9 of 66 
4 LIST OF ABBREVIATIONS 
ANCOVA 
Analysis of covariance 
CFB 
Change from baseline 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CRO 
Contract research organization 
CRF 
Case report form 
ECG 
Electrocardiogram 
ET 
Early termination 
FCS 
fully conditional specifications 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HCl 
Hydrochloride 
ICH 
International Conference on Harmonisation  
IGA 
Investigator’s Global Assessment 
IP 
Investigational product 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
Intent-to-treat 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
MMRM 
Mixed-effects  model repeated measures 
NONMEM 
Nonlinear mixed-effects modeling 
OC 
Observed cases 
PHI 
Protected health information 
PK 
Pharmacokinetic 
PP 
Per-protocol  
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SEM 
Standard error of the mean 
SV 
Screen Visit 
US 
United States 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 10 of 66 
WHO 
World Health Organization  


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 11 of 66 
5 ETHICS 
5.1 Ethical Conduct of Study 
The study will be conducted in accordance with Good Clinical Practice (GCP) as contained 
in International Conference of Harmonisation (ICH) Guidelines and United States (US) Code 
of Federal Regulations (CFR) governing the protection of human subjects (Title 21, Part 50) 
and the obligations of clinical investigators (Title 21, Parts 312.60 through 312.69).  The 
study will also be conducted in accordance with the World Medical Association Declaration 
of Helsinki and all amendments. 
The Sponsor is responsible for the ongoing safety evaluation of the study drug and will 
expedite the notification of all participating investigators and regulatory authorities of 
findings that are both serious and unexpected and/or that could adversely affect the safety of 
subjects, the conduct of the study or alter the Institutional Review Board’s (IRB’s) approval 
to continue the study. 
5.2  Institutional Review Board 
The protocol and supporting documents for this study will be reviewed and approved by an 
appropriately constituted Institutional Review Board (IRB) prior to study initiation.  All 
reviews and approvals will be in accordance with Good Clinical Practice (GCP) as contained 
in the International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) Guidelines (E6) and United States 
(US) Code of Federal Regulations (CFR) governing IRBs (Title 21, Part 56). 
A letter from the IRB documenting approval of the Investigator (who must be identified by 
name), the protocol (must be identified by title), and the subject consent form must be 
received by Warner Chilcott (US), LLC, US Regulatory Agent of Warner Chilcott 
Company, LLC, an Allergan Affiliate (referred to hereafter as the Sponsor) or its designee 
prior to study initiation.  A progress report will be submitted by the Investigator to the IRB at 
intervals specified by the IRB, but not less than annually.  A copy of this progress report will 
be sent to the Sponsor.  After completion of the study, the Investigator will submit a signed 
clinical safety summary of the study to the IRB. 
5.3  Subject Information and Consent 
The Investigator will ensure that written informed consent (and/or assent, if applicable) is 
obtained from each subject (and parent(s) or legal guardian(s), if applicable) in accordance 
with applicable regulations.  Subjects under the age of majority or per IRB requirements 
must sign the Assent Form.  In such cases, it is recommended that both parent(s) or legal 
guardian(s) sign the Informed Consent Form unless one parent is deceased, unknown, 
incompetent, or not reasonably available, or when one parent has legal responsibility for the 
care and custody of the child. 
Subjects and their parent(s) or legal guardian(s), if applicable, will be interviewed at the 
initial screening visit by qualified staff at the site and will be provided with a full description 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 12 of 66 
of the nature and purpose of the study.  The subject and their parent(s) or legal guardian(s), if 
applicable, will be given adequate time to consider the risks associated with participation in 
the study.  Each subject will provide written informed consent (and/or assent if applicable 
and according to IRB regulations) prior to participating in any study procedures.  Original 
signed consent and assent forms will be retained on file at the clinical site and copies will be 
given to the subjects.  Case histories (subject charts) will also document that informed 
consent/assent was obtained prior to the subjects’ participation in the study. 
Each subject will provide a written informed consent (and/or assent if applicable and 
according to IRB regulations) prior to participating in pharmacokinetic (PK) sampling 
procedures.  Subjects that select no PK sampling as their option will still need to give consent 
to be able to participate in the main study. 
5.4 Subject Confidentiality 
The Sponsor ensures that the following have permission to review all study-related 
documents: monitor, auditor, IRB/IEC and regulatory authorities.  The subject’s identity and 
study-related records (including photographs) will remain confidential throughout the 
duration of the study data collection and reporting process. 
A unique subject identification code will be assigned to each potential study subject.  The 
identification code protects the subject’s identity and is used in lieu of the subject’s name 
when reporting subject data.  The data will always maintain the confidentiality of the subject. 
The Investigator or designee will review the subject data, which will be referenced using the 
subject identifier.  At the conclusion of the study, the data obtained may be presented to 
regional regulatory authorities but the subject’s identity will not be revealed.  In addition, if 
any clinical data obtained from the study are published in scientific journals or presented at 
scientific meetings, the subject’s identity will not be revealed. 
5.5  Authorization to Disclose Protected Health Information 
As required under Health Insurance Portability and Accountability Act regulations, subjects 
will be informed of the following information: 
• the Sponsor of the study; 
• any contractors that may be involved in the study; 
• the purpose of the protected health information (PHI) being collected; 
• the possibility that the PHI may be re-disclosed; 
• the duration of the authorization; 
• the subject’s rights to revoke the authorization; and, 
• the right of the subject to refuse signature and limit access to PHI during the conduct of 
the trial (US CFR Title 45, Parts 160 and 164); 
• Authorization to disclose PHI must be obtained before the subject enters the study. 




Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 14 of 66 
7 INTRODUCTION 
Acne vulgaris is a common disease of both males and females, usually manifesting initially 
during adolescence.  The primary pathologic events are initiated in the pilo-sebaceous units, 
especially of sebaceous-gland-bearing areas of the face, chest, and back as a result of 
increased androgen stimulation initiated at adrenarche or puberty.  As a result of both 
abnormal keratinization of the infra-infundibular portion of the sebaceous follicle and 
increased sebum produced in the gland, a blockage of the duct results in the inapparent 
clinical lesion of the microcomedone.  Continued blockage, colonization of the follicle by 
Propionibacterium acnes, and generation of multiple chemoattractant and proinflammatory 
moieties may result in non-inflammatory clinical lesions, comedones, and inflammatory 
lesions: papules, pustules, nodules, and cysts.
1 
Sarecycline is a tetracycline-class antibiotic being developed as a treatment for acne vulgaris.  
Antibiotics, especially erythromycin, minocycline, and doxycycline, have been prescribed as 
acne treatments for many years.  These antibiotics effectively control the signs of 
inflammatory acne while patients continue to take them.  Nonclinical studies have 
demonstrated that sarecycline exhibits favorable characteristics, including potent gram-
positive activity, minimal gram-negative activity, efficacy in tissue-based models of 
infection, and effective anti-inflammatory activity, which supports its use as a novel 
treatment for acne.  
The Sponsor conducted a Phase 2 study (Study PR-10411) that evaluated the safety and 
efficacy of three different oral doses of sarecycline (approximately 0.75 mg/kg/day, 
1.5 mg/kg/day, and 3.0 mg/kg/day) compared with placebo in the treatment of moderate to 
severe facial acne vulgaris.  The results of this study indicated that a daily dose of sarecycline 
1.5 mg/kg was superior to placebo in decreasing the number of inflammatory lesions and 
improving the Investigator Global Assessment (IGA) of facial acne following 12 weeks of 
treatment.  The 0.75 mg/kg/day dose was not superior to the placebo.  No further 
improvement in efficacy was observed with the 3.0 mg/kg/day dose.  Based on the results of 
this study, the 1.5 mg/kg/day sarecycline dose was selected for continued development. 
 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 15 of 66 
8 STUDY OBJECTIVES 
The primary objective is to evaluate the efficacy of oral sarecycline 1.5 mg/kg/day compared 
to placebo in treating inflammatory acne lesions in subjects with moderate to severe facial 
acne vulgaris based on Investigator’s Global Assessment (IGA) score and inflammatory 
lesion counts. 
The secondary objectives are to evaluate the safety of oral sarecycline 1.5 mg/kg/day based 
on adverse events, vital signs, electrocardiograms (ECG), physical examinations and clinical 
laboratory tests. 
The other objective of the study is to characterize the pharmacokinetics of oral sarecycline 
1.5 mg/kg/day in the relevant population with acne vulgaris. 
 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 16 of 66 
9 INVESTIGATIONAL PLAN 
9.1  Overall Study Design and Plan 
This Phase 3 multicenter, randomized, double-blind, placebo-controlled, parallel group study 
will evaluate efficacy and safety of an approximate 1.5 mg/kg/day dose of oral sarecycline 
compared to placebo in the treatment of moderate to severe facial acne vulgaris.  The study 
will include approximately 1000 males and females 9 to 45 years of age with moderate to 
severe facial acne vulgaris and no disorders that would preclude the use of tetracycline-class 
antibiotics at approximately 50 sites. 
The study includes a screening period of up to 35 days to establish eligibility and baseline 
conditions followed by a 12-week treatment period.  Eligible subjects will be randomized in 
a 1:1 ratio to receive daily oral doses of either 1.5 mg/kg sarecycline tablets or placebo 
tablets.  Subjects will return to the clinic on an outpatient basis following 3, 6, 9 and 
12 weeks of treatment.  At each clinic visit, facial acne will be evaluated through lesion 
counts and IGA scores by visual inspection; non-facial inflammatory acne will also be 
evaluated by IGA of the neck, chest, and back.  The co-primary efficacy endpoints of the 
study are the absolute change from baseline in the facial inflammatory lesion count at Week 
12 and a dichotomized IGA (dichotomized to reflect either ‘success’ or ‘failure’ with 
‘success’ defined as at least a 2-point decrease from baseline in the IGA assessment and a 
score of clear [0] or almost clear [1] on the IGA assessment) at Week 12.  Safety evaluations 
(adverse events, vital signs, clinical laboratory evaluations, ECG and physical examinations) 
will be conducted at specific treatment period visits and at study termination. 
The study will collect PK samples for analysis of plasma sarecycline and R-sarecycline 
concentrations.  The sarecycline concentration data will be used to assess population PK and 
may be used in PK/pharmacodynamic (PD) analyses. 
A study schedule of events is provided in Appendix 1.  Details and descriptions of study 
procedures are contained in the following sections. 
9.2  Rationale for Study Design and Control Group 
A prospective, randomized, double-blind, placebo-controlled, parallel group trial design is an 
accepted method of evaluating the efficacy and safety of therapeutic agents.  The purpose of 
a placebo group is to account for the effects of treatment that do not depend on the study drug 
itself.  Placebo-controlled trials also provide the maximum ability to distinguish adverse 
effects caused by a drug from those resulting from underlying disease or intercurrent illness.  
The study design is representative of designs used to determine drug treatments for acne 
vulgaris and is consistent with the Food and Drug Administration (FDA) draft guidance 
“Acne Vulgaris: Developing Drugs for Treatment”2 dated September 2005. 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 17 of 66 
9.3  Selection of Study Population 
The study will include approximately 1000 subjects (approximately 500 subjects per arm) 
who meet all of the inclusion and none of the exclusion criteria. 
9.3.1 Inclusion Criteria 
A subject will be considered for inclusion in the study if he/she meets all of the following 
criteria: 
IN01. Has signed the informed consent or assent form (Section 9.5.1) 
IN02. Is a male or female, 9 to 45 years of age, inclusive 
IN03. Has a body weight between 33 kg and 136 kg, inclusive 
IN04. Has facial acne vulgaris with: 
- 20 to 50 inflammatory lesions (papules, pustules, and nodules) 
- up to 100 noninflammatory lesions (open and closed comedones) 
- No more than two nodules 
- IGA score of moderate (3) or severe (4) 
IN05. Has a negative urine pregnancy test at baseline - females of childbearing potential 
only 
IN06. Agrees to use an effective method of contraception throughout the study, if applicable 
(see Section 9.4.6.3) 
IN07. Refrain from use of any other acne medications and medicated cleansers, and avoid 
excessive sun exposure and tanning booths for the duration of the study 
IN08. Is able to fulfill the requirements of the protocol, has indicated a willingness to 
participate in the study, and agrees to all study procedures (including mandatory 
photography) by providing written informed consent/assent and an authorization to 
disclose PHI 
IN09. Is able to swallow the tablets 
 
9.3.2 Exclusion Criteria 
A subject will be excluded from participation if he/she meets any of the following criteria: 
EX01. Has a dermatological condition of the face (e.g., skin burn, sunburn, beard, mustache) 
that could interfere with the clinical evaluations 
EX02. Has a history of any of the following: 
- Allergy to tetracycline-class antibiotics or to any ingredient in the study drug 
- Pseudomembranous colitis or antibiotic-associated colitis 
- Treated for any type of cancer within the last 6 months 
- Has known resistance to other tetracyclines 




Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 19 of 66 
Subjects must be withdrawn from the study for any of the following events: 
• Elevated AST or ALT 3 times upper limit of normal (ULN) or greater and 
elevated bilirubin greater than 2 times ULN and no other explanation of these 
abnormal tests 
• An SAE assessed as related to study treatment by the Investigator or Medical 
Monitor 
• Clinically significant worsening of acne status requiring change of treatment in 
acne management (eg. increased size or number of nodules) 
Subjects may be withdrawn from the study for one of the following events: 
• Adverse Event: An AE that, in the opinion of the Investigator or Sponsor, 
suggests that continued participation in the study is not in the subject’s best 
interest for safety reasons. Only a primary AE leading to withdrawal should be 
noted to be the reason for withdrawal. 
• Abnormal Laboratory Result: Any clinically significant laboratory abnormality 
that requires withdrawal of the subject from the study should be considered an AE 
leading to withdrawal.  If possible, laboratory tests will be repeated for any results 
that were clinically significantly abnormal until the abnormality is resolved or 
stabilized to the satisfaction of the Investigator in consultation with the Medical 
Monitor. 
• Lost to Follow-up: Confirmed at minimum by 2 phone calls and a traceable letter 
without answer. 
• Subject Request: Subject requests for any reason to be withdrawn or withdraws 
his/her consent. 
• Protocol Deviation: A subject may be withdrawn from the study at the discretion 
of the Investigator or Sponsor due to poor compliance with protocol requirements 
that may compromise the study results or subject safety. 
• Other:  Other reasons include but are not limited to: Investigator decision that it is 
in the subject’s best interest to be withdrawn, administrative reasons, relocation of 
subject, etc.  If a subject becomes pregnant during the study, the subject will be 
withdrawn from the study and followed through to the conclusion of the 
pregnancy. 
If a subject withdraws, or is withdrawn from the study by the Investigator, the reasons and 
circumstances for such early termination (ET) must be fully documented.  Subjects who are 
withdrawn from the study will not be reenrolled. 




Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 21 of 66 
Table 9-1: Study drug Quantity and Dispensing Schedule 
Visit 
Quantity Dispensed 
Screen Visit (SV) 2 
30 
1 
30 
2 
30 
3 
30 
Authorized site personnel will use the IRT system to assign a bottle number that corresponds 
to the randomization schedule. 
SUBJECTS PARTICIPATING IN PK SCHEDULE 3 
Subjects who participate in PK Schedule 3 will receive one dose of active study 
treatment at Visit 4 (Week 12) regardless of randomized study treatment (active or 
placebo).  To obtain the active study treatment, the site will contact their clinical 
research associate (CRA) a full week before the visit.  The CRA will notify the clinical 
supply group to ship 1 bottle of active investigational product.  The shipment will be 
documented on the drug accountability log. 
9.4.2.3 
Storage and Accountability 
The study drugs should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted from 
15°C to 30°C (59°F to 86°F).  Where storage conditions exceed 30°C or drop below 15°C, 
the Sponsor should be notified immediately. 
The investigator or designee will confirm the receipt of the study drug, will verify the 
condition under which the drug was received and will verify the contents of the shipment 
using the IRT system, immediately upon receipt of the product. 
The Investigator shall maintain accurate study drug inventory records, including the 
quantities and date of receipt of supplies from the Sponsor, and the quantities and dates of 
dispensing to study participants.  All study drug supplies must be accounted for at study 
termination and a written explanation provided for any discrepancies.  All unused supplies 
shall be returned to the Sponsor or, if authorized in writing by the Sponsor, destroyed 
properly at the study site.  Shipping and handling of all study drugs will conform to FDA 
regulations for investigational drug products (CFR 312.57(a), 312.59, 312.61, 312.62(a)). 
Reasons for departure from the expected dispensing regimen will also be recorded.  At 
completion of the study, to satisfy regulatory requirements regarding study drug 
accountability, all study drugs will be stored, inventoried, reconciled, and destroyed or 
returned to the Sponsor according to applicable state and federal regulations.  A written 
explanation must be provided for any discrepancies.  The study monitor must review all 
records of study drug accountability prior to the return or destruction of any supplies. 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 22 of 66 
SUBJECTS PARTICIPATING IN PK SCHEDULE 3 
Subjects who participate in PK Schedule 3 will receive one dose of active study 
treatment at Visit 4 (Week 12) regardless of randomized study treatment (active or 
placebo).  The shipment of 1 bottle of active investigational product for this study 
treatment will be documented on the drug accountability log. 
9.4.3 Method of Assigning Subjects to Treatment 
At Screening Visit 2 (baseline assessment), authorized site personnel will use the IRT system 
to randomize the subject.  The randomization program will assign the subject to a double-
blind treatment group and will assign a bottle number that corresponds to the assigned 
treatment group.  Subjects will be randomized to either sarecycline or placebo in a 1:1 ratio 
using block randomization.  At Visit 1, Visit 2 and Visit 3, site personnel will again use the 
IRT system to dispense subsequent bottles associated with the assigned treatment group.  
Only bottle numbers provided by the IRT should be dispensed to subjects.  
The randomization schedule will be prepared by a statistician not involved with this study 
(e.g., an independent, randomization statistician) using SAS
® PROC PLAN. 
9.4.3.1 
Subjects Participating in PK Schedule 3 
Subjects who participate in PK Schedule 3 will receive one dose of active study 
treatment at Visit 4 (Week 12) regardless of randomized study treatment (active or 
placebo). 
9.4.4 Selection of Doses and Timing of Administration in the Study 
The approximate 1.5 mg/kg/day dose was selected for inclusion in this study based on the 
results of a Phase 2 study that evaluated three doses of sarecycline (approximately 
0.75 mg/kg/day, 1.5 mg/kg/day and 3.0 mg/kg/day) in comparison to placebo in the treatment 
of moderate to severe facial acne vulgaris.3  The results indicated that the 1.5 mg/kg dose was 
superior to placebo in reducing inflammatory lesion counts and the proportion of subjects 
with a successful outcome based on IGA score from baseline to study conclusion.  The 
0.75 mg/kg dose was not effective for either co-primary efficacy endpoint and the higher 
dose did not result in additional efficacy beyond that seen with the 1.5 mg/kg dose group.   
The appropriate tablet strength will be determined based on the body weight of the subject as 
described in Table 9-2. 
Table 9-2: Study drug Dose Selection 
Body Weight 
Tablet Strength 
Total Dose per 
Weight Mass 
33 to 54 kg 
60 mg tablet 
1.8 to 1.1 mg/kg 
55 to 84 kg 
100 mg tablet 
1.8 to 1.2 mg/kg 
85 to 136 kg 
150 mg tablet 
1.8 to 1.1 mg/kg 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 23 of 66 
 
One tablet should be taken orally at approximately the same time each day, at least 1 hour 
prior to, or 2 hours after eating. 
9.4.4.1 
Subjects Participating in PK Schedule 3 
Subjects who participate in PK Schedule 3 will receive one dose of active study 
treatment at Visit 4 (Week 12) regardless of randomized study treatment (active or 
placebo). 
9.4.5 Blinding 
This study employs a double-blind design with treatment allocated randomly and blinding 
maintained throughout the study by the use of identically appearing active and placebo 
tablets.  In the event of an emergency where the subject’s well-being requires knowledge of 
the treatment assignment, the Investigator should make an attempt, if time permits, to contact 
the Medical Monitor prior to unblinding to discuss the reason(s) for unblinding.  If an 
Investigator, site personnel performing assessments, or a subject is unblinded, the subject 
must be discontinued from the study.  The date of the code break and the reason for the break 
must be recorded in the subject’s source documents. 
Before breaking the blind for a subject, the Investigator should determine that the 
information is necessary (i.e., that it will alter the subject’s immediate course of treatment 
and will contribute to the management of the adverse event).  In many cases, particularly 
when the emergency is clearly not related to study drug, the problem may be effectively 
managed by assuming that the subject is receiving active study drug without the need for 
unblinding.  Every effort should be made to alert the Medical Monitor before requesting that 
the blind be broken.  If this is not possible, the Medical Monitor should be immediately 
notified of the breaking of the blind. 
If unblinding is necessary, the study drug identity can be obtained by the Investigator through 
the IRT.  The subject will be withdrawn from the study and Week 12/ET assessments will be 
completed. 
The bioanalytical laboratory responsible for analyzing PK samples for sarecycline/ 
R-sarecycline concentrations will be unblinded so that they can identify which samples were 
obtained from subjects on active treatment. 
9.4.6 Prior and Concomitant Therapy 
All medications used in the 30 days prior to SV1, any hormonal contraceptives or any acne 
medications used in the 3 months prior to SV1 will be documented in the case report form 
including the name of the drug, the route of administration, date of initiation and 
discontinuation, and the reason for administration.  New medications and changes in 
medication use during the study will be recorded in a similar manner.  If an exclusionary 
medication is required, the subject should be discontinued from the study. 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 24 of 66 
Non-medicated facial hygiene products are permitted to be used in this study if approved by 
the Sponsor.  Non-medicated facial hygiene products such as cleansers could be provided to 
randomized subjects for use during the study. 
9.4.6.1 
Excluded Medications and Therapies 
Subjects must abstain from use of all excluded medications and therapies (Section 9.3.2) 
after the initial screening visit and throughout the treatment period.   
Subjects may use non-medicated cleansers approved by the Sponsor as a facial cleanser 
during the study.  All other treatments for acne including topical and medicated cleansers and 
therapies are prohibited during the study.  Subjects should be encouraged to maintain a 
consistent facial cleansing regimen throughout the study. 
The use of systemic antibiotics for indications other than acne will be considered on a case-
by-case basis with the Medical Monitor.  In addition, initiation or change of hormonal 
contraception use within 12 weeks of screening is exclusionary, and initiation or change of 
hormonal contraception during the study is prohibited. 
9.4.6.2 
Medication Washout Prior to Study Randomization 
Subjects receiving excluded medications/therapies at screening may washout from those 
therapies to continue eligibility in the study as described in Table 9-3.  Under no 
circumstances should a subject be placed at risk by the withdrawal of a current medication. 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 25 of 66 
Table 9-3: Medication Washout Requirements 
Medication Type 
Minimum Washout  
(days prior to SV2 baseline) 
Medicated facial cleansers 
7 days 
Topical acne treatments (other 
than those listed below) 
Topical antibiotics and azelaic 
acid containing medication 
Topical non-prescription anti-
inflammatories (other than those 
listed below)  
2 weeks 
Topical retinoids 
4 weeks 
Topical corticosteroids 
Systemic antibiotics 
Note:  Use of systemic retinoids, systemic corticosteroids, or systemic androgens/anti-androgens 
within 12 weeks of randomization is exclusionary. 
 
9.4.6.3 
Use of Contraception 
Tetracycline-class antibiotics can cause fetal harm when administered to a pregnant woman.  
Tetracycline-class antibiotics used during tooth development (last half of pregnancy, infancy, 
and childhood to the age of 8 years) may cause permanent discoloration of teeth (yellow-
gray-brown).  Also, the effect of sarecycline on sperm is unknown.  Due to the teratogenic 
effects of tetracycline-class antibiotics, male subjects who have female partners of 
childbearing potential must also use an effective method of birth control throughout the 
study. 
Prior to study enrollment, subjects must be advised of the importance of avoiding pregnancy 
during study participation and the potential risk factors for an unintentional pregnancy.  
Females of childbearing potential include any female who has experienced menarche and 
who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation 
or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea >12 consecutive 
months). 
Female subjects of childbearing potential must have a negative urine pregnancy test.  Male 
subjects and females of childbearing potential and/or their partners must use an effective 
method of birth control throughout the study, such as: 
• Abstinence 
• Diaphragm with spermicide 
• Condom (male or female) with spermicide 
• Intrauterine device (hormonal or non-hormonal) 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 26 of 66 
• Implants 
• Injections 
• Transdermal patch 
• Intravaginal ring 
• Oral contraceptives – however, oral antibiotics such as sarecycline may lessen the 
effectiveness of oral contraceptives; therefore, a second form of birth control must be 
utilized by subjects using oral contraceptives. 
 
After the last dose of study drug, subjects should be advised to continue using an effective 
method of birth control (30 days for females and 90 days for males).  In addition, male 
subjects must be advised not to donate sperm for a period of 90 days after the last dose of 
study drug. 
9.4.7 Treatment Compliance 
Compliance with the assigned treatment regimen will be assessed by comparing the number 
of tablets expected to be used, based on the total number of treatment days, with the actual 
number used (expressed as a percentage of used/expected) at each clinic visit and for the 
study overall. 
9.5 Study Activities 
This study will consist of a screening period to establish eligibility, washout from excluded 
therapies, and conduct of baseline evaluations; and a study drug treatment period of 12 weeks 
in duration.  The following sections provide details of the study activities which are 
summarized in the Schedule of Events (Appendix 1). 
Any visit/procedure that has a defined time period for evaluation should be completed within 
the specified window in the protocol. 
9.5.1 Screening Period 
Prior to conducting any screening procedures, subjects will be given a full description of the 
nature and purpose of the study and will be required to provide written consent.  The 
investigator or a designated, medically qualified member of the study staff will interview 
potential participants to establish their eligibility for inclusion in the study.  Potential subjects 
will be screened according to the inclusion and exclusion criteria (Section 9.3.1 and 
Section 9.3.2.) within 35 days prior to beginning treatment.  The investigator will maintain a 
log of all subjects screened for participation and record the reason(s) for excluding potential 
subjects. 
Subjects will undergo the following procedures at the study visits indicated. 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 27 of 66 
9.5.1.1 
Screen Visit 1 (SV1) 
• Consent subject 
• Assign subject number using the IRT 
• Obtain demographic data 
• Obtain medical and surgical history  
• Collect prior and concomitant medication use (Section 9.4.6) 
• Obtain blood and urine samples for clinical laboratory evaluations, hematology, 
chemistry, urinalysis, and lipids (Appendix 2) 
• Obtain blood sample for thyroid function evaluation (Appendix 2) 
• Perform urine pregnancy test – females of childbearing potential only  
• Record 12-lead ECG 
• Adverse event query  
• Perform physical exam 
• Measure height and weight  
• Obtain vital signs 
 
If no drug/therapy washout is required: 
• Review inclusion/exclusion criteria 
• Schedule SV2 
 
If drug/therapy washout is required: 
• Schedule SV2 based on duration of required treatment washout 
 
9.5.1.2 
Screen Visit 2 (SV2)/Baseline 
For subjects who required medication/therapy washout: 
Perform physical exam 
 
All subjects: 
• Measure weight 
• Obtain vital signs 
• Perform the IGA for face  


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 28 of 66 
• Perform facial lesion count of inflammatory and noninflammatory lesions 
• Obtain facial photographs  
• Perform the IGA for neck, chest, and back 
• Update concomitant medication use 
• Record adverse events 
• Perform urine pregnancy test – females of childbearing potential only 
• Administer Skindex questionnaire 
• If washout duration exceeded 5 weeks, re-draw blood and urine samples for clinical 
laboratory evaluations 
• Review inclusion/exclusion 
 
If all screening assessments are acceptable and all inclusion criteria and no exclusion criteria 
have been met, the subject may be randomized to study treatment using the IRT system. 
• Dispense one bottle (30 tablets) of study drug using the IRT.  Instruct the subject on the 
frequency and timing of study drug administration 
• Provide a diary to subjects who consented to PK sampling and remind them to record the 
dose administration times for the 2 doses taken prior to Visit 1/Week 3 in the diary 
• Schedule next clinic visit 
 
9.5.2 Treatment Period 
9.5.2.1 
Telephone Contact (Week 1 ± 3 days) 
Site personnel will contact each subject to ascertain appropriate study drug compliance.  
Subjects will be queried about the number of tablets used and adherence to study 
requirements.  Subjects will also be queried about adverse events.  The subjects participating 
in PK sampling will be instructed to record the dose administration times for the 2 doses 
taken prior to Visit 1/Week 3 in the diary. 
9.5.2.2 
Visit 1 (Week 3 ± 3 days) 
The following procedures will be performed: 
• Measure blood pressure and heart rate 
• Collect blood and urine samples for clinical laboratory tests, hematology, chemistry, 
urinalysis, and lipids (Appendix 2) 
• Perform urine pregnancy test – females of childbearing potential only 
• Perform the IGA for face  


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 29 of 66 
• Perform facial lesion count of inflammatory and noninflammatory lesions 
• Perform IGA for the neck, chest, and back 
• Obtain facial photographs 
• Record concomitant medications 
• Adverse event query 
• Review and collect completed subject diary pages 
• For subjects participating in PK sampling, collect blood samples as directed in 
Section 9.6.3.4 for Visit 1/Week 3 for PK Schedule 1, PK Schedule 2, and PK 
Schedule 3 
• Collect previously dispensed study drug (including empty bottles) and perform study 
drug accountability 
• Dispense one bottle (30 tablets) of study drug using the IRT 
• Schedule the next study visit 
 
9.5.2.3 
Visit 2 (Week 6 ± 3 days) 
The following procedures will be performed: 
• Measure blood pressure and heart rate 
• Perform urine pregnancy test – females of childbearing potential only  
• Perform the IGA for face  
• Perform facial lesion count of inflammatory and noninflammatory lesions 
• Obtain facial photographs 
• Perform IGA for the neck, chest, and back 
• Record concomitant medications 
• Adverse event query 
• Collect previously dispensed study drug and perform study drug accountability and 
assess study drug compliance  
• Dispense one bottle (30 tablets) of study drug using the IRT 
• Schedule the next study visit 
 
 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 30 of 66 
9.5.2.4 
Visit 3 (Week 9 ± 3 days) 
The following procedures will be performed: 
• Measure blood pressure and heart rate 
• Perform urine pregnancy test – females of childbearing potential only  
• Perform the IGA for face  
• Perform facial lesion count of inflammatory and noninflammatory lesions 
• Obtain facial photographs 
• Perform IGA for the neck, chest, and back 
• Record concomitant medications 
• Adverse event query 
• Collect previously dispensed study drug and perform study drug accountability and 
assess study drug compliance  
• Dispense one bottle (30 tablets) of study drug using the IRT 
• For subjects participating in PK sampling, remind them to record the dose administration 
times for the 2 doses taken prior to Visit 4/Week 12 in the diary. Also remind subjects 
participating in PK Schedule 3 that study drug should not be administered at home 
or recorded in the diary the day of Visit 4/Week 12 (subjects receive study drug in 
clinic at Visit 4/Week 12). 
• Schedule the next study visit 
 
9.5.2.5 
Visit 4 (Week 12 ± 3 days) 
• Perform physical examination, including weight 
• Measure blood pressure and heart rate 
• Perform 12-lead ECG 
• Collect blood and urine samples for clinical laboratory tests hematology, serum 
chemistry, urinalysis, and lipids (Appendix 2) 
• Obtain blood sample for thyroid function evaluation (Appendix 2) 
• Perform urine pregnancy test – females of childbearing potential only 
• Perform the IGA for face 
• Perform facial lesion count of inflammatory and noninflammatory lesions 
• Obtain facial photographs 
• Perform IGA for the neck, chest, and back 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 31 of 66 
• Record concomitant medications 
• Administer Skindex questionnaire 
• Adverse event query 
• Review and collect completed subject diary pages 
• For subjects participating in PK sampling, collect blood samples as directed in 
Section 9.6.3.4 for Visit 4/Week 12 for PK Schedule 1, PK Schedule 2, and PK 
Schedule 3 
• Collect previously dispensed study drug and perform study drug accountability and 
assess study drug compliance 
• Record date of last study drug dose and the dose taken in clinic at the Visit 4/Week 12 
• For subjects participating in PK Schedule 3, schedule the next study visit at 
Visit 5/Week 13 ± 3 days 
• Complete Study Termination Form (unless subject is participating in PK Schedule 3) 
 
9.5.2.6 
Visit 5 (Week 13 ± 3 days) (for subjects participating in PK Schedule 3) 
• Perform physical examination, including weight 
• Measure blood pressure and heart rate 
• Perform urine pregnancy test – females of childbearing potential only 
• Record concomitant medications 
• Adverse event query 
• Complete Study Termination Form 
 
9.5.2.7 
Early Termination Visit 
Study site personnel will attempt to follow the progress of every subject admitted to the study 
through to study completion.  If a subject fails to return for a scheduled visit, a reasonable 
effort should be made to contact the subject and ascertain the reason(s) for not returning. 
If a subject does not complete the study for any reason (including Investigator discretion), the 
reason and circumstances for the subject’s early termination must be fully documented.  If 
possible, the assessments specified for the Visit 4 should be performed.  Withdrawn subjects 
may not be re-enrolled in the study and will not be replaced. 
In the event subjects are unable to swallow the sarecycline tablets after enrollment, they will 
be discontinued from the study and the reason for study discontinuation will be recorded as 
the inability to swallow tablets. 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 32 of 66 
9.6 Study Assessments 
Treatment efficacy will be evaluated based on the co-primary endpoints of IGA scores and 
absolute change in inflammatory lesion counts recorded at baseline and at Week 12.  Safety 
will be evaluated in terms of adverse events, clinical laboratory evaluations, vital sign 
measurements, physical examinations and ECGs made during the treatment period. 
9.6.1 Efficacy Assessments 
9.6.1.1 
Facial Investigator’s Global Assessment  
The IGA scale for inflammatory lesions of acne vulgaris will be used by the Investigator to 
assess the severity of a subject’s facial acne (Table 9-4).  The IGA should be representative 
of the investigator’s overall general assessment of the subject’s inflammatory lesions and 
take into account the quality, as well as the quantity, of lesions.  The IGA must be performed 
prior to the lesion counts (Section 9.6.1.3) and will be performed at baseline and at each 
treatment period visit. 
The same evaluator should perform all evaluations for a subject and when this is not possible, 
another Sponsor-approved evaluator may perform the evaluations. 
Table 9-4: Investigator’s Global Assessment of Inflammatory Acne 
Score 
Grade 
Description 
0 
Clear 
No evidence of papules or pustules  
1 
Almost Clear Rare: inflammatory papules (papules must be resolving and may be 
hyperpigmented, though not pink-red) 
2 
Mild 
Few: inflammatory lesions (papules/pustules only; no nodulocytic 
lesions) 
3 
Moderate Multiple: inflammatory lesions present; many papules/pustules; there 
may or may not be a few nodulocytic lesions 
4* 
Severe 
Inflammatory lesions are more apparent, many papules/pustules; there 
may or may not be a few nodulocytic lesions 
*Acne that worsens beyond Grade 4 must be recorded as an adverse event on the case report form (CRF). 
 
9.6.1.2 
Non-facial Investigator’s Global Assessment 
The following body areas will be evaluated for acne using the IGA (Table 9-4) 
• Chest 
• Back 
• Neck 
 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 33 of 66 
9.6.1.3 
Facial Lesion Counts 
The facial area lesion counts will be made at the forehead, left and right cheeks, nose and 
chin at baseline and at each treatment period visit.  Facial inflammatory lesions (pustules, 
papules, and nodular lesions) and noninflammatory lesions (open and closed comedones) will 
be counted and recorded separately.  At baseline, the total of both inflammatory and non-
inflammatory lesions will also be calculated. 
Lesion counts will be based on the following definitions: 
Inflammatory lesions 
- Papule:  A solid, elevated lesion less than 0.5 cm in diameter (by inspection) with 
surrounding erythematous halo 
- Pustule:  An elevated lesion containing pus less than 0.5 cm in diameter (by 
inspection) with surrounding erythematous halo 
- Nodule:  Palpable solid erythematous lesion greater than 0.5 cm in diameter (by 
inspection); has depth, not necessarily elevated 
 
Noninflammatory lesions  
- Open comedones (blackhead):  Non-infected plugged hair follicle with dilated/open 
orifice; black in color 
- Closed comedones (whitehead):  Non-infected plugged hair follicle: small 
(microscopic) opening at skin surface  
 
9.6.2 Safety Assessments 
Safety evaluations will include adverse events, clinical laboratory tests, physical 
examinations, vital signs, ECGs, and urine pregnancy tests. 
9.6.2.1 
Adverse Events 
Adverse events will be assessed from the time of signing the consent/assent form until exit 
from the study.  At every study visit, subjects will be asked a standard question to elicit any 
medically related changes in their well-being.  They will also be asked if they have been 
hospitalized, had any accidents, used any new medications, or changed any current 
medication regimens (both prescription and over-the-counter medications). 
Definition of Terms 
Adverse Event:  Any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  In addition to novel events, an adverse 
event may be an exacerbation of a pre-existing medical condition that was present before the 
subject was assigned to a treatment group.  Each adverse event is described using the 
following classifications: severity, relatedness, and seriousness. 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 34 of 66 
Severity:  An adverse event may present in different severities, as categorized below. 
Mild:  Noticeable to the subject, does not interfere with the subject’s daily activities, and 
usually does not require additional therapy or dose adjustment.  
Moderate:  May interfere with the subject’s daily activities and may require additional 
therapy. 
Severe:  May severely limit the subject’s daily activities and typically requires therapy or 
intervention.  
Relatedness: The determination of whether an adverse event is related to treatment is based 
on information regarding the degree to which the study drug has caused or contributed to the 
event and will be categorized according to the following criteria: 
Not Related: There is no medical evidence to suggest that the AE may be related to study 
drug usage. 
Possibly Related: There is medical evidence to suggest that the AE may be related to study 
drug usage.  However, other medical explanations cannot be excluded as a possible cause. 
Related: There is strong medical evidence to suggest that the AE is related to study drug 
usage. 
Serious: An adverse event is considered “serious” if, in the view of either the investigator or 
Sponsor, it results in any of the following outcomes:  
• Death: the adverse event causes or contributes to the death.  Death is usually considered 
to be the outcome of an event; the event that leads to death is defined as the serious 
adverse event (SAE). 
• A life-threatening adverse event: if, in the view of the investigator or Sponsor, its 
occurrence places the subject at immediate risk of death. It does not include an adverse 
event that, had it occurred in a more severe form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization: the adverse event 
requires at least a 24-hour inpatient hospitalization or prolongs a hospitalization beyond 
the expected length of stay. Hospital admissions for surgery planned before study entry, 
for social reasons or for normal disease management procedures are not to be considered 
an SAE according to this criterion.  Where the protocol or the standard management of 
the disease under study requires planned hospitalizations for disease or treatment 
management, this should not be considered a serious criterion leading to expedited 
reporting. 
• Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• Congenital anomaly/birth defect: an adverse outcome in a child or fetus of a patient 
exposed to the study drug before conception or during pregnancy. 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 35 of 66 
• Important medical event: such an event may not result in death, be life-threatening, or 
require hospitalization but may be considered serious when, based upon appropriate 
medical judgment; it may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
For the purpose of this study, all events that meet the regulatory definition of an SAE that 
occur during the treatment period will be reported to the Sponsor as SAEs.  Any SAE 
requires expedited reporting to Sponsor regardless of its relationship to the study drug.  Non-
serious adverse events are all other adverse events not deemed serious. 
Investigator Obligations 
Assessing and Following:  The Investigator is responsible for assessing all adverse events 
that occur at any time during the study.  The Investigator must make a determination of 
relatedness, seriousness, and severity on the Adverse Events page of the case report form for 
each adverse event.  All adverse events must be followed to adequate resolution or 
stabilization.  If the adverse event has not resolved or stabilized by the time the subject 
completes the final study visit, the Investigator will follow the status of the subject’s adverse 
event for at least 30 days beyond the subject’s final study visit, unless directed otherwise by 
the Sponsor.  If Investigator becomes aware of any SAEs that occurred within 30 days after 
the subject completed the study, the SAE must be reported to the Sponsor. 
Documenting:  All adverse events during the study will be documented in the subject’s 
medical record.  This information will then be transcribed on the adverse events page of the 
case report form by designated study personnel.  Required information includes a description 
of the event, date of onset, date of resolution, if death occurred, the action taken to manage 
the adverse event, as well as relatedness, seriousness, and severity. 
Adverse event information must be recorded regardless of its relatedness to the use of the 
study drug.  Adverse events resulting from concurrent illnesses, reactions to concurrent 
medications, or progression of disease states must also be reported. 
Reporting:  1) The investigator is responsible for reporting adverse events to the IRB 
according to agreements and instructions from that board or committee that oversees this 
research, as well as according to applicable regulations.  2) Additionally, all adverse events 
will be reported to the Sponsor on the case report form, and all serious adverse events, 
whether expected or unexpected, related or unrelated, must be reported to the Sponsor, by 
telephone  or facsimile using the “Serious Adverse Event Report” form provided by the 
Sponsor, within 24 hours after the Investigator first learns of the event. 
Warner Chilcott Clinical Pharmacovigilance: 
Phone: 
 or 
 
Fax: 
 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 36 of 66 
Email:
 
 
The Investigator is responsible for reporting any new or relevant follow-up information on 
the adverse event as the information becomes known to the Investigator.  The Investigator 
should cooperate and furnish additional information, including copies of pertinent records if 
necessary, to assist Sponsor personnel in their evaluation of the event. 
Medical Emergencies and Emergency Protocol Deviations 
An investigator shall notify the Medical Monitor and the reviewing IRB of any deviation 
from the investigational plan to protect the life or physical well-being of a subject in an 
emergency.  Such notice shall be given as soon as possible after the emergency occurred.  
Except in such an emergency, prior approval by the Medical Monitor is required for any 
changes in or deviations from the protocol. 
Sponsor Reporting Obligations 
The sponsor will forward all reportable adverse events to the appropriate regulatory 
authorities and participating investigators according to 21 CFR 312, and any other applicable 
regulations. 
9.6.2.2 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations (chemistries, hematology, lipid profile, thyroid hormones and 
urinalysis) outlined in Appendix 2 will be performed on all subjects prior to enrollment to 
verify eligibility.  Clinical laboratory evaluations will be repeated at Visit 1 and at Visit 4/ET 
to identify changes that may have occurred as a result of participation in the study.  If a 
clinically significantly abnormal laboratory result is a reason for a subject being withdrawn 
from the study or requiring treatment for the abnormality, this abnormal result must also be 
reported as an adverse event. 
Urine pregnancy test will be performed on females of childbearing potential only at each 
visit. 
9.6.2.3 
Physical Examinations 
Physical examinations will be performed at screening (SV1 and SV2, as necessary) and at 
Visit 4/ET and Visit 5 (for subjects participating in PK Schedule 3).  Physical 
examinations will include an evaluation of the following: body as a whole, skin, head, ears, 
eyes, nose and throat, cardiovascular, respiratory, musculoskeletal, neurologic, 
lymphatic/thyroid, abdomen, body weight, and height (screening only).  
Clinically significant findings identified during screening will be captured in Medical 
History.  Clinically significant changes from baseline during the study will be captured as an 
adverse event. 




Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 38 of 66 
9.6.3.1 
Photography 
Photographs of the face documenting acne distribution will be made at baseline and at each 
treatment period visit. 
 
9.6.3.2 
Skindex-16 Questionnaire 
The Skindex-16 is a single-page 16-item quality of life questionnaire that asks patients about 
bother from their skin condition; responses are reported as three scales: Symptoms, 
Emotions, and Functioning.  The following questions (items) correspond to each scale: 
Scale 
Items 
Symptoms 
1-2-3-4 
Emotion 
5-6-7-8-9-10-11 
Functioning 
12-13-14-15-16 
 
Item scores are transformed to a 0 – 100 scale.  A scale score is determined by the average of 
scores in each scale.  A total score is the average of all 16 items. 
The questionnaire will be administered at baseline and at Visit 4/ET. 
A copy of the questionnaire is contained in Appendix 4. 
9.6.3.3 
Concomitant Medication Use 
Subjects will be queried at each clinic visit concerning the use of medications (see 
Section 9.4.6). 
9.6.3.4 
Pharmacokinetic Sampling 
PK SCHEDULE 1 
Subjects who elected to participate in PK Schedule 1 will have blood samples collected at the 
timepoints specified in Table 9-5.  
Visit 1/Week 3 
Make all efforts to schedule the visit to accommodate the subjects’ routine schedule of 
dosing.  For example, if the subject regularly takes the drug at night, an afternoon visit is 
preferable for PK sampling.  In case it is not possible to schedule an afternoon appointment, a 
minimum of 12 hours should elapse between the dose taken at the visit and the previous 
dose. 
Subjects will be instructed to: 
• NOT take their Visit 1/Week 3 dose at home and to wait to take their 
Visit 1/Week 3 dose at the site 
• Take their investigational product (IP) with them to the clinic at Visit 
1/Week 3 and take the dose while observed by clinic staff 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 39 of 66 
• Resume their dosing at the regularly scheduled time the next day 
 
Visit 4/Week 12 
Subjects will be instructed to take their doses at home approximately 3 hours prior to the 
visit.  At least 12 hours should elapse between the dose taken 3 hours prior to the visit and 
the dose from the day prior to that. 
Table 9-5 Sampling Times for PK Schedule 1 
Visit 
Sample Times 
Visit 1 (Week 3 ± 3 days) 
(1) Predose:  Within 0.5 hours before dose administration 
(2) Postdose:  Between 0.5 hours and 1 hour after dose 
administration 
(3) Postdose:  Between 1.5 hours and 3 hours after dose 
administration 
Visit 4 (Week 12 ± 3 days) 
(1) Postdose:  Between 4 hours and 5 hours after dose 
administration 
(2) Postdose:  Between 6 hours and 8 hours after dose 
administration 
 
PK SCHEDULE 2 
Subjects who are in PK Schedule 2 will be instructed to take their dose at their usual/regular 
time and proceed with Visit 1/Week 3 and Visit 4/Week 12 (Table 9-6).  During the visit, a 
blood sample for PK analyses can be taken at any time. 
Table 9-6 Sampling Times for PK Schedule 2 
Visit 
Sample Time 
Visit 1 (Week 3 ± 3 days) 
At any time during the visit 
Visit 4 (Week 12 ± 3 days) At any time during the visit 
 
PK SCHEDULE 3 
PK Schedule 3 will only be an option for 9 to 11 year-old subjects who elect PK 
sampling.  Subjects who elected to participate in PK Schedule 3 will have blood samples 
collected at the timepoints specified in (Table 9-7). 
Visit 1/Week 3 
Subjects who are in PK Schedule 3 will be instructed to take their dose at their 
usual/regular time prior to Visit 1/Week 3. 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 40 of 66 
Visit 4/Week 12 
Subjects who are in PK Schedule 3 will be instructed not to take their dose on the day of 
their Visit 4/Week 12.  Instead, subjects will be dosed in clinic with active study 
treatment after all visit assessments are done.  Make all efforts to schedule the visit to 
accommodate the subjects’ routine schedule of dosing.  For example, if the subject 
regularly takes the drug at night, an afternoon visit is preferable for PK sampling.  In 
case it is not possible to schedule an afternoon appointment, a minimum of 12 hours 
should elapse between the dose taken at the visit and the previous dose. 
Subjects will have a follow-up visit (Visit 5/Week 13) 1 week after Visit 4 as described in 
Section 9.5.2.6. 
Table 9-7 Sampling Times for PK Schedule 3 
Visit 
Sample Time 
Visit 1 (Week 3 ± 3 days) 
At any time during the visit 
Visit 4 (Week 12 ± 3 days) (1) Postdose:  Between 0.5 hours and 1 hour after dose 
administration 
(2) Postdose:  Between 1.5 hours and 2 hours after dose 
administration 
(3) Postdose:  Between 3 hours and 4 hours after dose 
administration 
 
Blood samples will be collected, processed, stored, and shipped as described in Appendix 3.  
Diary for Recording Dose Administrations for PK Analysis 
For subjects participating in PK Schedule 1, PK Schedule 2, and PK Schedule 3, a diary will 
be dispensed at Screening Visit 2/Baseline and at Visit 3/Week 9, the visits prior to PK 
sampling.  The subjects participating in PK sampling will be instructed to record the dose 
administration times for the 2 doses taken prior to Visit 1/Week 3 and Visit 4/Week 12 in the 
diary and on the day of Visit 4/Week 12. 
The subjects participating in PK sampling will be instructed to record the dose administration 
times for the 2 doses taken prior to Visit 1/Week 3 in the diary. 
During Visit 1/Week 3 and Visit 4/Week 12, the responsible personnel at the site will review 
and collect the pages from the subjects’ diary.  The dose date and time will be recorded in the 
eCRFs. 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 41 of 66 
10 QUALITY CONTROL AND ASSURANCE 
The Sponsor will implement and maintain quality control procedures to ensure that this study 
is conducted and data are generated, documented, and reported in compliance with the 
protocol, GCP, and applicable regulatory requirements. 
The Sponsor or designee will routinely conduct monitoring and/or auditing visits to the study 
centers to verify the adherence to the study protocol, the protection of the rights and well-
being of the subjects, and the accuracy and completeness of reported study data recorded on 
the source documentation. 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 42 of 66 
11 PLANNED STATISTICAL METHODS 
Detailed plans for the statistical methods will be provided in a Statistical Analysis Plan which 
will be finalized prior to database lock. 
11.1  Determination of Sample Size 
The sample size was selected to provide an adequate number of subjects to compare the 
efficacy of sarecycline treatment to placebo and to provide an adequate number of subjects 
needed for a safety database. 
Sample size estimates were calculated for each of the co-primary efficacy endpoints, absolute 
change from baseline (CFB) in facial inflammatory lesion counts and facial IGA success 
(based on at least 2-point decrease from baseline in IGA score), and the first secondary 
efficacy endpoint, percent CFB in facial inflammatory lesion counts at Week 12 using a last 
observation carried forward (LOCF) method of imputation.  The results from a recent study 
(Study PR-10411) of sarecycline compared to placebo treatment were used to estimate the 
sample size needed to show a significant difference between the treatments at α=0.05 and 
90% power using two-sided tests and a 1:1 randomization.  It should be noted that one outlier 
in the data for Study PR-10411 was removed from the estimate for absolute CFB in 
inflammatory lesion counts in order to provide more accurate estimates for the sample size 
determination.  Results of the calculations and the estimates used in the calculations are 
provided below: 
Continuous 
Endpoints1 
Sarecycline  
CFB or 
%CFB 
Placebo  
CFB or 
%CFB 
Common  
SD 
Sample per 
Treatment 
Total 
Sample Size 
Absolute CFB in 
inflammatory lesion 
counts (co-primary) 
16 
13 
12 
338 
676 
Percent CFB in 
inflammatory lesion 
counts (secondary) 
39% 
52% 
41% 
210 
420 
1 Sample size was based on a two sample t-test of no difference between the treatments. 
 
Dichotomous 
Endpoints1 
Sarecycline 
Rate 
Placebo 
Rate 
Difference 
in Rates 
Sample per 
Treatment 
Total 
Sample Size 
IGA Success 
(2-point decrease in 
IGA score from 
baseline and a score of 
clear/almost clear; co-
primary) 
 
23% 
 
10% 
 
13% 
 
170 
 
340 
1 Sample size was based on a χ2 test of no difference between the proportions. 
 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 43 of 66 
While the IGA scale proposed for the Phase 3 studies is slightly different than the IGA scale 
in the Phase 2, the number of subjects to be enrolled (500 per treatment; 1000 total) should 
provide more than sufficient power for the efficacy evaluations.  Additionally, a larger 
sample is needed in order to provide sufficient numbers of subjects on sarecycline treatment 
for a safety database. 
11.2  Analysis Populations and Datasets 
Statistical analysis and data tabulation will be performed using the following analysis 
populations unless specified otherwise: 
• Safety population – includes all randomized subjects who receive at least one dose of 
study drug.  All summaries of this population will be based on the study drug each 
subject received. 
• Intent-to-treat (ITT) population (primary efficacy population) – includes all randomized 
subjects.  All summaries of this population will be based on the study drug each subject 
was randomized to receive. 
• Per-protocol (PP) population (supportive secondary efficacy population) – includes all 
randomized subjects who complete the treatment period, do not have any major protocol 
deviations, and have overall study drug compliance of at least 80%.  All summaries of 
this population will be based on the study drug each subject received.  Major protocol 
deviations that could potentially impact the efficacy data may include the following: 
• Entering the study without satisfying the entry criteria; 
• Receiving an excluded concomitant treatment. 
• Receiving wrong study  treatment 
 
Three “visit types” will be defined for the purposes of analysis and summaries: 
• Observed Cases (OC) – includes assessments collected at each scheduled visit.  All 
applicable efficacy and safety variables will be summarized for OC visits.   
• Multiple Imputation Data – for the primary and secondary efficacy endpoints only, 
missing data will be imputed using multiple imputation procedures further 
described in Section 11.4.3. 
• LOCF – defined as the last post-baseline data recorded for each efficacy variable.  This 
visit will be denoted as Week 12 (LOCF) and will only be used to summarize efficacy 
data.  The LOCF visit provides missing value imputation for subjects who do not provide 
data for the Week 12 visit.   
 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 44 of 66 
11.3  General Statistical Procedures 
11.3.1 Overview 
For superiority testing, all inference tests will be conducted at α=0.05 (two-sided) on the null 
hypothesis of no difference between treatments.  All analyses will be conducted with SAS 
using procedures appropriate for the particular analysis. 
11.3.2 Summary Statistics 
The descriptive statistics for all the continuous variables will include the mean, median, 
25th percentile, 75th percentile, standard deviation (SD), standard error of mean (SEM), 
minimum, maximum, and number of subjects.  Descriptive summaries will be provided for 
raw, CFB, and %CFB values for continuous efficacy endpoints.  Frequency distributions for 
all the categorical variables will be presented as counts and percentages.  Summaries will be 
provided by visit and treatment, as appropriate. 
11.3.3 Site Pooling Algorithm 
While every effort will be made to randomize a sufficient number of subjects at each study 
site, in the event that this is not possible, study sites may be pooled for statistical inference 
testing.  Study sites (centers) will be pooled by geographical location based on region 
definitions from the US Census Bureau (Northeast, Midwest, South, and West) (US 
Census Bureau, 2013) for analysis purposes so that in each pooled site the number of 
subjects is reasonably large and consistent in size between pooled sites.  Sites within a 
geographic location will be pooled starting with the sites that have the lowest number of 
randomized subjects pooled together such that the pooled site has a minimum of 
12 randomized subjects after pooling.  
The sites to be pooled for each geographic location will be documented in a signed memo 
prior to unblinding of the treatment code.  A list of sites and the corresponding pooled sites 
will be presented. 
11.4 Efficacy Parameters 
11.4.1 Co-primary Efficacy Endpoints 
There will be two co-primary efficacy endpoints for this study.  The first co-primary efficacy 
endpoint will be the absolute CFB in inflammatory lesion counts at Week 12.  This variable 
will be considered a continuous variable. 
The second co-primary efficacy endpoint will be IGA success at Week 12.  IGA success will 
be a dichotomous variable defined as at least 2-point decrease from baseline on the IGA 
assessment as well as a score of clear (0) or almost clear (1) on the IGA assessment. 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 45 of 66 
11.4.2 Secondary Efficacy Endpoints 
There will be four secondary efficacy endpoints for this study, percent CFB in inflammatory 
lesion counts at Week 12, and absolute and percent CFB in inflammatory lesion counts 
at Weeks 9, 6, and 3.  These variables will be considered continuous variables. 
11.4.3 Missing Data Handling for Co-Primary and Secondary Endpoints 
For the co-primary and secondary efficacy analyses, the primary missing data 
imputation method is multiple imputation (MI), as outlined in the following 
procedures:  
• The SAS PROC MI procedure with a fully conditional specifications (FCS) method 
will be used to create 20 imputations.  The FCS is proposed as it allows for 
accommodation of categorical variables and it has the versatility to handle arbitrary 
missing data patterns.  Based on these 20 imputations, the relative efficiency will be 
0.995 for 10% of missing data and 0.990 for 20% of missing data (Rubin, 1976, 
1987, 1996).   
• For inflammatory lesion counts, if any of the subtypes (papules, pustules, and 
nodules/cysts) is missing, the inflammatory lesion count is missing.  The variables 
included in the imputations are age, sex, and the raw measurements of the 
corresponding endpoint counts at baseline, Week 3, Week 6, Week 9, and Week 12  
• For IGA, the raw scores will be used for the imputation.  The variables included in 
the imputations are age, sex, and the measurements of the endpoint at baseline, 
Week 3, Week 6, Week 9, and Week 12  
• All imputations will be performed by treatment group based on the randomized 
study medication.  The number of imputations is set at 20 with number of 50 burn-
in iterations.  The seed used for imputation for all endpoints is  
.  For IGA raw 
scores and lesion counts, regression with predictive mean matching method will be 
used.  The imputed values will be rounded to the nearest integer.  
• An analysis of covariance (ANCOVA) model for continuous endpoints 
(inflammatory lesion counts) will be performed for each of the imputed datasets.  
• A Cochran-Mantel-Haenszel (CMH) analysis for the binary endpoint (IGA success) 
will be performed for each of the imputed datasets. 
• The SAS PROC MIANALYZE procedure will be used to produce final parameter 
estimates, including the point estimates and standard errors, adjusted treatment 
differences, confidence intervals and p-values for the primary and secondary 
variables. 
• For the CMH test, the Wilson-Hilferty transformation (Wilson & Hilferty, 1931, 
O'Kelly & Ratitch, 2014) will be used.  Under the null hypothesis, the transformed 
statistic is approximately normally distributed: 
 
  
 




Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 47 of 66 
p-value used for each of these tests will be the median p-value after the analysis has 
been performed on each dataset.  If the data do not meet the normality or homogeneity 
assumptions of the parametric analyses, then a rank transformation will be applied to the raw 
data and the primary analysis will proceed using an ANCOVA model on the ranks with 
the baseline value as a covariate and effects of treatment and (pooled) site.  Tied values 
will receive the mean value (midranks) of the corresponding ranks.   
As site is included in the primary ANCOVA model, a treatment-by-site interaction will be 
investigated as an exploratory analysis to assess the homogeneity of treatment effects across 
site.  This effect will be investigated analytically prior to any pooling of sites by adding the 
interaction term to the ANCOVA model and testing for significance.  Because interactions 
are not powered in this study, testing for significance will be at the 0.10 level.  However, any 
significant interaction findings at the 0.10 level will also take into account the potential for 
spurious results.  Further exploration may be done graphically with interaction plots to 
determine the nature of the interaction and to identify any “outlier” sites with attention 
focused on qualitative differences in treatment effects.  If large differences in treatment 
effects are seen in any “extreme” sites, then sensitivity analyses will be performed that 
exclude sites with the highest extreme treatment effect values from the analysis.  Any such 
sites may be further investigated for explanation involving study conduct, subject 
demographics, current medications, etc. 
11.5.2 IGA Success 
The co-primary efficacy endpoint, percentage of subjects of IGA success at Week 12, will be 
analyzed for the ITT population using the Cochran-Mantel-Haenszel (CMH) test with 
adjustment for (pooled) site.  Missing data will be imputed using the MI approach 
described in Section 11.4.3.  The rate difference and the 95% CIs for the rate difference 
and the relative rate and the 95% CIs for the relative rate will be presented as well.  The CIs 
for the treatment rate difference will be based on two-sided 95% Wald type CIs with 
CMH weights (Kim & Won, 2013, Yan & Su, 2012).  
The homogeneity of treatment effects across (pooled) site will be investigated as an 
exploratory analysis using the Breslow-Day test.  If the Breslow-Day test indicates large 
heterogeneity in the odds ratios across (pooled) site, then further exploration may be done 
graphically or with further investigation for explanation involving study conduct, subject 
demographics, current medications, etc. 
11.5.3 Secondary Endpoint Analyses 
A hierarchical testing approach will be used for the secondary efficacy endpoints, percent 
CFB in inflammatory lesion counts at Week 12, and absolute and percent CFB in 
inflammatory lesion counts at Weeks 9, 6, and 3 (using ANCOVA), such that statistical 
testing will only be performed if both co-primary efficacy endpoints are statistically superior 
to placebo at α=0.05.  In addition, statistical testing of the secondary endpoints will be 
conducted in the following order, with all tests proceeding at the 0.05 level if and only if 
the previous tests were all significant at the 0.05 level: 






Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 50 of 66 
primary efficacy analysis, further analyses will be performed to investigate the causes of 
the difference.  However, the results from the primary efficacy analysis will be 
considered the primary efficacy results. 
Sensitivity Analyses for Categorical Variables 
• Efficacy data will be summarized and analyzed using the CMH test with adjustment 
for (pooled) site using the PP population with OC data.  
• For IGA success, subjects who discontinue from the study early will be coded as failures 
for the Week 12 analysis.  A sensitivity analysis of IGA success using this data handling 
convention will be performed using the CMH test with adjustment for (pooled) site on 
the ITT population.  
• For IGA success, subjects who discontinue from the study early will be coded as failures 
for subjects on sarecycline and successes for subjects on placebo for the Week 12 
analysis.  A sensitivity analysis of IGA success using this data handling convention will 
be performed using the CMH test with adjustment for (pooled) site on the ITT 
population. 
11.5.7 Subgroup Analyses 
Primary and secondary efficacy variable summaries will be repeated for the following 
subgroups if sample size allows by study visit using OC data: 
• Gender: male and female 
• Age groups: 9 to 17 years and ≥ 18 years 
• Race: white, African-American/Black, other 
• Body mass index: < 25 kg/m2 and ≥ 25 kg/m
2 
• Baseline acne severity (IGA score):  moderate and severe 
• Oral contraceptive use in females:  female subjects who use oral contraceptives versus 
female subjects who do not 
 
11.6 Safety Analyses 
11.6.1 Adverse Events 
Treatment-emergent adverse events will be classified into a standardized terminology using 
the Medical Dictionary for Regulatory Activities (MedDRA) system organ classifications 
and preferred terms.  Adverse events with onset on or after the first dose date of test or 
reference article and prior to or on study completion will be considered as “treatment-
emergent.” 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 51 of 66 
Although a preferred term or system organ class may be reported more than once for a 
subject, each subject will only be counted once in the incidence count for that preferred term 
or system organ class for each particular summary.  Summaries of safety data will be 
generated for the following summary types: 
• Overall summaries 
• Summaries by MedDRA system organ class, MedDRA preferred term, test or reference 
article relationship, and severity. 
• Summaries by MedDRA preferred term and test or reference article relationship in 
descending order. 
• Summaries of serious adverse events by MedDRA preferred term and test or reference 
article relationship in descending order. 
• Summaries of adverse events by MedDRA system organ class, MedDRA preferred term, 
and test or reference article relationship for the primary events leading to premature 
discontinuation from the study. 
 
These summaries will present the number and percentage of subjects reporting an adverse 
event by treatment and overall as well as the number of events reported.  The denominators 
for calculating the percentages by treatment will be based on the number of subjects exposed 
in the Safety population to each treatment and overall.  The treatment will be based on the 
double--blind treatment received. For subjects who are in PK Schedule 3, the 
treatment--emergent adverse event summary described above will comprise data prior 
to the active dose taken at the Week 12 visit. Further adverse events experienced after 
this Week 12 dose will be listed separately for these subjects. 
11.6.2 Extent of Exposure 
The number of doses taken and the duration of exposure to study drug will be summarized by 
treatment using descriptive statistics for the Safety population.  Duration of exposure will be 
calculated as the difference between the last double-blind dose date and the first dose date 
plus one day. 
Additionally, these summaries will present the number and percentage of subjects for each 
interval (1 week multiples) of total exposure in each treatment.  The denominators for 
calculating the percentages will be based on the number of subjects with exposure for each 
treatment. 
11.6.3 Clinical Laboratory Evaluations 
Continuous clinical laboratory analytes will be summarized by double--blind treatment, 
analyte, and visit using descriptive statistics.  Categorical laboratory analytes, classified as 
normal or abnormal, will be summarized by treatment analyte, and visit using the number 
and percentage of subjects in each category.  The denominators for calculating the 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 52 of 66 
percentages will be based on the number of subjects in each treatment with non-missing 
assessments at a particular visit for the Safety population. 
Shifts to values outside of the normal range will be presented by treatment and analyte and 
will be summarized by the number and percentage of subjects with evaluable shifts.  An 
evaluable shift is one where both the Screening Visit value and the on-treatment value or 
early termination value are recorded.  The denominators for calculating the percentages will 
be based on the number of subjects in each treatment group who have an evaluable shift for a 
particular analyte. 
11.6.4 Electrocardiograms 
Electrocardiographic evaluations and shifts will be presented by visit and double-blind 
treatment.  Evaluations will be summarized by the number and percentage of subjects for 
each interpretation and shift category.  The denominators for calculating the percentages will 
be based on the number of subjects with assessments in each treatment for the Safety 
population. 
11.6.5 Vital Signs 
Vital sign measurements will be summarized for the Safety population by double-blind 
treatment and visit using descriptive statistics.  Additionally, descriptive statistics will be 
presented by treatment and day for the CFB for vital signs.  The baseline values will be 
defined as the last value collected prior to the first dose of the study drug. 
11.7 Other Assessments or Analyses 
Other study assessments listed below will be summarized or provided in data listings as 
specified in the statistical analysis plan. 
11.7.1 Demographics and Baseline Characteristics 
Subject demographic and physical characteristic data will be summarized by treatment and 
overall for each analysis population using descriptive statistics (mean, median, 25th 
percentile, 75th percentile, SD, SEM, minimum, maximum, and number of subjects) for 
continuous variables and frequency distributions (counts and percentage of subjects) for 
categorical variables. 
Medical history items will be coded using standardized terminology from the MedDRA 
system organ classifications and preferred terms.  Medical history will be summarized using 
counts and percentages of subjects in each system organ class and preferred term by 
treatment and overall for the Safety population. 
11.7.2 Medications 
Medication usage will be coded using the World Health Organization (WHO) Drug 
Dictionary.  Medications will be presented by WHO Drug Anatomical/Therapeutic/Chemical 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 53 of 66 
category and WHO Drug preferred name.  Summaries will be presented for prior (prior to the 
first treatment period) medication use and concomitant (after first treatment has been given) 
medication use.  Medications with an end date occurring before the first study drug dose date 
in the treatment period will be identified as prior medications.  Medications with a start date 
occurring on or after the first study drug dose date in the treatment period or medications 
with a start date prior to the first dose  that are on-going or with end dates that are on or 
after the first treatment start date will be identified as concomitant medications.  
All summaries will present the number and percentage of subjects for each medication by 
treatment and overall.  The denominators for calculating the percentages will be based on the 
number of subjects in the Safety population for each treatment and overall. 
11.7.3 Compliance 
Compliance will be assessed by comparing the expected number of doses taken, based on the 
total number of treatment days within each visit and within the entire treatment period of the 
study, with the number of returned doses to the clinic at the end of each treatment visit.  
Treatment compliance will be calculated for each subject/visit and over all visits for the 
Safety population.  Compliance values that are less than 0% will be set to 0%.  Summaries 
will be presented using descriptive statistics for the Safety population. 






−
=
used
be
to
Expected
#
urned
Ret
#
Dispensed
#
Compliance
 
11.7.4 IGA for Non-facial Sites 
IGA scores for neck, chest, and back sites will be summarized by visit and treatment using 
counts and percentages for each site. 
11.7.5 Noninflammatory Lesion Counts 
There will be no statistical testing for absolute CFB in noninflammatory lesion counts at 
Week 12; however, descriptive summaries will be provided including 95% CIs for each 
treatment and for the treatment difference using an ANCOVA model with the baseline 
value as a covariate and additional terms included to represent effects of treatment and 
(pooled) site with OC visit data and the ITT population. 
11.7.6 Skindex Questionnaire 
Scoring, scaling, and the handling of missing data will be handled in accordance with the 
recommendations accompanying the Skindex-16 and will be described in more detail in the 
Statistical Analysis Plan.  Descriptive summaries will be provided for the ITT population for 
scale scores and total score by treatment and visit.  Additionally, CFB for scale and total 
scores will be provided for each treatment.  Change from baseline in scale and total scores 
will be analyzed using an ANCOVA model with the baseline value as a covariate and 
additional terms included to represent effects of treatment and (pooled) site.  Analyses will 
be provided for the ITT population.  The adjusted means with associated 95% CIs from the 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 54 of 66 
ANCOVA model will also be presented for each treatment and for the difference between the 
treatments. 
11.7.7 Photographs 
No statistical summaries based on photographic images are planned for the clinical study 
report. 
11.7.8 Pharmacokinetics 
Individual sarecycline and R-sarecycline plasma concentrations will be listed. 
Sarecycline plasma concentration data obtained in the study will be utilized to estimate 
population PK parameters using nonlinear mixed-effects modeling (NONMEM).  The effects 
of covariates on PK parameters will be evaluated as part of the analysis.  The analysis will be 
described in a separate analysis plan. 
 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 55 of 66 
12 DOCUMENTATION REQUIREMENTS AND RECORDKEEPING 
12.1 Source Documentation 
The CRFs represent a record of the subject’s experience in the study, therefore, the CRF data 
must be supported by original (or source) medical records, as appropriate.  CRF data 
recorded directly into the CRF is also considered source data when there are no other written 
or electronic records preceding the CRF entry. 
Prior to enrolling a subject in the study, the Investigator must document his/her review of 
subject eligibility criteria in the source records for the subject, including the Investigator’s 
signature and date on any medical and laboratory reports indicating a review of the source 
data occurred.  The Investigator will continue to follow this practice for any subsequent 
medical and laboratory reports generated as a result of the clinical study. 
The Investigator agrees that the Sponsor or its designated agents, the IRB, the FDA or 
foreign regulatory agencies will have reasonable access to study source documentation for 
purposes of audit and monitoring visit review both during and after completion of the study.  
Monitoring visits provide the Sponsor with the opportunity to evaluate the progress of the 
study; to verify the accuracy and completeness of CRFs; to ensure that all protocol 
requirements, applicable regulations and Investigator’s obligations are being fulfilled; and to 
resolve any inconsistencies in the study records.  All participating subjects will be required to 
signify their approval to permit inspection of their medical records by representatives of 
Sponsor, the IRB, the FDA and/or foreign regulatory agencies, as needed. 
12.2  Data Capture and Discrepancy Management 
Site personnel will be responsible for the completion and correction of CRFs according to the 
protocol and other instructions provided by the Sponsor or their designee.  The Investigator is 
responsible for ensuring the completeness and accuracy of the data as evidenced by the 
Investigator’s signature and date once the subject has completed the study and all required 
study data has been entered into the CRF. 
Since site personnel will enter data directly into a validated electronic CRF, programmatic 
data validation procedures will be employed to identify data discrepancies to site personnel at 
the time of entry and/or upon saving the data.  Designated site personnel will resolve any 
discrepancies via the electronic CRF.  Any additional findings upon clinical review by the 
Sponsor or their designee will be entered into the system for review and resolution by site 
personnel.  A full audit trail of data changes following entry will be captured during the study 
in the electronic data management system.  The Investigator will be provided with a copy of 
all CRF data for retention. 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 56 of 66 
13 OTHER INFORMATION 
13.1  Financing and Insurance 
Financing and insurance is addressed in a separate agreement. 
13.2  Publication and Disclosure Policy 
Publication and disclosure policy is addressed in a separate agreement. 
13.3 Termination of the Study 
If the study is terminated prematurely or suspended, the appropriate IRB and regulatory 
authority(ies) will be promptly informed of the termination or suspension and will be 
provided the reason(s) for the termination or suspension.  All obligations and responsibilities 
of the Sponsor and the Investigator under GCP, the US CFR and the Declaration of Helsinki 
will remain in force if the study is terminated prematurely. 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 57 of 66 
14 REFERENCE LIST 
1. Brown SK, Shalita A R; Acne Vulgaris, Follicutitis, and Acne Rosacea.  Lancet 
351:1871-76, 1998. 
2. Guidance for Industry: “Acne Vulgaris: developing Drugs for Treatment”.  September 
2005; FDA Draft Guidance. 
3. A. Bernstein, G. Hoel, H. Thomas. A Randomized, Multicenter, Double-blind, Placebo-
controlled Study to Evaluate the Safety and Efficacy of 3 Different Doses of a Novel 
Tetracycline Compared to Placebo in the Treatment of Facial Acne Vulgaris, Study PR-
10411. Warner Chilcott Research Report RR-02613. 27 February 2014.  
4. US Census Bureau. US Department of Commerce Economics and Statistics 
Administration US Census Bureau.  Census Regions and Divisions of the United 
States. 2013 Apr 17. Available from: http://www2.census.gov/geo/pdfs/maps-
data/maps/reference/us_regdiv.pdf. Accessed 2015 Oct 06. 
5. Kim, Y, Won S;  Adjusted proportion difference and confidence interval in 
stratified randomized trials.  PharmaSUG Proceedings.  2013;SP04. 
6. O'Kelly, M and Ratitch, B; Clinical Trials with Missing Data: A Guide for 
Practitioners. Chichester: John Wiley & Sons, Inc. 2014. 
7. Rubin DB; Inference and Missing Data.  Biometrika 63:581-92, 1976. 
8. Rubin DB; Multiple Imputation for Nonresponse in Surveys. New York: John Wiley 
& Sons, Inc. 1987. 
9. Rubin DB; Multiple Imputation After 18+ Years.  Journal of the American 
Statistical Association, 91:473–89, 1996. 
10. Wilson EB and Hilferty, MM; The distribution of chi-square.  Proceedings of the 
National Academy of Sciences of the United States of America, 17:684–88, 1931. 
11. Yan, X, Su, XG;  Stratified Wilson and Newcombe confidence intervals for multiple 
binomial proportions.  Statistics in Biopharmaceutical Research.  2010;2:3,329-335. 
 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 58 of 66 
15 APPENDICES 
Appendix 1 
Study Schedule of Events 
Appendix 2 
Clinical Laboratory Evaluations 
Appendix 3 
Collection, Processing, Storage and Shipment Instructions for PK Samples 
Appendix 4 
Skindex Questionnaire 
Appendix 5 
Investigator Signature 
Appendix 6 
Sponsor Signatures 
 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 59 of 66 
Appendix 1  
Study Schedule of Events 
 
 
Screening Period 
Treatment Period 
SV1 
SV2  
(Baseline 
Assessment) 
Telephone 
Contact 
Week 1 
 ± 3 d 
Visit 1 
Week 3 
 ± 3 d 
Visit 2 
Week 6  
± 3 d 
Visit 3 
Week 9  
± 3 d 
Visit 4 
Week 12 
/ET 
± 3 d 
Visit 5d 
Week 13 
/ET 
± 3 d 
Informed 
Consent 
X 
 
 
 
 
 
 
 
Assign Subject 
Number using 
the IRT 
X 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion 
X 
X 
 
 
 
 
 
 
Demographic 
Data 
X 
 
 
 
 
 
 
 
Medical/ 
Surgical 
History 
X 
 
 
 
 
 
 
 
Physical 
Examination 
X 
Xa 
 
 
 
 
X 
X 
Height & 
Weight 
X 
Weight  
only 
 
 
 
 
Weight 
only 
Weight 
only 
Vital Signs 
X 
X 
 
X 
X 
X 
X 
X 
Hematology, 
Serum 
Chemistry, 
Urinalysis and 
Lipids 
X 
Xb 
 
X 
 
 
X 
 
TSH, Free T4 
and T3 
X 
 
 
 
 
 
X 
 
Urine 
pregnancy test  
X 
X 
 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
 
X 
 
Facial 
Investigator’s 
Global 
Assessment   
 
X 
 
X 
X 
X 
X 
 
Facial Lesion 
Counts 
 
X 
 
X 
X 
X 
X 
 
Facial 
Photographs 
 
X 
 
X 
X 
X 
X 
 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 60 of 66 
 
Screening Period 
Treatment Period 
SV1 
SV2  
(Baseline 
Assessment) 
Telephone 
Contact 
Week 1 
 ± 3 d 
Visit 1 
Week 3 
 ± 3 d 
Visit 2 
Week 6  
± 3 d 
Visit 3 
Week 9  
± 3 d 
Visit 4 
Week 12 
/ET 
± 3 d 
Visit 5d 
Week 13 
/ET 
± 3 d 
Non-facial 
Investigator’s 
Global 
Assessment 
 
X 
 
X 
X 
X 
X 
 
Skindex 
Questionnaire 
 
X 
 
 
 
 
X 
 
Dispense Diary 
for Subjects 
Participating in 
PK Sampling 
 
X 
 
 
 
X 
 
 
PK Blood 
Sample 
Collection for 
PK 1, PK 2, 
and PK 3 
C 
 
 
 
X 
 
 
X 
 
Review and 
Collect Diaries 
 
 
 
X 
 
 
X 
 
Randomization  
 
X 
 
 
 
 
 
 
Dispense 
Study drug 
 
X 
 
X 
X 
X 
Xd 
 
Study drug 
Accountability
/Compliance 
 
 
X 
X 
X 
X 
X 
 
Concomitant 
Medication 
Use 
X 
X 
 
X 
X 
X 
X 
X 
Adverse 
Events 
X 
X 
X 
X 
X 
X 
X 
X 
ECG= electrocardiogram; ET= End of treatment; Xa: Only for subjects requiring medication/therapy washout;
 
Xb: Re-draw blood and urine samples for clinical laboratory evaluations only if washout duration exceeded 5 
weeks. 
C PK Schedule 1, PK Schedule 2, or PK Schedule 3 should be performed at selected sites based on what 
the subject chose in the ICF, 
dFor subjects participating in PK Schedule 3 only. 
 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 61 of 66 
Appendix 2 
Clinical Laboratory Evaluations 
Hematology 
Hemoglobin 
Mean cell volume 
Hematocrit 
White blood cell & Differential 
Red blood cell count 
Platelet count 
Serum Chemistry 
Albumin 
Total protein 
Alanine aminotransferase  
Serum creatinine 
Aspartate aminotransferase  
Sodium 
Blood urea nitrogen  
Potassium 
Gamma glutamyl transferase  
Calcium 
Glucose 
Chloride 
Lactate dehydrogenase  
Bicarbonate 
Total bilirubin 
Phosphorus 
Creatine phosphokinase 
 
Urinalysis  
Color 
Protein 
Specific gravity 
Glucose 
Potential for hydrogen (pH) 
Blood 
Leukocytes 
Bilirubin 
Ketones 
 
Lipid Profile 
Total cholesterol 
Triglycerides 
Thyroid Function 
Thyroid stimulating hormone 
Free T4 and T3 
Other 
Urine pregnancy test 
 




Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 63 of 66 
Appendix 4  
Skindex Questionnaire 




Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 65 of 66 
Appendix 5  
Investigator Signature 
Study Title: 
A Randomized, Multicenter, Double-blind, Placebo-controlled 
Study to Evaluate the Efficacy and Safety of 1.5 mg/kg per Day of 
Sarecycline Compared to Placebo in the Treatment of Acne Vulgaris 
Study Number: 
SC1401 
Final Date: 
15-Aug-2014 
Amendment 1 
15-Sep-2014 
Amendment 2 
13-Mar-2015 
Amendment 3 
16-Dec-2015 
 
I have read the protocol described above.  I agree to comply with all applicable regulations 
and to conduct the study as described in the protocol. 
 
Signed:  _________________________________ Date:  ___________________ 
 


Sarecycline Tablets 
 
Warner Chilcott, LLC 
Study: SC1401 
Protocol Amendment 3 
16-Dec-2015 
 
CONFIDENTIAL 
Page 66 of 66 
Appendix 6  
Sponsor Signatures 
Study Title: 
A Randomized, Multicenter, Double-blind, Placebo-controlled 
Study to Evaluate the Efficacy and Safety of 1.5 mg/kg per Day of 
Sarecycline Compared to Placebo in the Treatment of Acne 
Vulgaris 
Study Number: 
SC1401 
Final Date: 
15-Aug-2014 
Amendment 1 
15-Sep-2014 
Amendment 2 
13-Mar-2015 
Amendment 3 
16-Dec-2015 
This clinical study protocol was subject to critical review and has been approved by the 
Sponsor.  The following personnel contributed to writing and/or approving this protocol: 
  
  
  
Clinical Development  
 
 Signature 
 
Month/Day/Year 
  
  
  
Statistical Science 
 
 Signature 
 
Month/Day/Year 
 
  
  
Medical Writing 
 
 Signature 
 
Month/Day/Year 
 

SAP_001.pdf: