Clinical trial NCT03073486
Conditions: Acne Vulgaris
Sponsor: Dermira, Inc.
Start date: 2017-02-06; Completion date: 2017-12-21
Enrollment: 744 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objectives of this study are to assess the safety and efficacy of Olumacostat Glasaretil Gel compared to vehicle in patients with acne vulgaris

Detailed description:

Arms: arm 1: Olumacostat Glasaretil Gel, 5.0%, applied twice daily to the face for 12 weeks arm 2: Olumacostat Glasaretil Gel, Vehicle, applied twice daily to the face for 12 weeks
Interventions: intervention 1: Olumacostat Glasaretil Gel, 5.0% intervention 2: Olumacostat Glasaretil Gel, Vehicle
Intervention descriptions: intervention 1: Gel containing Olumacostat Glasaretil intervention 2: Vehicle (placebo) gel

Protocol documents:
Prot_000.pdf: 
Dermira, Inc. 
 
Olumacostat Glasaretil Gel 
 
DRM01B-ACN04 
 
 
 
A RANDOMIZED, DOUBLE-BLIND, VEHICLE-CONTROLLED, EFFICACY AND 
SAFETY STUDY OF OLUMACOSTAT GLASARETIL GEL IN SUBJECTS WITH 
ACNE VULGARIS 
 
Protocol Number 
DRM01B-ACN04 
Protocol Final Date 
06 October 2016 
IND Number 
121136 
Study Drug 
Olumacostat Glasaretil Gel 
Sponsor 
Dermira, Inc. 
 
275 Middlefield Road 
 
Suite 150 
 
Menlo Park, CA 94025 
 
USA 
 
CONFIDENTIAL INFORMATION 
The information contained herein is confidential and the proprietary property of 
Dermira. Any use or disclosure of such information without the prior written 
authorization of Dermira is expressly prohibited. 
 
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Dermira, Inc. 
 
Olumacostat Glasaretil Gel 
 
DRM01B-ACN04 
A RANDOMIZED, DOUBLE-BLIND, VEHICLE-CONTROLLED, EFFICACY  
AND SAFETY STUDY OF OLUMACOSTAT GLASARETIL GEL IN  
SUBJECTS WITH ACNE VULGARIS 
CRO Personnel 
TKL Research 
Name: Lynda McMahon 
Title: Project Director 
Tel: 201.587.0500, ext 5140 
Mobile: 508.525.2203 
Email: lmcmahon@tklresearch.com 
SAE/Emergency Contact Information 
Dermira 
Name: Jubin Ryu, MD 
Title: Medical Monitor 
Mobile: +617-869-4169  
Fax: +650-365-3410 
Email: jubin.ryu@gmail.com 
Sponsor Personnel  
Dermira 
Name: Beth Zib 
Title: Clinical Lead 
Tel: +650-421-7210 
Mobile: +650-996-7838 
Fax: +650-365-3410 
Email: beth@dermira.com 
 
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Dermira, Inc.
Olumacostat Glasaretil Gel
DRMOlB-ACNO4
SPONSOR SIGNATURE PAGE
A RANDOMTZED, DOUBLE-BLIND, VEHICLE-CONTROLLED, EF'FICACY
AND SAFETY STUDY OF OLUMACOSTAT GLASARETIL GEL IN
SUBJECTS WITH ACNE VULGARIS
Protocol Number
DRMOlB.ACNO4
Protocol Final Date
06 October 2016
The signature below constitutes approval of this protocol. I certify that I have the authority to
approve this protocol on behalf of the Sponsor, Dermira, Inc. The study will be conducted in
accordance with this protocol and all applicable laws, rules, and regulations and with the
International Conference on Harmonisation Good Clinical Practice (ICH GCP), regulations of
Canada and the United States (US) Food and Drug Administration (FDA) and the ethical
principles that have their origin in the Declaration of Helsinki.
Authorized by:
tLOÐ br/
Sponsor Signature
Eugene A. Bauer, MD
Chief Medical Officer
Date (DD MMM YYYY)
06 October 2016
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Dermira, Inc. 
 
Olumacostat Glasaretil Gel 
 
DRM01B-ACN04 
INVESTIGATOR SIGNATURE PAGE 
A RANDOMIZED, DOUBLE-BLIND, VEHICLE-CONTROLLED, EFFICACY  
AND SAFETY STUDY OF OLUMACOSTAT GLASARETIL GEL IN  
SUBJECTS WITH ACNE VULGARIS 
I have read this protocol, including the appendices, and agree that it contains all necessary details 
for carrying out the study as described. I will conduct this protocol as outlined herein, according 
to the ethical principles that have their origin in the Declaration of Helsinki, International 
Conference on Harmonisation (ICH) Guidelines for Good Clinical Practice (GCP) and applicable 
laws, rules and regulatory requirement(s) including those of Canada and the United States (US) 
Food and Drug Administration (FDA). 
I agree to obtain the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
approval of the protocol and informed consent prior to the start of the study. 
I agree to obtain formal written informed consent in accordance with applicable federal and local 
regulations and international guidelines from all subjects prior to their entry into the study. 
I have received and reviewed the Investigator’s Brochure including the potential risks and side 
effects of the product and instructions for use. 
I agree to report to the Sponsor any adverse events that occur during the course of the study in 
accordance with the ICH GCP guideline and the protocol. 
I agree to ensure that all associates, colleagues, and employees assisting me with the conduct of 
the study are informed of their responsibilities in meeting the above commitments and the 
commitments set forth in the Investigator’s Agreement. 
I agree to maintain adequate and accurate records and to make those records available for 
inspection in accordance with the ICH GCP guideline, and federal and local requirements. 
I understand that the study may be terminated or enrollment suspended at any time by the 
Sponsor, with or without cause, or by me if it becomes necessary to protect the best interests of 
the study subjects. 
 
 
_____________________________________ 
________________________ 
Investigator’s Signature 
Date (DD MMM YYYY) 
 
 
_____________________________________ 
Investigator’s Name (print) 
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Dermira, Inc. 
 
Olumacostat Glasaretil Gel 
 
DRM01B-ACN04 
PROTOCOL SYNOPSIS 
Title: 
A Randomized, Double-Blind, Vehicle-Controlled, Efficacy and Safety Study of 
Olumacostat Glasaretil Gel in Subjects with Acne Vulgaris 
Protocol Number: 
DRM01B-ACN04 
Phase: 
3 
Number of Sites: 
Approximately 50 
Study Population 
Subjects ≥ 9 years of age with acne vulgaris  
Sample Size 
Approximately 700 subjects 
Study Treatment 
Olumacostat Glasaretil Gel, 5.0%, applied twice daily 
Olumacostat Glasaretil Gel, Vehicle, applied twice daily 
Randomization 
2:1 (active:vehicle) 
Study Objective: 
To assess the efficacy and safety of Olumacostat Glasaretil Gel, 5.0% compared 
to Olumacostat Glasaretil Gel, Vehicle when applied twice daily to the face for 
12 weeks in subjects with acne vulgaris. 
Duration of Subject 
Participation: 
• Screening: maximum duration of 35 days  
• Treatment period: 12 weeks 
Maximum total participation: 17 weeks  
Study Visit Schedule 
Screening, Baseline/Day 1, Weeks 1, 2 (phone call), 4, 8, 12 (Exit)  
Study Design/Summary: 
This study is a randomized, double-blind, vehicle-controlled, parallel group study, designed to assess the 
efficacy and safety of Olumacostat Glasaretil Gel, 5.0% compared to Olumacostat Glasaretil Gel, Vehicle 
in subjects with acne vulgaris on the face. All subjects will sign an informed consent or assent (pediatric 
subjects) and undergo screening for study eligibility.  
Approximately 700 eligible subjects, ≥ 9 years of age, will be randomized, in a 2:1 fashion, to 
Olumacostat Glasaretil Gel, 5.0% or Olumacostat Glasaretil Gel, Vehicle treatment, respectively. Study 
drug will be applied twice daily to the face for 12 weeks. Subjects will return to the study clinic at 
Weeks 1, 4, 8 and 12 (Study Exit). A follow-up phone call at Week 2 will be made to assess safety 
(adverse events) only.  
Primary efficacy will be assessed through acne lesion counts (inflammatory and non-inflammatory 
lesions) and investigator global assessment of acne (IGA). All efficacy endpoints will be assessed from 
baseline to Week 12.  
Safety will be assessed through adverse events, local skin reactions (LSRs), serum chemistry, hematology 
and urinalysis laboratory testing, ECG testing, physical examination and vital signs. 
Photographs of the face will be taken in all subjects at a subset of sites in order to visually assess the 
appearance of acne vulgaris during the course of the study. During clinic visits, subjects will be asked to 
complete Acne Patient Self-Questionnaire.  
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Olumacostat Glasaretil Gel 
 
DRM01B-ACN04 
TABLE OF CONTENTS 
Page 
PROTOCOL SYNOPSIS ..............................................................................................................5 
TABLE OF CONTENTS ..............................................................................................................6 
1 
INTRODUCTION ................................................................................................................9 
1.1 
Product Development Rationale .................................................................................9 
1.2 
Summary of Investigational Program .......................................................................10 
1.3 
Study Conduct Statement ..........................................................................................13 
2 
STUDY SUMMARY...........................................................................................................14 
3 
STUDY OBJECTIVES ......................................................................................................14 
4 
STUDY ENDPOINTS ........................................................................................................14 
5 
STUDY DESIGN ................................................................................................................15 
5.1 
Duration of the Study ................................................................................................15 
5.2 
Study Population and Number of Subjects ...............................................................15 
5.3 
Selection of Subjects .................................................................................................15 
5.3.1  Inclusion Criteria ..........................................................................................15 
5.3.2  Exclusion Criteria .........................................................................................15 
5.3.3  Females – Non-childbearing Potential ..........................................................17 
5.3.4  Females – Childbearing Potential .................................................................17 
6 
STUDY DRUG ....................................................................................................................17 
6.1 
Investigational Medicinal Product ............................................................................17 
6.2 
Packaging, Labeling and Storage ..............................................................................18 
6.3 
Treatment Assignment ..............................................................................................18 
6.4 
Study Drug Dispensing and Return ..........................................................................18 
6.5 
Study Drug Application ............................................................................................19 
6.6 
Treatment Compliance ..............................................................................................19 
6.7 
Study Drug Accountability .......................................................................................20 
7 
CONCOMITANT MEDICATIONS AND PROCEDURES ...........................................20 
7.1 
Permitted Treatments and Procedures ......................................................................20 
7.2 
Prohibited Treatments and Procedures .....................................................................20 
8 
STUDY PROCEDURES ....................................................................................................21 
8.1 
Screening (Day -35 to -1) .........................................................................................21 
8.2 
Baseline Visit/ Day 1 ................................................................................................22 
8.3 
Week 1 (+/-2 days) ...................................................................................................23 
8.4 
Week 2 Telephone Contact (+/-2 days) ....................................................................23 
8.5 
Week 4 (+/-4 days) ...................................................................................................23 
8.6 
Week 8 (+/-4 days) ...................................................................................................23 
8.7 
Week 12 (+/-4 days) Study Exit or Early Termination Visit ....................................24 
8.8 
Unscheduled Visits ...................................................................................................24 
9 
DETAILS OF ASSESSMENTS .........................................................................................24 
9.1 
Screening Assessments .............................................................................................25 
9.1.1  Demographics ...............................................................................................25 
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DRM01B-ACN04 
9.1.2  Medical History ............................................................................................25 
9.1.3  Disease Specific Information ........................................................................25 
9.2 
Assessment of Efficacy .............................................................................................25 
9.2.1  Investigator Global Assessment ....................................................................25 
9.2.2  Acne Lesion Count .......................................................................................26 
9.3 
Other Assessments ....................................................................................................26 
9.3.1  Photographs...................................................................................................26 
9.3.2  Acne Patient Self-Questionnaire ...................................................................27 
9.4 
Assessment of Safety ................................................................................................27 
9.4.1  Physical Examination....................................................................................27 
9.4.2  Vital Signs .....................................................................................................27 
9.4.3  ECGs .............................................................................................................27 
9.4.4  Laboratory Evaluations .................................................................................28 
9.4.5  Local Skin Reactions (LSRs) ........................................................................28 
9.4.6  Adverse Events .............................................................................................29 
9.4.7  Serious Adverse Events ................................................................................30 
9.4.8  Dosing Changes due to AEs .........................................................................32 
9.4.9  Pregnancy ......................................................................................................32 
10 
STUDY DISCONTINUATIONS .......................................................................................33 
10.1 
Discontinuation of the Study ....................................................................................33 
10.2 
Early Study Termination of Study Subjects..............................................................33 
10.3 
Study Drug Discontinuation .....................................................................................34 
11 
STATISTICAL CONSIDERATIONS ..............................................................................34 
11.1 
General Statistical Methodology...............................................................................34 
11.2 
Populations Analyzed ...............................................................................................35 
11.3 
Primary Efficacy .......................................................................................................35 
11.4 
Secondary Efficacy ...................................................................................................36 
11.5 
Other Supportive Efficacy Analyses .........................................................................36 
11.6 
Pooling Analysis .......................................................................................................37 
11.7 
Missing Efficacy Data Imputations ..........................................................................38 
11.8 
Sensitivity Efficacy Analyses ...................................................................................40 
11.9 
Subgroup Analyses ...................................................................................................41 
11.10  Exposure and Compliance ........................................................................................41 
11.11  Adverse Events .........................................................................................................42 
11.12  Local Skin Reactions ................................................................................................42 
11.13  Other Safety Data ......................................................................................................42 
11.14  Sample Size Determination .......................................................................................43 
12 
STUDY ADMINISTRATION ...........................................................................................44 
12.1 
Compliance with the Protocol ...................................................................................44 
12.2 
Informed Consent Procedures ...................................................................................44 
12.3 
Study Documentation and the Electronic Case Report Form ...................................45 
12.4 
Study Monitoring ......................................................................................................45 
12.5 
Retention of Study Documentation ...........................................................................46 
13 
ACRONYMS AND DEFINITIONS ..................................................................................46 
13.1 
Acronyms ..................................................................................................................46 
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DRM01B-ACN04 
14 
REFERENCES ...................................................................................................................48 
15 
APPENDIX 1 – SCHEDULE OF EVENTS .....................................................................49 
16 
APPENDIX 2 – ACNE PATIENT SELF- QUESTIONNAIRE .....................................50 
LIST OF TABLES  
Table 1: 
Fitzpatrick Skin Type .................................................................................................. 25 
Table 2: 
Investigator Global Assessment .................................................................................. 26 
Table 3: 
Subject Assessed Local Skin Reactions ...................................................................... 29 
Table 4: 
Investigator Assessed Local Skin Reactions ............................................................... 29 
 
 
 
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Olumacostat Glasaretil Gel 
 
DRM01B-ACN04 
1 
INTRODUCTION 
1.1 
Product Development Rationale 
Acne arises from a combination of physiological changes in the skin including altered sebaceous 
gland cell differentiation, heightened sebum production, localized bacterial colonization and 
inflammation. Although acne is generally viewed as a benign dermatological disease of 
adolescence, more severe forms may lead to permanent scar formation, with some of these 
patients suffering from psychological injury and significant loss of self-worth. Recent scientific 
advances in the understanding of the complex multi-factorial nature of this common disease offer 
great opportunity for scientific innovation through selective targeting of key elements of the 
disease process. 
Sebum is a waxy/oily substance comprised of cholesterol, fatty acids, fatty alcohols, triglycerides 
(TGs), wax esters, sterol esters and squalene produced by sebaceous gland cells [1]. Sebaceous 
glands are associated with hair follicles. The basal layer of sebocytes just inside the basement 
membrane consists of small, nucleated cells devoid of lipid droplets. This layer contains the 
dividing cells that replenish the gland as cells are lost in the process of holocrine rupture. As 
cells move from the basal layer towards the center of the gland, they differentiate and produce 
lipids that accumulate in droplets. Eventually the cells become distended with lipid droplets and 
the nuclei and other sub-cellular structures disappear. As the cells approach the sebaceous duct, 
they disintegrate and release their contents through holocrine secretion. In acne, diglycerides and 
free fatty acid levels may be increased by bacterial degradation of diglycerides and triglycerides 
present within sebum. Free fatty acids may promote inflammatory response in acne by activating 
local immune cells and their subsequent release of pro-inflammatory factors. 
A direct correlation between the degree of acne improvement and the extent of sebum reduction 
produced by different oral anti-acne medications has been established [2]. The oral retinoid 
13-cis-retinoic acid (13-cis-RA, Accutane®) is particularly effective at reducing sebum 
output although its mode-of-action is not likely related to a direct effect on sebum synthesis 
pathways [3]. 
Topical agents routinely prescribed for acne, including antibiotics, retinoids and combinations 
thereof, often produce only modest therapeutic benefits and do not affect sebum production. A 
locally-delivered medication that selectively inhibited sebum formation would represent a 
breakthrough advance in reducing the pathogenic influences of sebum overproduction in acne. 
Acetyl-coenzyme A carboxylases (ACCs) have crucial roles in fatty acid metabolism in humans 
and most other living organisms [4]. ACC catalyzes the carboxylation of acetyl-CoA to form 
malonyl-CoA. This is the first committed step in fatty acid biosynthesis and is the rate limiting 
reaction for the pathway [5, 6, 7]. These fatty acids then can be stored or converted to 
triglycerides (TGs) and phospholipids. In addition to its role as a substrate in fatty acid 
biosynthesis, malonyl-CoA, also plays an important regulatory role in controlling mitochondrial 
fatty acid uptake through allosteric inhibition of carnitine palmitoyltransferase I (CPT-I), the 
enzyme catalyzing the first committed step in mitochondrial fatty acid oxidation [8]. Malonyl-
CoA, therefore, is a key metabolic signal for the control of fatty acid production and utilization 
in response to dietary changes and altered nutritional requirements in animals [6]. As a result of 
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Olumacostat Glasaretil Gel 
 
DRM01B-ACN04 
its unique position in intermediary metabolism, inhibition of ACC offers the ability to inhibit 
de novo fatty acid production in lipogenic tissues, such as liver, adipose tissue, and sebaceous 
glands. 
A variety of structurally diverse ACC inhibitors has recently been described in the scientific and 
patent literature for potential use in metabolic syndrome. One class of ACC inhibitors, including 
TOFA (5-(tetradecyloxy)-2-furancarboxylic acid), consists of lipophilic fatty acid mimetics that 
compete with acetyl-CoA in the ACC-mediated formation of malonyl-CoA. Investigators have 
demonstrated that TOFA reduced fatty acid synthesis and TG secretion both in cultured hepatic 
cells [8, 10] and in experimental animals [11, 12], reduced plasma cholesterol and TGs in 
experimental animals including rhesus monkeys [10, 11], and reduced body weight [13]. 
The ability to deliver TOFA topically could offer a means to inhibit de novo fatty acid 
production in sebaceous glands, introducing a new treatment paradigm for acne vulgaris.  
1.2 
Summary of Investigational Program 
Dermira, Inc. is pursuing the development of olumacostat glasaretil, previously referred to as 
DRM01B, a pro-drug of TOFA, sarcosine ester, as a topically applied sebum inhibitor for the 
treatment of acne vulgaris. Olumacostat glasaretil is hydrolyzed by esterases in vivo to form the 
pharmacologically active moiety, TOFA. TOFA is converted to Tofyl-CoA intracellularly, which 
competes with acetyl-CoA in the ACC-mediated formation of malonyl-CoA. As a result, 
inhibition of malonyl-CoA synthesis offers a means to inhibit de novo fatty acid production in 
the sebaceous glands in subjects with acne vulgaris. Olumacostat glasaretil is a new chemical 
entity and has been formulated for clinical development as Olumacostat Glasaretil Gel, 5.0%.  
A summary of clinical and nonclinical pharmacology, toxicology and metabolism data is 
presented below. Detailed information is provided in the current Investigator’s Brochure. 
Safety pharmacology studies were conducted with olumacostat glasaretil administered 
intravenously (IV) which included neurobehavioral and pulmonary function studies in rats and a 
cardiovascular study in telemetered minipigs. These studies revealed no adverse findings 
attributable to olumacostat glasaretil. In vitro studies assessing the effects of olumacostat 
glasaretilel and TOFA upon human ether-à-go-go-related gene (hERG) ionic conductance in 
human embryonic kidney (HEK) cells also revealed no significant inhibition at the maximum 
concentrations tested. Overall, the results from the safety pharmacology showed no adverse 
effects at exposures to parent drug and/or TOFA several orders of magnitude beyond that 
anticipated to be seen following topical application in humans. 
Following IV administration in rats and minipigs, olumacostat glasaretil was quickly 
metabolized to TOFA; no evidence of any gender-specific differences or accumulation upon 
repeated dosing of either olumacostat glasaretil or TOFA was observed. With oral administration 
in rats, low ng/mL levels of olumacostat glasaretil were noted while exposure to TOFA reached 
levels exceeding 1 µg/mL. In vitro metabolism and plasma protein binding experiments indicated 
that olumacostat glasaretil was metabolized and bound to plasma protein in a similar manner 
between humans and the species utilized for toxicology and safety pharmacology assessments 
(rat and minipig).  
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Olumacostat Glasaretil Gel 
 
DRM01B-ACN04 
Toxicokinetic assessments conducted following the topical dermal application of Olumacostat 
Glasaretil Gel to minipigs indicated that olumacostat glasaretil and TOFA were poorly absorbed; 
peak plasma levels recorded in these studies were below the detectable limit for olumacostat 
glasaretil and while TOFA was detectable following application of the highest strength of 
Olumacostat Glasaretil Gel (7.5% w/w), mean values did not exceed 6 ng/mL for TOFA. The 
test article used in this study is the same formulation and concentration that was used in the 
clinical proof of concept study (DRM01B-ACN01) and the same formulation that was one of the 
strengths included in the clinical dose ranging trial (DRM01B-ACN02).  
Toxicology studies conducted with olumacostat glasaretil included dermal studies in minipigs of 
up to 13 weeks in duration, IV studies in rats and minipigs of up to 4 weeks in duration, and oral 
studies in rats of up to 90 days in duration. Based upon the nonclinical studies conducted to date 
olumacostat glasaretil, has exhibited an acceptable safety profile. No test article-related effects 
were noted in any nonclinical study, aside from histological findings associated with the non-
glandular stomach (fore-stomach) in the 13-week rat oral study. This finding was considered a 
direct local effect (not due to systemic absorption), reversible and non-adverse, and is of doubtful 
clinical relevance given the absence of this structure in humans. In the other toxicology studies, 
there were no remarkable olumacostat glasaretil-related findings and olumacostat glasaretil was 
well tolerated. No adverse systemic effects were associated with mean peak plasma exposures to 
olumacostat glasaretil and TOFA up to 9955 and 3630 ng/mL, respectively, which are 
concentrations exceeding 4000-fold that seen following the dermal application of maximum 
feasible doses (10 mg/kg) to minipigs. In vivo and in vitro studies conducted to assess dermal 
sensitization, ocular irritation, and phototoxicity did not reveal any remarkable effects following 
the exposure of cells/tissues to olumacostat glasaretil. Genetic toxicology results indicated that 
olumacostat glasaretil was neither mutagenic nor clastogenic. Predictive software assessments 
indicated there were no potential theoretical manufacturing impurities or metabolic products that 
were of mutagenic concern. Overall, the results of the nonclinical toxicology and safety 
pharmacology studies suggest the safety risks posed by Olumacostat Glasaretil Gel are low. 
Two clinical studies, DRM01B-ACN01 and DRM01B-ACN02, have been completed as part of 
the Phase 2 development program. DRM01B-ACN01 was a proof of concept study which 
assessed the safety and efficacy of one strength of Olumacostat Glasaretil Gel compared to 
vehicle gel in adult subjects with acne vulgaris. DRM01B-ACN02 was a dose ranging study 
which assessed the safety and efficacy of multiple strengths and regimens of Olumacostat 
Glasaretil Gel and vehicle gel in adult subjects with acne vulgaris. In both studies, Olumacostat 
Glasaretil Gel was shown to be well-tolerated and demonstrated statistically significant 
improvements in acne lesions counts and severity. Additional information on these studies is 
provided below.  
Study DRM01B-ACN01 
DRM01B-ACN01 was randomized, vehicle controlled, parallel group study designed to assess 
the safety and tolerability of Olumacostat Glasaretil Gel, 7.5% in healthy volunteers (Phase 1) 
before assessing the safety, tolerability and preliminary efficacy of the drug in subjects with acne 
vulgaris (Phase 2a). In the Phase 1 portion of the study, 6 healthy volunteers applied study 
Olumacostat Glasaretil Gel twice daily, to the face, for one week. Review of the data from 
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DRM01B-ACN04 
Phase 1 showed that Olumacostat Glasaretil Gel was well tolerated with no safety concerns. As 
such, the Phase 2a portion of the study was conducted. 
In the Phase 2a portion of the study, Olumacostat Glasaretil Gel was applied, twice daily, to the 
face in 108 adult subjects with acne vulgaris for a 12–week treatment period. Similar to Phase 1, 
Olumacostat Glasaretil Gel was well tolerated with most AEs reported as mild to moderate in 
severity. Subjects treated with Olumacostat Glasaretil Gel had significantly greater reductions in 
inflammatory and noninflammatory lesion counts from Baseline to Week 12 compared with 
subjects treated with vehicle gel. In addition, a significantly greater proportion of subjects treated 
with Olumacostat Glasaretil Gel had a successful improvement in IGA score (corresponding to 
less severe acne) than subjects treated with vehicle gel.  
Study DRM01B-ACN02 
Study DRM01B-ACN02 was a Phase 2 dose-ranging study in adult subjects with acne vulgaris 
on the face. The study was a randomized, vehicle controlled, parallel group study designed to 
assess the efficacy and safety of Olumacostat Glasaretil Gel at a concentration of 7.5% BID, 
7.5% QD, and 4.0% QD, compared to vehicle BID or QD in subjects with moderate to severe 
facial acne.  
A total of 420 adult subjects were randomized to active and vehicle in a 2:2:2:1:1 fashion. Study 
treatments continued for 12 weeks. Subjects returned to the study clinic at Weeks 1, 2 (phone 
call only), 4, 8 and 12 (study exit).  
The results of the study showed that all three Olumacostat Glasaretil Gel treatment groups 
demonstrated statistically significantly greater reductions in the absolute change in inflammatory 
lesion counts from baseline to Week 12 than the combined vehicle group. The LS mean changes 
in inflammatory lesion counts were −14.6 and −14.5, and −15.0 for the Olumacostat Glasaretil 
Gel, 4.0% QD, 7.5% QD, and 7.5% BID groups, respectively, compared with −10.7 for the 
combined vehicle QD group (P = 0.011, P = 0.014, and P = 0.011 respectively). All 
3 Olumacostat Glasaretil Gel treatment groups showed statistically significantly greater 
reductions in the absolute change in noninflammatory lesion counts from baseline to Week 12 
than the combined vehicle group. The LS mean changes in noninflammatory lesion counts at 
Week 12 were −15.3, −13.4, and −17.5 for the DRM01B Olumacostat Glasaretil Gel 4.0% QD, 
7.5% QD, and 7.5% BID groups, respectively, compared with −9.3 for the combined vehicle 
group (P = 0.004, P = 0.050, and P < 0.011 respectively).  
The Olumacostat Glasaretil Gel 4.0% QD and 7.5% BID groups each had a statistically 
significantly greater proportion of subjects achieve a minimum 2-grade improvement (reduction) 
in IGA score from baseline at Week 12 compared with the combined vehicle group. The percent 
of subjects achieving this endpoint was 21.6% in the Olumacostat Glasaretil Gel 4.0% QD and 
25.9% of subjects in the Olumacostat Glasaretil Gel 7.5% BID group (compared with 9.8% in 
the combined vehicle QD group (P = 0.024 and P = 0.004, respectively). 
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Pharmacokinetic (PK) results, assessed in a subset of subjects, showed that plasma 
concentrations of Olumacostat Glasaretil Gel on Day 1 were undetectable for all but 1 subject, 
who had a plasma concentration of 0.304 at 1 time point (2 hours post-dosing). Plasma 
concentrations of Olumacostat Glasaretil Gel at Week 8 were undetectable for all tested subjects. 
Plasma concentrations of TOFA on Day 1 were undetectable in most subjects, but detectable in a 
few subjects in each dose group, with values ranging from 0.101 to 1.02 ng/mL. Plasma 
concentration of TOFA at Week 8 were undetectable for most subjects in the DRM01B QD dose 
groups, but detectable in a few subjects, with values ranging from 0.100 to 0.299 ng/mL. In the 
Olumacostat Glasaretil Gel, 7.5% BID group, approximately half of the tested subjects had 
detectable TOFA levels at each time point, with mean values ranging from 0.156 to 
0.340 ng/mL. 
The most common AEs reported during the study were nasopharyngitis, upper respiratory tract 
infection, and application site pruritus. Most AEs were mild or moderate in severity. Erythema 
was the most common LSR. Laboratory values, vital signs, and ECGs measured at the end of the 
study were generally consistent with baseline values, with no clinically significant trends. 
There were no deaths during the study however, one subject in the 7.5% QD group had an SAE 
of uterine leiomyoma considered unrelated to treatment. Seven subjects prematurely 
discontinued study drug due to an AE, 4 of these discontinuations were considered to be 
treatment related.  
Study Rationale 
Data from the completed Phase 2 dose ranging study, DRM01B-ACN02, and data from study 
DRM01B-ACN01, have shown that Olumacostat Glasaretil Gel was well tolerated at multiple 
concentrations. Olumacostat Glasaretil Gel at a strength of 5.0% has been selected as the 
concentration to take forward in Phase 3 development. Two Phase 3 pivotal trials are planned as 
part of the Phase 3 development program and will include adults and adolescents (ages 9 years 
and older) in order to confirm the efficacy and safety of Olumacostat Glasaretil Gel, 5.0% for the 
treatment of acne vulgaris.  
This study, DRM01B-ACN04, is one of the two confirmatory Phase 3 trials being conducted to 
assess the efficacy and safety of Olumacostat Glasaretil Gel, 5.0% in subjects with acne vulgaris. 
1.3 
Study Conduct Statement 
This study will be conducted in compliance with the protocol, according to current United States 
federal regulations (Title 21, Code of Federal Regulations [CFR] Parts 11, 50, 54, 56,312, and 
314 as appropriate) and the principles of the International Conference on Harmonisation (ICH) 
(ICH E6 1997) Good Clinical Practice (GCP), Food and Drug Administration (FDA) guidelines, 
Canadian guidelines and the Declaration of Helsinki, 1964 (as amended in Edinburgh [2000]). 
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2 
STUDY SUMMARY 
This study is a randomized, double-blind, vehicle-controlled, parallel group study, designed to 
assess the efficacy and safety of Olumacostat Glasaretil Gel,5.0% compared to Olumacostat 
Glasaretil Gel, Vehicle in subjects with acne vulgaris on the face. All subjects will provide 
informed consent or assent (pediatric subjects) and undergo screening for study eligibility.  
Approximately 700 eligible subjects ≥ 9 years of age will be randomized, in a 2:1 fashion, to 
Olumacostat Glasaretil Gel, 5.0% or Olumacostat Glasaretil Gel, Vehicle treatment, respectively. 
Study drug will be applied twice daily to the face. Subjects will return to the study clinic at 
Weeks 1, 4, 8 and 12 (Study Exit). A follow-up phone call at Week 2 will be made to assess 
safety (adverse events) only.  
Primary efficacy will be assessed through acne lesion counts (inflammatory and non-
inflammatory lesions) and investigator global assessment of acne (IGA). All efficacy endpoints 
will be assessed as the change from Baseline to Week 12. 
Safety will be assessed through adverse events, local skin reactions (LSRs), serum chemistry, 
hematology and urinalysis laboratory testing, ECG testing, physical examination and vital signs. 
Photographs of the face will be taken for all subjects in subset of study sites in order to visually 
assess the appearance of acne vulgaris during the course of the study.  
During clinic visits, subjects will be asked to complete the Acne Patient Self-Questionnaire. 
3 
STUDY OBJECTIVES 
The objective of this study will be to assess the efficacy and safety of Olumacostat Glasaretil Gel 
at a concentration of 5.0%, compared to Olumacostat Glasaretil Gel, Vehicle when applied twice 
daily for 12 weeks in subjects with acne vulgaris. 
4 
STUDY ENDPOINTS 
Primary Efficacy Endpoints: 
• Mean absolute change in acne lesion counts (inflammatory and non-inflammatory 
lesions) from baseline to Week 12. 
• Proportion of subjects who achieved ≥ 2-grade improvement and a grade of 0 or 1, in the 
investigator global assessment of acne (IGA) from baseline to Week 12. 
Secondary Efficacy Endpoints: 
• Percent change in acne lesion counts (inflammatory and non-inflammatory lesions) from 
baseline to Week 12. 
• Proportion of subjects who achieved ≥ 2-grade improvement in the investigator global 
assessment of acne (IGA) from baseline to Week 12. 
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5 
STUDY DESIGN 
5.1 
Duration of the Study 
The duration of the study for each subject is approximately 17 weeks (up to 35 days screening 
and 12 weeks treatment).  
5.2 
Study Population and Number of Subjects 
Approximately 700 subjects, ≥ 9 years of age, with acne vulgaris on the face, will be enrolled.  
5.3 
Selection of Subjects 
Subject selection criteria are outlined below. Any questions on the eligibility of a subject for this 
study must be referred to the Sponsor or their designee, prior to enrollment. No exceptions to 
inclusion or exclusion criteria will be made. 
5.3.1 
Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible for study participation: 
1. 
Signed informed consent and, for subjects under legal adult age, signed assent  
2. 
Age ≥ 9 years  
3. 
Willing to comply with the protocol. Subjects under legal adult age will be assessed by the 
investigator as to their ability to comply with the protocol  
4. 
Male or non-pregnant (negative serum pregnancy test at screening for female subjects of 
child-bearing potential), non-lactating females 
5. 
In the case of females of childbearing potential), are using an acceptable form of birth 
control (Section 5.3.4) 
6. 
In the case of females of childbearing potential, have a negative urine pregnancy test at 
Baseline/Day 1  
7. 
Clinical diagnosis of facial acne vulgaris defined as: 
• At least 20 inflammatory lesions, and  
• At least 20 non-inflammatory lesions, and 
• Investigator Global Assessment of 3 or greater 
8. 
Willing to refrain from using any treatments for acne vulgaris, other than the 
investigational product, including topical or systemic antibiotics.  
5.3.2 
Exclusion Criteria 
Subjects meeting any of the following criteria are not eligible for study participation: 
1. 
Previous active treatment in Olumacostat Glasaretil (DRM01B) Gel trials 
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2. 
Females who are currently pregnant, lactating or planning to become pregnant during the 
course of the study 
3. 
Known hypersensitivity to Olumacostat Glasaretil or its excipients 
4. 
Any skin condition which may interfere with the evaluation of safety or, of acne vulgaris 
(e.g., rosacea; seborrheic dermatitis; perioral dermatitis; corticosteroid-induced acne or 
folliculitis) 
5. 
Excessive facial hair that would interfere with diagnosis or assessment of acne vulgaris 
6. 
Excessive sun exposure that could affect the clinical state of acne, in the opinion of the 
investigator or, anticipated use of tanning booths 
7. 
Active cystic acne or acne congoblata, acne fulminans, and secondary acne 
8. 
Two or more active nodulocystic lesions on the face 
9. 
Screening clinical chemistry, hematology, or urinalysis laboratory value, deemed clinically 
significant, by the Investigator 
10. Abnormal findings on screening ECG, deemed clinically significant by the Investigator  
11. Subjects who are actively participating in an experimental therapy study or who have 
received experimental therapy within 30 days or 5 half-lives (whichever is longer) of the 
Baseline visit 
12. Subjects who are a poor medical risk because of other systemic diseases or active 
uncontrolled infections, in the opinion of the investigator 
13. Any other condition which, in the judgment of the investigator, would put the subject at 
unacceptable risk for participation in the study 
14. Treatment with over-the-counter topical medications for the treatment of acne vulgaris 
including benzoyl peroxide, topical anti-inflammatory medications, corticosteroids, 
α-hydroxy/glycolic acid on the face within 2 weeks prior to Baseline 
15. Treatment with systemic corticosteroids (use of intranasal and inhaled corticosteroids 
allowed for seasonal allergies and asthma) within 4 weeks prior to Baseline 
16. Treatment with systemic antibiotics or systemic anti-acne drugs within 4 weeks prior to 
Baseline 
17. Prescription topical retinoid use on the face within 4 weeks prior to Baseline (e.g., 
tretinoin, tazarotene, adapalene) 
18. Treatment with a new hormonal therapy or dose change to existing hormonal therapy 
within 12 weeks prior to Baseline (hormonal therapies include, but are not limited to, 
estrogenic and progestational agents such as birth control pills). 
19.  Use of androgen receptor blockers (such as spironolactone or flutamide) within 2 weeks 
prior to Baseline. 
20. Oral retinoid use (e.g., isotretinoin) within 12 months prior to Baseline or vitamin A 
supplements greater than 10,000 units/day within 6 months prior to Baseline 
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21. Facial procedures (chemical or laser peel, microdermabrasion, etc.) within 8 weeks prior to 
Baseline or if anticipated during the study 
5.3.3 
Females – Non-childbearing Potential 
Female subjects of non-childbearing potential are women 45 years or older and at least 2 years 
postmenopausal or surgically sterile (e.g., total hysterectomy, bilateral oophorectomy). All other 
female subjects will be considered to be of childbearing potential. 
5.3.4 
Females – Childbearing Potential 
Pregnancy hormones may cause acne to flare. To avoid confounding the assessment of efficacy 
pregnancy should be avoided. Acceptable contraceptive methods for sexually active female 
subjects of childbearing potential include one of the following: 
• Abstinence 
• Oral/implant/injectable/transdermal contraceptives 
• Intrauterine device 
• Condom with spermicide 
• Diaphragm with spermicide 
• Partner vasectomized or 
• Tubal ligation 
Abstinence or vasectomies are acceptable if the female subject agrees to implement one of the 
other acceptable methods of birth control if her lifestyle/partner changes. Female subjects of 
childbearing potential must use acceptable methods of contraception starting from the Screening 
Visit and throughout the study.  
6 
STUDY DRUG 
6.1 
Investigational Medicinal Product 
Study medication, will be supplied as Olumacostat Glasaretil Gel, 5.0% and Olumacostat 
Glasaretil Gel, Vehicle.  
Olumacostat Glasaretil Gel is formulated as an alcohol based gel for topical application. 
Olumacostat Glasaretil Gel, 5.0% contains 50 mg of olumacostat glasaretil per gram of gel, 
ethanol, isopropanol, polyethylene glycol 400, dimethyl isosorbide and hydroxypropy-cellulose 
and appears as a translucent, colorless to faintly yellow gel.  
Olumacostat Glasaretil Gel, Vehicle has the same appearance and contains the same ingredients 
as Olumacostat Glasaretil Gel, 5.0%, with the exception of olumacostat glasaretil. 
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6.2 
Packaging, Labeling and Storage 
The Olumacostat Glasaretil Gel, 5.0% and Olumacostat Glasaretil Gel, Vehicle gel will be 
packaged in identical 45g aluminum tubes. Each tube contains approximately 40g of gel.  
Study drug for each subject enrolled will be packaged in a study kit. Each kit will contain 6 tubes 
to allow for 12 weeks of study drug application.  
Study drug tubes and kits will be labeled with the study number, a unique kit number, contents, 
storage conditions, manufacturer and Sponsor information, and precautionary statements and 
expiry date, if applicable.  
Study drug kits are to be stored at room temperature (25°C with allowable excursion to 15-30°C) 
in a secure, locked facility accessible only to authorized study personnel. Study drug must not be 
placed in refrigerator or frozen, exposed to heat or stored at high temperatures. This product is 
flammable. Avoid fire, flame, or smoking during and immediately following application. 
6.3 
Treatment Assignment 
Randomization and IWRS 
At the Baseline/Day 1 visit, qualified subjects will be randomized to treatment using an 
Interactive Web-based Randomization System (IWRS). The IWRS will assign a study drug kit 
number based on a predetermined randomization schedule. The kit number will be recorded in 
the electronic case report form (eCRF). Approximately 467 subjects will be randomized to active 
treatment and approximately 233 subjects will be randomized to vehicle treatment for a total of 
approximately 700 subjects. Subjects will be randomized to treatment groups in such a manner to 
balance treatment allocation within study sites in a 2:1 fashion. 
Each subject screened will be assigned a unique subject number.  
Study Blinding 
The Sponsor, the CRO, the Investigator, study site personnel and subjects will be blinded to the 
treatment assignment. 
The integrity of this clinical study must be maintained by observing the treatment blind. If an 
adverse event occurs which cannot be managed without knowing whether the subject is receiving 
active study drug or vehicle solution, the IWR system will be used to obtain treatment 
assignment information. The Medical Monitor must be notified whenever study medication is 
unblinded, preferably prior to unblinding a subject. 
6.4 
Study Drug Dispensing and Return 
It is the responsibility of the Investigator to ensure that study drug is only used on study subjects 
enrolled in this study. The study drug must only be dispensed from official study sites by 
authorized personnel according to the protocol and local regulations.  
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Study drug will be dispensed by the study site to the subject at each study visit. Two tubes 
contain enough study drug for 1 month of application. At each visit, the subject will be dispensed 
enough tubes to allow dosing until the next visit. Partially used tubes may be re-dispensed at the 
site’s discretion. 
Subjects are to return all study medication tubes (used and unused) to the study site. Study tubes 
will be weighed prior to dispensing and upon return. Sites are allowed to re-dispense tubes. If 
required, tubes will be re-weighed prior to re-dispensing Weights will be recorded in the source 
documents and eCRF.  
Each subject is to be instructed on the importance of returning study drug at the next study visit. 
If a subject does not return study drug, they will be instructed to return it as soon as possible. The 
site staff will visually inspect the tube to ensure product usage is consistent with the subject’s 
dosing diary.  
6.5 
Study Drug Application 
Subjects will be instructed on the application of the study medication. The first dose of the study 
drug will be applied in the clinic for instructional purposes. Subjects are to apply the study drug 
twice daily (morning and evening) to a clean dry face.  
Study drug is to be applied topically, to the entire face (forehead, nose, cheeks, and chin) by 
squeezing approximately ½ inch or slightly more than 1 centimeter long line of gel, onto a finger 
and spreading the gel over the face, avoiding the skin around the eyes, eyelids and mouth, until 
the face is completely covered.  
Subjects are to be instructed to wash their hands prior to and immediately following study drug 
application. 
Subjects should avoid washing the face or swimming within 2 hours after applying study 
medication.  
Missed doses should be applied, provided there is at least an 8 hour window until the next 
scheduled dose.  
6.6 
Treatment Compliance 
Treatment compliance will be assessed at each visit using a subject-completed diary and visual 
inspection of the tubes. Subjects will be given a paper diary at each visit in conjunction with 
study drug. The subject-completed diary will collect application information for the face. 
Subjects will be instructed to bring all study medication and diaries to the clinic at the next study 
visit. 
A subject deviating significantly from the assigned dosing regimen will be counseled. All diaries 
will be maintained as source documentation.  
The first and last dates of study drug usage, location and any missed applications will be 
recorded in the eCRF. 
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6.7 
Study Drug Accountability 
The Investigator or designee will be responsible for study drug accountability and records at the 
site. Study drug accountability records will document the receipt, dispensing and return of study 
drug and provide a complete account of all used and unused drug product. Study drug 
accountability records will be reviewed regularly throughout the study by the Sponsor/designee. 
Study medication will be returned to the Sponsor, or designee, at the end of the study, following 
final study drug accountability.  
7 
CONCOMITANT MEDICATIONS AND PROCEDURES 
All medications (including over-the-counter drugs, vitamins, antacids and skin care products) 
taken during screening and throughout the study will be recorded on the eCRF. In addition, to 
ensure that the subject meets the acne treatment and medication exclusion criteria, all acne 
treatment and medications, including, any past isotretinoin, facial procedures, Vitamin A and 
hormonal therapy use will be recorded on the eCRF.  
Medication entries should be specific to the generic name (if a combination drug, then marketed 
product name) and will include the dose, unit, frequency, route of administration, start date, 
discontinuation date, and indication. When listing medications indicated for acne, the area 
treated will be collected.  
The Investigator should examine the acceptability of all concomitant procedures, medications, 
topical preparations and dietary supplements not explicitly prohibited in this study. In order to 
ensure that appropriate concomitant therapy is administered, subjects will be instructed to 
consult with the Investigator prior to taking any medication (either self-administered non-
prescription drugs or prescription therapy prescribed by another physician). 
7.1 
Permitted Treatments and Procedures 
The use of concomitant medications for medical conditions (e.g., hypertension, diabetes, acute 
infections) or treatment of an adverse event is permitted during this study as long as medications 
are not explicitly prohibited by the protocol.  
Non-medicated moisturizers and make-up may be used during study participation, provided 
application occurs after study medication is applied. On study visit days, non-medicated 
moisturizers and make-up must be removed prior to each study visit as instructed by the 
Investigator. Subjects’ skin care regimen should remain stable/unchanged during study 
participation.  
Non-medicated moisturizers, soaps, and make-up do not need to be recorded as concomitant 
medications. 
7.2 
Prohibited Treatments and Procedures 
Subjects should not undergo any elective medical procedure without prior consultation with the 
Investigator. Elective out-patient procedures (e.g., minor outpatient surgery) that might require 
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hospitalization or anesthesia should be deferred until after the study, whenever clinically 
appropriate. However, subjects may continue in the study if not contraindicated by the procedure 
and if continuation is deemed in the subject’s best interest. 
The following medications and treatments are prohibited during the study:  
• Over-the-counter topical medications for acne vulgaris including benzoyl peroxide, 
topical anti-inflammatory medications, corticosteroids, α-hydroxy/glycolic acid  
• Systemically absorbed anti-acne drugs 
• Systemic corticosteroids (use of intranasal and inhaled corticosteroids allowed for 
seasonal allergies and asthma) 
• Systemic antibiotics (except in the case of acute medical need to treat infections) 
• Prescription topical retinoid use(e.g., tretinoin, tazarotene, adapalene) 
• New hormonal therapy or dose change to existing hormonal therapy. Hormonal therapies 
include, but are not limited to, estrogenic and progestational agents such as birth control 
pills.  
• Use of androgen receptor blockers (such as spironolactone or flutamide) 
• Oral retinoid use (e.g., isotretinoin) or vitamin A supplements greater than 
10,000 units/day  
• Facial procedures (chemical or laser peel, microdermabrasion, etc.) 
• Sun exposure which in the opinion of the investigator could affect the course of acne or 
any tanning booth use 
8 
STUDY PROCEDURES 
The procedures required for subject evaluation at each study visit are outlined below and in the 
study Schedule of Visits and Procedures (see Appendix 1). The timing of each study day is 
relative to the day of initial dosing (Baseline/Day 1). Visit windows are provided to allow study 
sites some flexibility in maintaining the study visit schedule for participating subjects. Out of 
window visits may be unavoidable in certain circumstances. Out of window visits are not 
considered deviations to the protocol. 
8.1 
Screening (Day -35 to -1) 
The screening evaluation period may take up to 35 days in order to provide adequate washout 
time for subjects taking certain medications. The purpose of the screening visit is to ensure that 
appropriate subjects are entered into the study and remain stable during the pre-treatment period. 
Questions on eligibility will be referred to the Sponsor or their designee. Screen failures may be 
re-screened one time and must be assigned a new screening number. Screen failure information 
will be recorded in the eCRF. Screening procedures, excluding lab evaluations, may be done any 
time during the screening period (prior to dosing on Day 1) and after the subject has given 
informed consent.  
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• Obtain written informed consent/assent. For subjects under legal adult age, both parents 
or legal representatives may be required to sign informed consent as applicable. 
• Collect demographic information 
• Complete medical history 
• Query subject for concomitant medication use 
• Perform a complete physical examination 
• Record height and weight 
• Measure vital signs 
• Assess Inclusion/Exclusion criteria 
• Collect a 12 lead ECG 
• Draw blood samples for laboratory tests and urine for urinalysis. Include serum 
pregnancy test for women of childbearing potential 
• Determine concomitant medication washout duration 
• Schedule next visit 
8.2 
Baseline Visit/ Day 1  
Evaluations are to be done prior to the first dose of study drug 
• Collect concomitant medication information 
• Conduct a symptom-directed physical exam – update medical history if appropriate 
• Measure vital signs 
• Conduct urine pregnancy test for women of childbearing potential 
• Conduct Investigator Global Assessment (IGA) 
• Collect acne lesion counts 
• Collect Acne Patient Self- Questionnaire 
• Evaluate face for pre-treatment local skin reactions (LSRs) 
• Collect photographs (selected sites) 
• Confirm subject eligibility (Inclusion/Exclusion criteria) and randomization to treatment 
• Instruct subject on study medication application and diary completion 
• Weigh tubes and dispense study drug and diary. Observe subject administering first dose 
• Schedule all subsequent visits 
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8.3 
Week 1 (+/-2 days) 
• Collect concomitant medication information 
• Conduct a symptom-directed physical exam 
• Measure vital signs 
• Review and record AEs 
• Assess LSRs 
• Review compliance/weigh tubes and dispense drug and diary 
• Schedule Week 2 Telephone Contact and next visit 
8.4 
Week 2 Telephone Contact (+/-2 days) 
• Call subject to review AEs and concomitant medications 
8.5 
Week 4 (+/-4 days) 
• Collect concomitant medication information 
• Conduct a symptom-directed physical exam 
• Collect urine pregnancy for women of childbearing potential 
• Measure vital signs 
• Review and record AEs 
• Conduct IGA 
• Collect acne lesion counts 
• Collect Acne Patient Self-Questionnaire 
• Assess LSRs 
• Collect photographs (selected sites) 
• Review compliance/weigh tubes and dispense drug and diary  
8.6 
Week 8 (+/-4 days) 
• Collect concomitant medication information 
• Conduct a symptom-directed physical exam 
• Collect urine pregnancy for women of childbearing potential 
• Measure vital signs 
• Review and record AEs 
• Conduct IGA 
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• Collect acne lesion counts 
• Collect Acne Patient Self-Questionnaire 
• Assess LSRs 
• Collect photographs (selected sites) 
• Review compliance/weigh tubes and dispense drug and diary 
8.7 
Week 12 (+/-4 days) Study Exit or Early Termination Visit 
• Collect concomitant medication information 
• Measure vital signs 
• Review and record AEs 
• Conduct a complete physical exam 
• Measure weight  
• Collect a 12-lead ECG 
• Draw blood samples for laboratory tests. Include serum pregnancy test for women of 
childbearing potential. 
• Conduct Investigator Global Assessment 
• Conduct acne lesion counts 
• Collect Acne Patient Self-Questionnaire 
• Assess LSRs 
• Collect photographs (selected sites) 
• Review compliance/weigh tubes and collect all study medication and diary 
8.8 
Unscheduled Visits 
Additional visits may be scheduled as necessary to ensure the safety and well-being of subjects 
who experience AEs. Laboratory evaluations, if necessary, will be collected and analyzed using 
the central laboratory for this study. Data will be recorded in the eCRF. 
9 
DETAILS OF ASSESSMENTS 
Parental assistance for study drug application and study conduct procedures may be needed for 
younger subjects qualifying for study participation. 
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9.1 
Screening Assessments 
9.1.1 
Demographics  
At the screening visit, demographic information including age, gender, race, Fitzpatrick Skin 
Type (Table 1) and ethnicity will be collected and recorded on the eCRF for each subject.  
Table 1: 
Fitzpatrick Skin Type 
Fitzpatrick Skin Type 
Definition 
I 
Burns easily, rarely tans 
II 
Burns easily, tans minimally 
III 
Burns moderately, tans gradually 
IV 
Burns minimally, tans well 
V 
Rarely burns, tans profusely 
VI 
Never burns, deeply pigmented 
9.1.2 
Medical History 
A complete medical history will be collected as part of the screening assessment and include all 
clinically relevant past or coexisting medical conditions or surgeries. The medical history will be 
updated prior to treatment on Baseline/Day 1, should new findings emerge after the screening 
visit. Findings will be recorded in the eCRF. 
9.1.3 
Disease Specific Information 
Information on the subject’s acne vulgaris will be collected as part of the screening assessment 
and include the date of onset of acne, anatomical areas affected at baseline, and past treatments 
used for acne vulgaris. Information will be recorded in the eCRF.  
9.2 
Assessment of Efficacy 
9.2.1 
Investigator Global Assessment 
The IGA is a static assessment of acne severity (Table 2) on the face only and will be conducted 
for each subject by the Investigator or designee prior to assessing lesion counts or conducting the 
LSR assessment. Where possible, the same efficacy assessor should assess acne severity on the 
same subject at all visits. Individuals performing the IGA will be trained and certified prior to 
conducting any assessments on the study. IGA grades will be entered into the eCRF.  
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Table 2: 
Investigator Global Assessment 
Investigator Global Assessment 
Grade 
Description 
0 
Clear; normal, clear skin with no evidence of acne vulgaris 
1 
Almost clear; Rare non-inflammatory lesions present, with rare non-inflamed papules (papules 
must be resolving and may be hyperpigmented, though not pink-red) 
2 
Mild; some non-inflammatory lesions are present, with few inflammatory lesions (papules/pustules 
only; no nodulocystic lesions) 
3 
Moderate; non-inflammatory lesions predominate, with multiple inflammatory lesions evident: 
several to many comedones and papules/pustules, and there may or may not be one small 
nodulocystic lesions 
4 
Severe; Inflammatory lesions are more apparent, many comedones and papules/pustules, there may 
or may not be a few nodulocystic lesions 
9.2.2 
Acne Lesion Count 
The investigator/designee will perform a count of inflammatory lesions (papules, pustules and 
nodules) and non-inflammatory lesions (open and closed comedones) and will be conducted after 
the IGA assessment is completed. Lesion counts are confined to the face (including forehead, 
nose, cheeks, and chin) and exclude submental lesions. Where possible, the same efficacy 
assessor should perform all lesion count assessments on the same subject at all visits. 
Individuals performing the acne lesion counts will be trained and certified prior to conducting 
any assessments on the study. Lesion counts will be entered into the eCRF. 
9.3 
Other Assessments 
9.3.1 
Photographs 
Photographs of the face will be collected for all subjects, who have provided consent, at a subset 
of the study sites participating in this study.  
Subjects will have full face and side view photographs taken and anonymized prior to Sponsor 
use. 
Study sites selected for photography will be trained and receive standardized photographic 
equipment by a centralized photographic vendor. Photographs will be electronically transferred 
from the site to the vendor.  
At the end of the study, the site will receive an electronic file of all subject photographs for 
archiving.  
The central photography vendor will tabulate and transfer all subject photos to the Sponsor 
during the course of the study. 
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9.3.2 
Acne Patient Self-Questionnaire 
Subjects will be asked to complete Acne Patient Self-Questionnaire. The questionnaire is paper-
based and will be completed by subjects during clinic visits (see Appendix 2). Subject responses 
will be entered in the eCRF by the study site and the completed questionnaires kept as part of the 
subject’s source document. Study site staff must review all forms to ensure complete responses 
prior to a subject leaving the study site.  
9.4 
Assessment of Safety 
9.4.1 
Physical Examination 
A complete physical examination will be conducted at screening and Week 12 or Early 
Termination visits and cover general appearance, dermatological, head, ears, eyes, nose, throat, 
respiratory, cardiovascular, abdominal, neurological, musculoskeletal, and lymphatic body 
systems. Height and weight will be recorded as part of the screening physical exam and only the 
subject’s weight will be recorded with the end of study physical exam. A symptom-directed 
physical exam may be performed at subsequent visits as needed. Following baseline, any new 
findings or findings that have worsened in severity should also be recorded as an AE.  
Physical exam findings will be recorded in the eCRF. 
9.4.2 
Vital Signs 
Vital signs, including body temperature, respiratory rate (breath per minute), pulse (beats per 
minute), and blood pressure (mmHg), will be obtained with the subject in the seated position, 
after sitting for at least 5 minutes. Any abnormal findings which are new or worsened in severity 
and clinically significant, in the opinion of the Investigator, will be recorded as an AE.  
Vital sign measurements will be recorded in the eCRF. 
9.4.3 
ECGs 
12-lead ECG measurements will be obtained in all subjects. The subject should rest quietly for at 
least 5 minutes in a supine position prior to ECG collection. The ECG should be obtained either 
prior to the time of blood collection, or at least 15 minutes afterwards.  
At screening, the Investigator will use the machine-read ECG to determine subject eligibility. 
The medical monitor may be consulted if needed for interpretation of ECGs. 
All study sites will be supplied with standardized, validated digital 12-lead ECG (12-lead at 
25 mm/sec reporting rhythm, ventricular rate, the RR interval, the PR interval, QRS duration, QT 
and QTcF intervals) equipment capable of recording, storing, and printing producing high 
resolution 12-lead ECG data by the central laboratory. Study sites will be trained on the use of 
the equipment prior to study start.  
Machine-read ECG recordings will be collected and analyzed centrally. Data will be transferred 
electronically to the database. 
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9.4.4 
Laboratory Evaluations  
Laboratory tests will be collected to evaluate safety in all study subjects and analyzed using a 
central laboratory. Labs will be collected per the Schedule of Visits and Procedures (see 
Appendix 1) or more frequently as clinically indicated. Laboratory samples are to be shipped on 
the same day as collected. No more than 4 mL/kg total will be collected over an 8 week period in 
subjects under legal adult age. Laboratory tests are described below.  
Hematology: hematocrit, hemoglobin, red blood cell (RBC) count, white blood cell count and 
differential (%), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin 
concentration (MCHC), mean corpuscular volume, platelet count, absolute neutrophils, absolute 
lymphocytes, absolute monocytes, absolute eosinophils, and absolute basophils. RBC 
morphology should be performed if indicated. 
Chemistry:  sodium, potassium, chloride, calcium, phosphorus, bicarbonate, uric acid, blood urea 
nitrogen (BUN), creatinine, total protein, albumin, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase, bilirubin (total and direct), and glucose (fasting or 
non fasting). 
Serum pregnancy testing will be performed at the screening and Week 12 (study exit) or Early 
Termination visits. Urine pregnancy testing (beta human chorionic gonadotropin [β-hCG]) will 
be performed at Baseline/Day 1, and the Weeks 4 and 8 visits for all females unless post-
menopausal/sterile.  
Urinalysis:  pH, specific gravity, protein, glucose, ketones, bilirubin, blood, nitrite, urobilinogen, 
leukocyte esterase. A microscopic examination of urine will be performed if clinically indicated 
(e.g. a positive dipstick for protein, blood, leucocyte esterase) in the opinion of the Investigator 
based on the findings of the urinalysis or clinical signs and symptoms. Any new or worsened 
clinically significant laboratory result is to be recorded as an AE after study drug dosing. 
Screening laboratory values must be reviewed by the Investigator prior to subject enrollment. 
Subjects will be screen failed for clinically significant laboratory values. Screening laboratory 
tests may be repeated one time in order to confirm out of range results clinical significance at the 
discretion of the investigator.  
The central laboratory must be used for any laboratory testing required for a subject during study 
participation, including laboratory testing needed for unscheduled visits. If an immediate result is 
required to adequately care for a subject, a duplicate sample may be submitted to a local lab. 
Clinically significant laboratory results must be recorded as an AE, preferably as a diagnosis 
rather than individual test results. Any subject who has a clinically significant laboratory test 
result will be evaluated by the Investigator, and will be treated and/or followed up until the value 
returns to clinically acceptable level, in the opinion of the investigator. 
9.4.5 
 
Local Skin Reactions (LSRs) 
All subjects will be assessed for LSRs, on the face, at each visit. LSRs include burning/stinging, 
pruritus, erythema, dryness and peeling. Each LSR will be scored as 0 (None), 1 (Mild), 
2 (Moderate) or 3 (Severe). LSRs observed on a visit day will not be recorded as adverse events 
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unless scored as 3 (Severe). Local skin reactions experienced by the subject in between study 
visits are to be recorded as an AE.  
Burning/stinging and pruritus will be assessed by the subject (Table 3) and erythema, dryness 
and peeling will be assessed by the Investigator/designee (Table 4). Subjects will be read the 
definition of each subject-assessed LSR and asked to select the appropriate definition. The 
corresponding score will be assigned by the site and entered in the eCRF. 
Table 3: 
Subject Assessed Local Skin Reactions 
Score 
Grade 
Burning/Stinging 
Pruritus 
0 
None 
No stinging/burning 
No pruritus 
1 
Mild 
Slightly warm, tingling sensation; not 
really bothersome 
Occasional, slight itching/scratching 
2 
Moderate 
Definite warm; tingling/stinging sensation 
that is somewhat bothersome 
Intermittent itching/scratching which does 
not disturb sleep 
3 
Severe 
Hot, tingling/stinging sensation that has 
caused definite discomfort 
Bothersome itching/scratching which 
disturbs sleep 
Table 4: 
Investigator Assessed Local Skin Reactions 
Score 
Grade 
Erythema 
Dryness 
Peeling 
0 
None 
None 
None 
None 
1 
Mild 
Slight erythema: very light-
pink 
Perceptible dryness with no 
flakes or fissure formation 
Mild diffuse peeling 
2 
Moderate 
Dull red, clearly 
distinguishable 
Easily noted dryness and 
flakes but no fissure 
formation 
Moderate diffuse peeling 
3 
Severe 
Deep/dark red 
Easily noted dryness with 
flakes and fissure formation 
Moderate to prominent, 
dense peeling 
9.4.6 
Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence associated with the use of 
a study drug in humans, whether or not considered drug related. An AE can, therefore, be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease 
temporally associated with the use of the study drug, whether or not related to the investigational 
product.  
AEs will be monitored throughout the study. Subjects will be instructed to inform the 
Investigator and/or study staff of any AEs. At each visit, subjects will be asked about AEs in a 
non-specific manner using open-ended questions so as not to bias the response (e.g., How have 
you been since the last visit?). Specific inquiry regarding reported AEs will be conducted when 
applicable. All AEs will be documented and recorded in the subject’s eCRF. 
Any subject who has an AE (serious or non-serious) or clinically significant abnormal laboratory 
test value will be evaluated by the Investigator, and will be treated and/or followed up until the 
symptoms or values return to normal or to clinically acceptable levels, as judged by the 
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Investigator. A physician, either at clinical site, or at a nearby hospital emergency room, will 
administer treatment for any serious adverse events (SAEs), if necessary. When appropriate, 
medical tests and examinations will be performed to document resolution of event(s). 
9.4.6.1 Reporting 
Only AEs that occur during or following study treatment with the study drug will be reported in 
the AE section of the eCRF. Events recorded prior to study treatment with the drug will be 
reported in the Medical History section of the eCRF as appropriate. All AEs occurring during the 
course of the study will be individually recorded in the eCRF. A condition that is present prior to 
administration of study drug and that worsens after administration of study drug should be 
reported as an AE. Information regarding the onset, duration, severity, action taken, outcome, 
and relationship to study drug will be recorded.  
New or worsening abnormal laboratory values and/or vital signs are to be recorded as AEs if 
they are considered to be of clinical significance by the Investigator or meet the criteria of an 
SAE as described in Section 9.4.7. 
Unless a diagnosis is available, signs and symptoms must be reported as individual AEs in the 
eCRF; a diagnosis is preferred. 
The severity of an AE will be designated as mild, moderate or severe. The term “severe” is used 
to describe the intensity of an adverse event; the event itself, however, may be of relatively 
minor clinical significance (e.g. ‘severe’ upper respiratory infection). Severity is not the same as 
“serious”. Seriousness of AEs is based on the outcome/action of an AE. (See Section 9.4.7.) 
The relationship of the AE to the study treatment should be determined by the Investigator and 
will be based on the following two definitions: 
Not related:  An AE is defined as “not related” if the AE is not judged to be associated with the 
study drug and is attributable to another cause 
Related:  An AE is defined as “related” where a causal relationship between the event and the 
study drug is a reasonable possibility (possibly or probably related). A reasonable causal 
relationship is meant to convey that there are facts (e.g., evidence such as dechallenge/ 
rechallenge) or other clinical arguments to suggest a causal relationship between the AE and 
study treatment.  
9.4.7 
Serious Adverse Events 
A Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any dose, 
• Results in death 
• Is immediately life-threatening (i.e., in the opinion of the Investigator, the AE places the 
subject at immediate risk of death; it does not include a reaction that, had it occurred in a 
more severe form, might have caused death) 
• Requires inpatient hospitalization or results in prolongation of an existing hospitalization 
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• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect 
• Is an important medical event that may not be immediately life-threatening, result in 
death, or require hospitalization, but may be considered an SAE when, based upon 
appropriate medical judgment, it jeopardizes the subject or may require medical or 
surgical intervention to prevent one of the outcomes listed above 
As soon as the Investigator becomes aware of an AE that meets the criteria for an SAE, the SAE 
should be documented to the extent that information is available. A report must be submitted by 
the study site to the Sponsor or designee within 24 hours. 
Any SAE, regardless of causal relationship, must be reported to the Sponsor immediately (within 
24 hours of the Investigator’s knowledge of the event).  
SAEs will be recorded from the time of informed consent/assent, through to end of the study. If, 
in the opinion of the Investigator, an SAE occurring outside the specified time window, (i.e., 
following subject completion or terminations of the study) is deemed to be drug-related, then the 
event should be reported with 24 hours as outlined above. 
The Investigator should institute any clinically necessary supplementary investigation of SAE 
information. In the case of subject death, any post-mortem findings/reports will be requested. 
9.4.7.1 Reporting of Serious Adverse Events 
All SAEs, as defined by the criteria above, must be reported to the Sponsor or designee using the 
SAE form provided, within 24 hours of the Investigator becoming aware of the event. 
Serious adverse events must be recorded on an SAE form. The minimum information required 
for SAE reporting includes the identity of the PI, site number, subject number, event description, 
SAE term(s), reason why the event is considered to be serious (i.e., the seriousness criteria), and 
PI’s assessment of the relationship of the event to study drug. Additional SAE information 
including medications or other therapeutic measures used to treat the event, and the 
outcome/resolution of the event should also be recorded on the SAE form. 
In all cases, the Investigator should continue to monitor the clinical situation and report all 
material facts relating to the progression or outcome of the SAE. The Investigator may be 
required to provide supplementary information as requested by the Sponsor or its designee. 
When reporting SAEs, the following additional points should be considered: 
• When the diagnosis of an SAE is known or suspected, the Investigator should report the 
diagnosis or syndrome as the primary SAE term, rather than as signs or symptoms; signs, 
symptoms and tests that support the diagnosis should be provided  
• Death should not be reported as an SAE, but as an outcome of a specific SAE, unless the 
event preceding the death is unknown. If an autopsy was performed, the autopsy report 
should be provided; 
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While most hospitalizations necessitate reporting of an SAE, some hospitalizations do not 
require SAE reporting, as follows:  
• Hospitalization for elective or previously scheduled surgery or procedure for a pre-
existing condition that has not worsened after administration of study drug (e.g., a 
previously scheduled ventral hernia repair). SAEs must, however, be reported for any 
surgical or procedural complication resulting in prolongation of the hospitalization; 
• Events that result in hospital stays for observation only of fewer than 24 hours and that do 
not require a therapeutic intervention/treatment (e.g., an emergency room visit for 
hematuria that results in a diagnosis of cystitis and discharge to home on oral antibiotics). 
The Sponsor will process and evaluate all SAEs as soon as the reports are received. For each 
SAE received, the Sponsor will make a determination as to whether the criteria for expedited 
reporting to relevant regulatory authorities have been met.  
The Sponsor will assess the expectedness of each SAE to the study treatment. The current 
Investigator’s Brochure will be used as the reference document to assessed expectedness of the 
event to study drug. 
9.4.8 
Dosing Changes due to AEs 
Dose interruptions are allowed should a subject experience intolerable treatment-related adverse 
events (e.g., pruritis) on study. In cases where the Investigator feels a dose interruption is 
warranted, the subject should be instructed to interrupt study drug application to allow symptoms 
to resolve. Subjects should be instructed to return to the twice daily application regimen within 2 
days of dose interruption.  
Dosing interruptions are to be recorded in the subject diary as a missed dose. 
Study drug must be discontinued if an adverse event is deemed persistent and if continuation of 
study drug would not be in the best interest of the subject.  
Refer to Section 10.3 for further information regarding discontinuation of study drug or early 
withdrawal. 
9.4.9 
Pregnancy 
Should a subject become pregnant during study participation, study drug dosing will be 
discontinued and the subject will be withdrawn from study. The Investigator must perform 
medical assessments as clinically indicated and continue to follow the subject for at least 
4 weeks after delivery. Details for both the mother and baby must be obtained. Pregnancy is not 
itself an AE or SAE; however, maternal/fetal complications or abnormalities will be recorded as 
AEs or SAEs, as appropriate. The Investigator must complete a study-specific pregnancy form 
upon confirmation of a pregnancy. Pregnancy reporting forms will be provided to the study site. 
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10 
STUDY DISCONTINUATIONS 
10.1 
Discontinuation of the Study 
The Sponsor has the right to terminate or to stop the study at any time. Should this be necessary, 
both the Sponsor and the Investigator will ensure that proper study discontinuation procedures 
are completed. The entire study will be stopped if: 
• Evidence has emerged that, in the collective opinion of the Investigators at each site with 
the concurrence of the Sponsor or the sole opinion of the Sponsor, makes the 
continuation of the study unnecessary or unethical 
• The stated objectives of the study are achieved 
• The Sponsor discontinues the development of the study drug 
Regardless of the reason for withdrawal, all data available for the subject at the time of 
discontinuation of follow-up must be recorded in the eCRF. All reasons for discontinuation of 
treatment must be documented. 
10.2 
Early Study Termination of Study Subjects 
The Investigator will make every reasonable effort to keep each subject in the study; however, a 
subject may voluntarily withdraw from study participation at any time. If the subject withdraws 
consent and discontinues from the study, the Investigator will attempt to schedule an Early 
Termination visit as soon as possible, determine the reason for discontinuation, and record the 
reason in the subject’s study records and in the eCRF.  
If at any time during the study, the Investigator determines that it is not in the best interest of the 
subject to continue, the subject will be discontinued from participation. The Investigator can 
discontinue a subject at any time if medically necessary. The Investigator may discontinue a 
subject’s participation if the subject has failed to follow study procedures or to keep follow-up 
appointments. Appropriate documentation in the subject’s study record and eCRF regarding the 
reason for discontinuation must be completed. 
All subjects who fail to return to the study site for the required follow-up visits will be contacted 
by phone to determine the cause(s) why the subject failed to return for the necessary visit or 
elected to discontinue from the study. If a subject is unreachable by telephone after a minimum 
of two documented attempts (one attempt on two different days), a registered letter will be sent 
requesting that subject contact the site regarding study follow-up.  
Subjects will be discontinued early from the study if any of the following occur: 
• Withdrawal of informed consent (subject’s decision to withdraw for any reason) 
• Any clinical adverse event, laboratory abnormality, or inter-current illness which, in the 
opinion of the Investigator, indicates that continued treatment and/or participation in the 
study is not in the best interest of the subject 
• Death 
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• Serious protocol violation, including persistent noncompliance or subject requiring 
medication or procedures prohibited by the protocol, to allow subjects to receive the 
appropriate medical attention.  
• Discontinuation of the study by the Sponsor 
10.3 
Study Drug Discontinuation 
For subjects who decide to prematurely discontinue study drug treatment, all reasonable efforts 
should be made to obtain all protocol-specified safety assessments and end of study procedures.  
The Investigator should stop study drug treatment in the following instances: 
• Inter-current illness that would, in the judgment of the Investigator, affect assessments of 
clinical status to a significant degree.  
• Any clinical adverse event which is clinically significant and is deemed persistent and 
probably or definitely related to study drug in the judgment of the Investigator. 
• Unacceptable toxicity 
11 
STATISTICAL CONSIDERATIONS 
11.1 
General Statistical Methodology 
All statistical processing will be performed using SAS® unless otherwise stated. No interim 
analyses are planned. Except where noted, all statistical tests will be two-sided and will be 
performed at the 0.05 level of significance.  
Descriptive statistics will be used to provide an overview of the efficacy and safety results. For 
categorical parameters, the number and percentage of subjects in each category will be 
presented. For continuous parameters, descriptive statistics will include n (number of subjects), 
mean, standard deviation (SD), median, minimum and maximum. Appropriate inferential 
statistics will be used for the primary, secondary, and exploratory efficacy variables. 
The primary method of handling missing efficacy data will be the method of Markov Chain 
Monte Carlo (MCMC) multiple imputation.  
Demographic data will be summarized by treatment group using descriptive statistics. Subjects’ 
baseline characteristics related to efficacy analyses will be compared between treatment groups 
to evaluate baseline balance between the treatment arms. 
The number of subjects in each analysis set will be summarized. Reasons for study withdrawal 
during the blinded study will be summarized using frequencies and percentages by treatment 
group. 
The primary method of dichotomizing the IGA score will be to consider a subject a “success” if 
the IGA at a post-baseline visit is 0 or 1 and 2 or more grades lower than at baseline; otherwise 
the subject will be considered a treatment “failure”. 
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A statistical analysis plan (SAP), describing all statistical analyses will be provided as a separate 
document. The SAP will be finalized prior to unblinding of the study treatments.  
11.2 
Populations Analyzed 
Listings and summaries will be provided for all randomized subjects. 
Approximately 700 subjects with acne vulgaris on the face will be randomized, in a 2: 1 fashion, 
to Olumacostat Glasaretil Gel, 5.0% BID, or Olumacostat Glasaretil Gel, Vehicle. Efficacy 
analyses will be performed using the intent-to-treat (ITT) population and the per-protocol (PP) 
population. Safety analyses will be performed using the safety population. 
All subjects who are randomized and dispensed study drug will be included in the ITT 
population.  
All subjects who are randomized, receive at least one confirmed dose of study drug and have at 
least one post-baseline safety assessment will be included in the safety population. 
The PP population will include all subjects in the safety population who complete the Week 12 
evaluation without any significant protocol violations (i.e., any subject or investigator activity 
that could have possibly interfered with the therapeutic administration of the treatment or the 
precise evaluation of treatment efficacy). The PP population will include subjects in the safety 
population who do not meet any of the following criteria: 
• Violated the inclusion/exclusion criteria; 
• Have taken any interfering concomitant medications; 
• Did not attend the Week 12 visit; 
• Have missed both the Week 4 and Week 8 study visits; 
• Have not been compliant with the dosing regimen (i.e. subjects must apply 80−120% of 
the expected applications of study medication during participation in the study); 
• Out of visit window at the Week 12 visit by ±5 days; 
Subjects that discontinue from the study due to an adverse event related to study treatment or 
documented lack of treatment effect will be included in the PP population. Prior to breaking the 
blind, other additional criteria may be added to the list to accommodate for unforeseen events 
that occurred during the conduct of the trial that result in noteworthy study protocol violations. 
11.3 
Primary Efficacy 
Absolute change from baseline to Week 12 in inflammatory and non-inflammatory lesion counts 
will be analyzed using either parametric or non-parametric methods consistent with the statistical 
assumptions required to support the analyses. Specifically, the tests of superiority will be based 
on an ANCOVA with factors of treatment and analysis center and the respective Baseline lesion 
count as a covariate or on ranked data submitted to an ANCOVA with factors of treatment and 
analysis center and the respective Baseline lesion count as a covariate. If the treatment-by-
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analysis center interaction effect is significant at an alpha less than 0.10, then the effect will be 
included in the model; otherwise it will be removed. 
A skewness test, based on the methods presented by J.H. Zar (1984) [14], will be applied to the 
residuals resulting from an ANCOVA. A two-sided p-value for the skewness test significant at 
0.01 will imply the use of the non-parametric method. If a parametric analysis is indicated, the 
results of the parametric analysis will be considered the primary analysis. Should a non-
parametric analysis be indicated, the absolute or percent changes in inflammatory and non-
inflammatory lesions will be rank transformed prior to submitting them to the ANCOVA. 
Results of the rank-transformed analyses then will be considered the primary analysis; however, 
results of the non-ranked transformed analyses will also be presented. 
The proportion of subjects who are dichotomized to success at Week 12 will be analyzed using 
the logistic regression test stratified by analysis center.  
11.4 
Secondary Efficacy 
The percent change from baseline to Week 12 in inflammatory and non-inflammatory lesion 
counts will be analyzed using the same ANCOVA method described for the primary endpoint. 
The proportion of subjects who are dichotomized to success (minimum 2-grade improvement 
from baseline) at Week 12 will be analyzed using the same logistic analysis method described 
for the primary endpoint. 
The following stepwise process will be conducted for testing the secondary efficacy endpoints in 
order to control for multiplicity. These tests will be performed for only the ITT population. The 
testing process will terminate whenever a statistical test for a step is not significant. All 
subsequent tests for the remaining steps will be considered not significant. The order of testing is 
percent change in inflammatory lesion count from baseline to Week 12, percent change in non-
inflammatory lesion count from baseline to Week 12, and the proportion of subjects who are 
dichotomized to success (minimum 2-grade improvement from baseline). 
11.5 
Other Supportive Efficacy Analyses 
The percent change and absolute change from baseline to Weeks 4 and 8 inflammatory and non-
inflammatory lesion counts will be analyzed using the same ANCOVA method described for the 
primary endpoint of absolute change in lesion counts from baseline to Week 12. The inclusion of 
p-values in these efficacy analyses is to assist in characterizing the therapeutic efficacy of the 
active formulation and dosage regimen. No adjustments will be made for multiple comparisons 
for the sportive efficacy analyses. 
Descriptive statistics will be presented for the following parameters by treatment group for both 
the ITT and PP populations: 
• Frequency and percent distributions of the IGA Score at Baseline and Weeks 4, 8, and 12. 
• Frequency and percent distributions of the dichotomized IGA Score at Baseline and 
Weeks 4, 8, and 12. 
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• Descriptive statistics including mean, median, standard deviation, minimum, and 
maximum will be used to summarize inflammatory and non-inflammatory lesion counts 
at Baseline and Weeks 4, 8, and 12.  
• Descriptive statistics including mean, median, standard deviation, minimum, and 
maximum will be used to summarize the absolute and percent change in inflammatory 
and non-inflammatory lesion counts at Weeks 4, 8, and 12. 
• Descriptive statistics including mean, median, standard deviation, minimum, and 
maximum will be used to summarize the Acne Patient Self-Questionnaire assessments at 
Weeks 4, 8, and 12. 
Means, standard deviations and frequency counts (rounded to the nearest whole number) will be 
computed from the multiply imputed MCMC data for the variable. 
11.6 
Pooling Analysis  
The clinical study will be conducted under a common protocol for each investigational site with 
the intention of pooling the data for analysis. Every effort will be made to promote consistency 
in study execution at each investigational site. The study is intended to be conducted in a manner 
such that a minimum of 5 subjects will be enrolled in each treatment arm for any investigator. In 
the event that there are too few subjects in a treatment arm for an investigator, then this 
investigator’s data will be combined to achieve the desired sample size minimum per arm. The 
combining of investigator’s data will be accomplished by taking the investigator with the 
smallest enrollment and combining it with the investigator with the largest. If there is a further 
need to combine data, then the data of the investigator with the second smallest enrollment will 
be combined with the investigator’s data which had the second largest enrollment, and so on. 
This process will continue for all investigators who did not have a minimum of 5 subjects per 
active treatment arm. The process of combining investigator data that have insufficient subjects 
per treatment arm will result in redefining the groups of investigators for the purposes of 
statistical analyses. These combined groups will be referred to as “analysis centers” in the 
statistical analyses based on ANCOVA and stratified logistic testing.  
Prior to investigating the treatment effect within the analysis centers, the magnitude of the site 
mail effect will be investigated to determine if the main site-to-site variability is such that it 
could mask the analysis center effects. Thus, if computationally possible, a one-way ANCOVA 
(for lesion count variables) or a logistic regression analysis (for dichotomized IGA) with a factor 
of site will be conducted prior to pooling. If the data structure interferes with the logistic 
regression, a descriptive analysis of the site effect will be undertaken. Conclusions appropriate to 
the findings of this step will be presented. 
The consistency of treatment response will be investigated across the analysis centers subsequent 
to combining the data as described above. Statistical tests will be conducted to identify if there 
are extreme analysis centers that could affect the interpretation of common statistical and clinical 
conclusions. An analysis center by treatment interaction will be included in the primary and 
secondary variable analyses to test for parallel treatment effect at an alpha level of 0.10. Change 
from baseline in inflammatory lesions and non-inflammatory lesions will be analyzed with an 
ANCOVA (unranked or ranked) with factors of treatment, analysis center, and treatment by 
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analysis center interaction and the respective baseline lesion count variable as a covariate. For 
the purpose of testing consistency of treatment response, the dichotomized IGA will be analyzed 
with a logistic regression procedure. Further examination will follow for any variables that have 
a significant ANCOVA or logistic regression interaction term. In the event that the ANCOVA or 
logistic regression interaction (referred to henceforth as the “appropriate test”) p-value is less 
than or equal to 0.10, a sensitivity analysis that excludes analysis centers with the extreme 
efficacy result will be performed to determine the robustness of the treatment effect. On the other 
hand, if the outcome of the appropriate test has a p-value greater than 0.10, then the conclusions 
from the pooled data will be considered to be free of the impact of extreme analysis centers. 
The first step in conducting a sensitivity analysis is to identify the extreme analysis center or 
centers that contribute to the statistical significance of the appropriate test. The process involves 
submitting subsets of analysis centers to the appropriate test and observing the appropriate test 
p-value for the subset. Subsets with p-values greater than 0.10 for the appropriate test are 
considered homogeneous. 
The search for an extreme analysis center begins by analyzing all subsets that can be created by 
excluding one analysis center. If one or more of the subsets result in an appropriate test p-value 
greater than or equal to 0.10, then the analysis center excluded from the subset with the largest 
p-value for the appropriate test is deemed to be the extreme analysis center. 
If all appropriate test subset p-values are less than or equal to 0.10, then the process will analyze 
the appropriate test for all subsets that can be created by excluding two analysis centers. If one or 
more of these subsets generate appropriate test p-values larger than 0.10, then the analysis 
centers excluded from the subset with the largest appropriate test p-value are deemed the extreme 
analysis centers. 
Thus, the process of identifying the extreme analysis centers will continue in a stepwise manner 
by first excluding one, then two, then three, etc., analysis centers until the appropriate test 
p-value exceeds 0.10. 
Once the extreme analysis center or centers have been identified, then the treatment p-values of 
the remaining analysis centers will be computed. Inferences will be drawn from the treatment 
p-value, as well as any pertinent observations regarding the extreme analysis center or centers. 
Additionally, it is noted that this process excludes subjects from the analysis in a non-random 
manner and has an unpredictable impact on the power of the treatment effect test. In the event 
that the treatment effect of the remaining subset is not statistically significant, due consideration 
of the post-hoc aspects of the process will be given when the results are interpreted. Conclusions 
will be presented by the sponsor as appropriate to the findings of the sensitivity analysis. 
11.7 
Missing Efficacy Data Imputations 
Lesion Count Variable Missing Data Imputation 
Missing 12 week data will be estimated by multiple imputation and subsequently analyzed. 
Missing lesion count data will be derived for the analysis using the method of Markov Chain 
Monte Carlo (MCMC) multiple imputation which does not rely on the assumption of data 
missing at random. Additionally, the pattern of missing observations in each treatment group 
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cannot influence the missing value estimation in the other because the imputation is being 
conducted independently for each treatment group. 
Multiple imputation and subsequent analysis will involve 4 distinct phases with these principal 
tasks: 
1. 
Calculated the number of missing values to be estimated by MCMC (nmiss) for 12-week 
value. 
2. 
Create a data set of subjects, one for each treatment group, with observed values and those 
needing estimation by MCMC. The missing lesion count values in each data set will be 
filled in using the MCMC method ‘5 x nmiss’ times to generate ‘5 x nmiss’ data sets. The 
resulting data sets for each treatment arm will be combined into one complete data set for 
each imputation. 
Syntax: 
proc mi data=datain out=dataout seed=&seed. Nimpute=5xnmiss <options>; 
  where trtpn=(1, or 2); 
  mcmc chain=multiple; 
  var baseline week4 week8 week12; 
run; 
3. 
For each complete data set, the absolute change in lesion counts for baseline minus the 
12-week value will be computed. Each complete data set will be analyzed as specified for 
the particular analysis. 
4. 
The results from these analyses will be combined into a single inference using SAS PROC 
MIANALYZE. 
A total of 4 random seeds will be needed to impute inflammatory lesion counts and fcnon-
inflammatory lesion counts for the two treatment groups. Those 4 random seeds have been pre-
specified by using a random number generator: 
• Inflammatory Lesion Counts; Olumacostat Glasaretil Gel: Seed= 195361148  
• Inflammatory Lesion Counts; Olumacostat Glasaretil Gel Vehicle: Seed= 2099102059  
• Non-Inflammatory Lesion Counts; Olumacostat Glasaretil Gel: Seed= 325230329  
• Non-Inflammatory Lesion Counts; Olumacostat Glasaretil Gel: Seed= 936128187  
IGA Missing Data Imputation 
A similar procedure will be used for the analyses based on proportion of IGA successes wherein 
the ANCOVA analysis is replaced with a logistic regression analysis. Specifically, missing 
12-week IGA values from which the dichotomized IGA is derived will be estimated by (MCMC) 
which does not rely on the assumption of data missing at random. Additionally, the pattern of 
missing observations in each treatment group cannot influence the missing value estimation in 
the other because the imputation is being conducted independently for each treatment group. 
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The missing 12 week IGA values will be derived for the analysis using the method of Markov 
Chain Monte Carlo (MCMC) multiple imputation. Multiple imputation and subsequent analysis 
will involve 4 principal tasks: 
1. 
Calculate the number of missing values to be estimated by MCMC (nmiss) for 12 week 
value. 
2. 
Create a data set, one for each treatment group, of subjects with observed values and those 
needing estimation by MCMC. The missing IGA values in each data set will be filled in 
using the MCMC method ‘5 x nmiss’ times to generate ‘5 x nmiss’ data sets. The resulting 
data sets for each treatment arm will be combined into one complete data set by imputation. 
Syntax: 
proc mi data=datain out=dataout seed=&seed. Nimpute=5xnmiss <options>; 
  where trtpn=(TRT);   /* Note TRT = [1, 2]; depending on treatment group */ 
; 
  mcmc chain=multiple; 
  var baseline week4 week8 week12; 
run; 
3. 
For each complete data set, the dichotomous success rate (clear or almost clear with a 
2-point change from baseline) will be computed. The 12-week estimated global values will 
be rounded to the nearest integer value prior to evaluating the success rate. Each complete 
data set will be analyzed with a logistic regression with factors of treatment group and 
analysis center. 
4. 
The results from these analyses will be combined into a single inference using SAS PROC 
MIANALYZE. 
A total of 2 random seeds will be needed to impute IGA for the two treatment groups. Those 
2 random seeds have been pre-specified by using a random number generator: 
• IGA; Olumacostat Glasaretil Gel: Seed= 322979853  
• IGA; Olumacostat Glasaretil Gel Vehicle: Seed= 1313477781  
11.8 
Sensitivity Efficacy Analyses 
Sensitivity analyses for absolute change in lesion count 
The first sensitivity analysis for absolute change in lesion count use a repeated measures 
ANCOVA, with treatment, analysis center, and visit (ie, Week 4, Week 8) as independent factors 
and a covariate of baseline lesion count. In this analysis, data from all post-baseline visits will be 
included with no imputation for missing data. 
The second sensitivity analysis will use the model based multiple imputation method to impute 
missing data for the absolute change in lesion counts at Week 12. Although the full details will 
be presented in SAP the Multiple imputation will involve 4 principal tasks: 
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1. 
Calculate the number of missing values (nmiss) for absolute change in lesion count. 
2. 
Missing values will be filled in ‘5 x nmiss’ times to generate ‘5 x nmiss’ complete data 
sets. The imputation model used will be an ANCOVA with factors of treatment group and 
analysis center, and a covariate of baseline lesion count (ie, the imputation model will be 
the same as the analysis model). Appropriate modifications will be made should the 
analysis be based on a non-parametric method. 
3. 
Each complete data set will be analyzed with an ANCOVA with factors of treatment group, 
and analysis center, and a covariate of baseline lesion count. 
4. 
Results from these analyses will be combined into a single inference. 
Sensitivity analyses for IGA 
The first sensitivity analysis for the dichotomized IGA success will use a repeated measures 
logistic regression model (generalized estimating equations), with dichotomized IGA success as 
the dependent variable and treatment, analysis center, and visit (ie, Week 4, Week 8) as 
independent factors. In this analysis, data from all post-baseline visits will be included with no 
imputation for missing data. 
The second sensitivity analysis will use the model based multiple imputation method to impute 
missing data for the dichotomized IGA data. Although the full details will be presented in SAP, 
the multiple imputation will involve 4 principal tasks: 
1. 
Calculate the number of missing values (nmiss) for absolute change in lesion count. 
2. 
Missing values will be filled in ‘5 x nmiss’ times to generate ‘5 x nmiss’ complete data 
sets. The imputation model used logistic regression with factors of treatment group and 
analysis center (ie, the imputation model will be the same as the analysis model). 
3. 
Each complete data set will be analyzed with a logistic regression a factors of treatment 
group and analysis center. 
4. 
Results from these analyses will be combined into a single inference. 
11.9 
Subgroup Analyses 
Subset analyses will be conducted for the ITT populations for the subgroups baseline global 
severity, gender, age, ethnicity and race. Age will be dichotomized to less than the median age of 
subjects and greater than or equal to the median age of subjects. An additional analysis will be 
include with categories of less than 18, 18 to less than the median age and greater than or equal 
to the median age. Subset analyses will be conducted on the variables absolute change from 
baseline in inflammatory lesions and non-inflammatory lesions at Week 12 as well as the 
dichotomized IGA score at Week 12. These analyses will contain only descriptive statistics. 
11.10 Exposure and Compliance 
The extent of exposure to study drug in each treatment group will be summarized by total 
number of days of exposure, total number of applications, number of missed applications and 
number and percentage of subjects who are compliant. A subject will be considered compliant 
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with the dosing regimen if the subject applied 80% to 120% of the expected number of 
applications while enrolled in the study.  
11.11 Adverse Events 
All AEs that occur during the study will be recorded and classified on the basis of Medical 
Dictionary for Regulatory Activities (MedDRA) terminology. Treatment-emergent AEs 
(TEAEs) are defined as AEs with an onset on or after the date of the first study drug application. 
Adverse events noted prior to the first study drug administration that worsen after baseline will 
also be reported as AEs and included in the summaries.  
All information pertaining to an AE noted during the study will be listed by subject, detailing 
verbatim term given by the PI or designee, preferred term, system organ class (SOC), onset date, 
resolution date, severity, seriousness, action taken, outcome and drug relatedness. The event 
onset will also be shown relative (in number of days) to date of first application.  
Treatment-emergent AEs will be summarized by treatment group, the number of subjects 
reporting a TEAE, SOC, preferred term, severity, relationship to study drug (causality), and 
seriousness. When summarizing AEs by severity and relationship, each subject will be counted 
once within a system organ class or a preferred term by using the event with the highest severity 
and greatest relationship within each classification. 
Serious AEs will be summarized by treatment group, severity and relationship to study drug, and 
individual SAEs will be listed by subject. In addition, a list of subjects who prematurely 
discontinue from the study due to an AE will be provided. 
11.12 Local Skin Reactions 
Local Skin Reactions (LSRs) include erythema, peeling, dryness, burning/stinging and pruritus. 
These will be scored as 0 (None), 1 (Mild), 2 (Moderate) or 3 (Severe). LSRs will be 
summarized by treatment group and visit using descriptive statistics. A by-subject listing of 
subjects with any LSR 3 or higher will be presented. 
11.13 Other Safety Data 
Laboratory test results will be summarized descriptively at Baseline and Week 12. Additionally, 
shifts from baseline to Week 12 in laboratory test results based on normal ranges will be 
summarized with descriptive statistics. Individual laboratory test results will be presented in a 
by-subject listing. Any clinically significant laboratory abnormalities will be captured as adverse 
events.  
Vital signs will be presented by treatment group and visit as observed values and changes from 
Baseline using descriptive statistics. 
Medical histories will be coded using the MedDRA dictionary and presented in a by-subject 
listing. 
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Descriptive statistics by treatment group and visit will be provided for the following ECG 
parameters: heart rate (HR), RR duration, QRS duration, PR duration, QT duration and QTc 
duration. Change from Baseline in ECG abnormalities will be summarized using shift tables at 
the Week 12 visit.  
Concomitant medications will be coded using the WHO-Drug dictionary. Concomitant 
medications will be summarized by treatment, drug class, and preferred term.  
Physical examination data will be presented in a by-subject listing.  
11.14 Sample Size Determination 
The sample size for this study was based on estimates from the DRM01B-ACN02 study 
observed Week 12 results. Estimates were combined for all three active treatment groups as well 
for the two vehicle groups. All power calculations were performed with nQuery Advisor Version 
7.0 for a two-sided test at alpha = 0.05. 
For inflammatory lesion change a sample size of 300 Olumacostat Glasaretil Gel and 
150 Olumacostat Glasaretil Gel Vehicle subjects has at least 95% power to detect a statistically 
significant difference with a significance level of 0.05 using the estimated absolute change from 
baseline in treatment means of -15.21 and -9.7 for Olumacostat Glasaretil Gel versus its vehicle, 
respectively, with a standard deviation of 11.00. 
For non-inflammatory lesion change a sample size of 450 Olumacostat Glasaretil Gel and 
225 Olumacostat Glasaretil Gel Vehicle subjects has 95% power to detect a statistically 
significant difference with a significance level of 0.05 using the estimated absolute change from 
baseline in treatment means of -14.73 and -9.70 for Olumacostat Glasaretil Gel versus its 
vehicle, respectively, with a standard deviation of 16.72. 
The success rate for dichotomized IGA is estimated to be 20.5% in the 5.0% BID subjects and 
9.6% in vehicle subjects. A sample size of 444 Olumacostat Glasaretil Gel and 222 Olumacostat 
Glasaretil Gel Vehicle will have 95% power to detect a statistically significant difference in 
proportions of successes. These calculations were performed with nQuery Advisor Version 7.0 
for a two-sided continuity corrected chi-square test at alpha = 0.05. 
To allow for a slight loss in power due to dropouts and withdrawals as well as to accommodate 
sufficient power in all three co-primary variables, a sample of 700 subjects randomized to 2 to 1 
for Olumacostat Glasaretil Gel (n=467) and vehicle (n=233), respectively, will be enrolled in the 
trial. 
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12 
STUDY ADMINISTRATION 
12.1 
Compliance with the Protocol  
The study shall be conducted as described in this protocol. All revisions to the protocol must be 
prepared by the Sponsor. The Investigator will not implement any deviation or change to the 
protocol without prior review and documented approval/favorable opinion from the IRB/EC of 
an Amendment, except where necessary to eliminate an immediate hazard(s) to study subjects. 
Any significant deviation must be documented and submitted to the: IRB/EC; the Sponsor or 
designee; and, if required, Regulatory Authority (ies). 
Documentation of approval signed by the chairperson or designee of the IRB(s)/EC(s) must be 
sent to the Sponsor and/or designee. 
12.2 
Informed Consent Procedures 
The Informed Consent Form (ICF) and Assent Forms for subjects under legal adult age must 
include all elements required by ICH/GCP and applicable regulatory requirements, and must 
adhere to GCP and to the ethical principles that have their origin in the Declaration of Helsinki. 
For subjects under legal adult age, both parents or legal representative may be required to sign 
informed consent as applicable. Assent to participate in a clinical trial applies to all subjects who 
are not legal adult subjects (in the state or location in which they are participating) and is defined 
as a child’s affirmative agreement to participate in research. Permission of the minor subject’s 
parent or legal guardian must also be obtained in compliance with part 50, subpart B of the Code 
of Federal Regulations and must include the elements of informed consent as described in 
Section 50.55 [15] and according to the regulations where the study is being conducted. 
Appropriate ICFs and assent forms will be provided according to local law/regulations. If a 
subject reaches legal adult age during the course of the trial, an adult ICF will be signed.  
The ICF and Assent Forms must also include a statement that the Sponsor and regulatory 
authorities have direct access to subject records. Prior to the beginning of the study, the 
Investigator must have the IRB/EC’s written approval/favorable opinion of the written ICF, 
Assent Forms and any other information to be provided to the subjects. 
The Investigator must provide the subject or legally acceptable representative with a copy of the 
consent form and written information about the study in the language in which the subject is 
most proficient. The language must be nontechnical and easily understood. The Investigator 
should allow time necessary for subject or subject’s legally acceptable representative to inquire 
about the details of the study, then the ICF must be signed and personally dated by the subject or 
the subject’s legally acceptable representative, by the Investigator and by the person who 
conducted the informed consent discussion as required by local law. The subject or legally 
acceptable representative should receive a copy of the signed ICF and any other written 
information provided to study subjects prior to subjects participation in the study. This also 
applies to Assent Forms. All subjects and/or the legally acceptable representative (i.e., parents or 
guardian) will be provided with a contact address where they may obtain further information 
regarding the study. 
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The ICF, Assent Forms and any other information provided to the subjects or the subject's 
legally acceptable representative, should be revised whenever important new information 
becomes available that is relevant to the subjects consent, and should receive IRB/EC approval/ 
favorable opinion prior to use. The Investigator or designee should fully inform the subject or the 
subject's legally acceptable representative of all pertinent aspects of the study and of any new 
information relevant to the subjects willingness to continue participation in the study. This 
communication to the subject should be documented in the source documents.  
During a subject’s participation in the study, any updates to the consent or assent forms and any 
updates to the written information will be provided to the subject. 
12.3 
Study Documentation and the Electronic Case Report Form 
The Investigator is responsible for ensuring that data are properly recorded in the eCRFs and on 
related documents. All entries must be supported by the subject’s medical records or source 
documents. The Investigator is to ensure that the observations and findings are recorded correctly 
and completely. 
All Investigator observations/assessments must be reported in the eCRF. The original reports and 
any traces and films must be reviewed, signed and dated and retained by the Investigator for 
future reference. 
The Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the investigation on each 
individual treated with the investigational product or entered as a control in the investigation. 
Data reported in the eCRFs that are derived from source documents must be consistent with the 
source documents or the discrepancies must be explained. 
The Investigator must certify that the data are complete and accurate at the time the subject ends 
the study or as instructed by the Sponsor or designee by applying an electronic signature to the 
eCRF study completion page. 
12.4 
Study Monitoring 
The Sponsor or designee will be responsible for the monitoring of the study. Study monitors will 
contact and visit the Investigators at regular intervals throughout the study. The study monitor 
will verify adherence to the protocol and completeness, consistency and accuracy of the data by 
comparing subjects’ medical records with entries in the eCRF. The study monitor must be 
allowed access to laboratory test reports and other subject records that are needed to verify the 
entries on the eCRF. The Investigators will allow the study monitor to inspect the various records 
of the study (eCRFs and other pertinent data), provided that subject confidentiality is maintained 
in accordance with local requirements. These records, and other relevant data, may also be 
reviewed by appropriate qualified personnel independent from the Sponsor or designee, who is 
appointed to audit the study. Subject confidentiality will be maintained at all times. 
The Investigators agree to co-operate with the study monitor to ensure that any problems 
detected in the course of the monitoring visits are resolved. 
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12.5 
Retention of Study Documentation 
The Investigator must retain study drug disposition records, copies of eCRFs and all study-
related source documents for the maximum period required by applicable regulations and 
guidelines, or Institution procedures, or for the period specified by the Sponsor, whichever is 
longer. The Investigator must contact the Sponsor prior to destroying any records associated with 
the study. 
If the Investigator withdraws from the study (e.g., relocation, retirement), the records will be 
transferred to a mutually agreed upon designee (e.g., another Investigator, IRB/Ethics 
Committee). Notice of such transfer will be given in writing to the Sponsor or designee. 
If the Investigator cannot guarantee this archiving requirement for any or all the documents at the 
investigational site, arrangements must be made between the Investigator and the Sponsor, to 
store these in a secure archive facility outside the site; they can therefore be returned to the 
Investigator in case of a regulatory audit. Where source documents are required for the continued 
care of the subject, appropriate copies should be made for storing outside the site. 
Following the study close-out visit data will be provided to the Investigator to store with the 
Investigator’s study file for archiving purposes. 
13 
ACRONYMS AND DEFINITIONS 
13.1 
Acronyms 
The acronyms listed below are a non-exhaustive list of those commonly used in Dermira study 
documents. Not all acronyms listed below are used within this document. 
Abbreviation 
Definition 
ACC 
acetyl-coenzyme A carboxylases 
AE 
adverse event(s) 
ALT 
alanine amino-transferase 
ANCOVA 
analysis of covariance 
AR 
adverse reaction(s) 
AST 
aspartate amino-transferase 
BID 
twice daily 
BUN 
blood urea nitrogen 
CFR 
code of federal regulations 
CMH 
Cochran-Mantel-Haenszel 
CRO 
clinical research organization 
eCRF 
electronic case report form 
ET 
early termination 
F 
Fahrenheit 
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Abbreviation 
Definition 
FDA 
food and drug administration 
GCP 
good clinical practice 
HCT 
hematocrit 
HGB 
hemoglobin 
ICF 
informed consent form 
ICH 
International Conference on Harmonization  
IEC 
independent ethics committee 
IGA 
Investigator’s global assessment 
IRB 
institutional review board 
ITT 
intent-to-treat 
IV 
Intravenous 
LDH 
lactate dehydrogenase 
LOCF 
last observation carried forward 
LSR 
local skin reactions 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
medical dictionary for regulatory activities 
NSAID 
non-steroidal anti-inflammatory drug 
PP 
per protocol 
QD 
once daily 
RBC 
red blood cells 
SAS 
statistical analysis software 
SSAR 
serious suspected adverse reaction(s) 
TG 
Triglycerides 
TK 
toxicokinetic  
UPT 
urine pregnancy test 
US 
united states 
WBC 
white blood cells 
WOCBP 
women of childbearing potential 
β-hCG 
beta-human chorionic gonadotropin 


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14 
REFERENCES 
1. 
Thiboutot D. Regulation of human sebaceous glands. J Invest Dermatol. 2004;123:1–12. 
2. 
Janiczek-Dolphin N, Cook J, Thiboutot D, Harness J, Clucas A. Can sebum reduction 
predict acne outcome? Br J Dermatol. 2010;163:683–688. 
3. 
Nelson AM, Zhao W, Gilliland KL, Zaenglein AL, Liu W, Thiboutot DM. Neutrophil 
gelatinase-associated lipocalin mediates 13-cis retinoic acid-induced apoptosis of human 
sebaceous gland cells. J Clin Invest. 2008;118:1468–1478. 
4. 
Tong L, Harwood HJ Jr. Acetyl-coenzyme A carboxylases: versatile targets for drug 
discovery. J Cell Biochem. 2006;99(6):1476–1488. 
5. 
Kim KH. Regulation of mammalian acetyl-coenzyme A carboxylase. Annu Rev Nutr. 
1997;17:77–99. 
6. 
Harwood HJ Jr. Treating the metabolic syndrome: acetyl-CoA carboxylase inhibition. 
Expert Opin Ther Targets. 2005;9(2):267–281. 
7. 
Tong L. Acetyl-coenzyme A carboxylase: crucial metabolic enzyme and attractive target 
for drug discovery. Cell Mol Life Sci. 2005;62(16):1784–1803. 
8. 
McGarry JD, Brown NF. The mitochondrial carnitine palmitoyltransferase system. From 
concept to molecular analysis. Eur J Biochem. 1997;244(1):1–14. 
9. 
McCune SA, Harris RA. Mechanism responsible for 5-(tetradecyloxy)-2-furoic acid 
inhibition of hepatic lipogenesis. J Biol Chem. 1979;254:10095–10101. 
10. Arbeeny CM, Meyers DS, Bergquist KE, Gregg RE. Inhibition of fatty acid synthesis 
decreases very low density lipoprotein secretion in the hamster. J Lipid Res. 
1992;33(6):843–851. 
11. Parker RA, Kariya T, Grisar JM, Petrow V. 5-(Tetradecyloxy)-2-furancarboxylic acid and 
related hypolipidemic fatty acid-like alkyloxyarylcarboxylic acids. J Med Chem. 
1977;20:781–91. 
12. Fukuda N, Ontko JA. Interactions between fatty acid synthesis, oxidation, and 
esterification in the production of triglyceride-rich lipoproteins by the liver. J Lipid Res. 
1984;25(8):831–842. 
13. Triscari J, Sullivan AC. Anti-obesity activity of a novel lipid synthesis inhibitor. Int J Obes. 
1984;8 Suppl 1:227–239. 
14. Zar, JH (1984), Biostatistical analysis, 2nd ed. Englewood Cliffs, New Jersey: P 118-119 
15. 21 CFR §50.55.


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15 
APPENDIX 1 – SCHEDULE OF EVENTS 
Visit 
Screening
Day 
-35 to -1 
Baseline/
Day 1 
Week 1 
(+/- 2 day) 
Phone 
Contact 
Week 4 
(+/- 4 days) 
Week 8 
(+/- 4 days) 
Exit / Early 
Termination 
Week 2  
(+/- 2 day) 
Week 12 
(+/- 4 days) / ET 
Informed Consent/Assent 
X 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
Complete Physical Exam, Heightc, Weight 
X 
 
 
 
 
 
X 
Symptom-directed Physical Exam 
 
X 
X 
 
X 
X 
 
Vital Signs 
X 
X 
X 
 
X 
X 
X 
Adverse Events 
 
Xa 
X 
X 
X 
X 
X 
Local skin reactions 
 
X 
X 
 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECGs 
X 
 
 
 
 
 
X 
Safety labs: Serum Chemistry, Hematology, 
Serum Pregnancy, Urinalysis 
X 
 
 
 
 
 
X  
Urine Pregnancy Test  
 
X 
 
 
X 
X 
 
Investigator Global Assessment 
 
X 
 
 
X 
X 
X 
Acne Patient Self-Questionnaire 
 
X 
 
 
X 
X 
X 
Acne Lesion Counts 
 
X 
 
 
X 
X 
X 
Photographsb 
 
X 
 
 
X 
X 
X 
Dispense Study Medication/Diary 
 
X 
X 
 
X 
X 
 
Study Medication Compliance 
 
 
X 
 
X 
X 
X 
a 
AEs to be collected after the first dose of study drug is applied. 
b 
Selected sites only. 
c  Height not required at Week 12. 


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16 
APPENDIX 2 – ACNE PATIENT SELF- QUESTIONNAIRE 
1. Over the past 7 days, rate how oily your face looked: 
• Asked at BL, wk 4, 8, 12, and OLE 12, 24, 36 
Not at all oily
 
Slightly oily
 
Moderately oily
 
Very oily
 
Extremely oily
 
 
2. Over the past 7 days, rate how your face looked overall as the result of your acne: 
• Asked at BL, wk 4, 8, 12, and OLE 12, 24, 36 
 
 0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
            Bad 
 
 
 
 
 
 
 
 
          Excellent 
3. Overall, how would you rate your acne now as compared to before starting the study 
treatment? 
• Only asked at wk 4, 8, 12, and OLE 12, 24, 36 
Very much improved
 
Moderately improved
 
No difference
 
Moderately worse
 
Very much worse
 
4. Over the past 7 days, how self-conscious did you feel about the way your face looks 
because of your facial acne? 
• Asked at BL, wk 4, 8, 12, and OLE 12, 24, 36 
1. Not at all self-conscious 
2. Slightly self-conscious 
3. Moderately self-conscious 
4. Very self-conscious 
5. Extremely self-conscious 
 
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5. Over the past 7 days, how insecure did you feel about the way your face looks 
because of your facial acne? 
• Asked at BL, wk 4, 8, 12, and OLE 12, 24, 36 
1. Not at all insecure 
2. Slightly insecure 
3. Moderately insecure 
4. Very insecure 
5. Extremely insecure 
 
6. Over the past 7 days, how often did you avoid interactions with other people because 
of your facial acne? 
• Asked at BL, wk 4, 8, 12, and OLE 12, 24, 36 
1. Never 
2. Rarely 
3. Some of the time 
4. Most of the time 
5. All of the time 
 
7. Over the past 7 days, how embarrassed were you by the way your face looked 
because of your facial acne? 
• Asked at BL, wk 4, 8, 12, and OLE 12, 24, 36 
1. Not at all embarrassed 
2. Slightly embarrassed 
3. Moderately embarrassed 
4. Very embarrassed 
5. Extremely embarrassed 
 
8. Over the past 7 days, how sad were you by the way your face looked because of you 
facial acne? 
• Asked at BL, wk 4, 8, 12, and OLE 12, 24, 36 
1. Not at all sad 
2. Slightly sad 
3. Moderately sad 
4. Very sad 
5. Extremely sad 
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D R M 0 1 B- A C N 0 4 
0 6 Oct o ber 2 0 1 6 
Pa ge 5 2 
C o nfi de ntial 
O n a scale of 1 t o 5 ( 1 = Very u ns atisfie d, 5 = Very s atisfie d ), h o w satisfie d were y o u 
wit h eac h of t he f oll o wi n g? 
•  T o be aske d j ust at wk 1 2 
 
1  –  V er y  
U ns atisfi e d  
2  –  
U ns atisfi e d  
3  –   
N e utr al  
4  –  
S atisfi e d  
5  –  V er y  
S atisfi e d  
9. 
E as e  of  pr o d uct  a p plic ati o n  
 
 
 
 
 
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1 1. H o w  t h e pr o d uct  f e els o n  my  
s ki n w hil e  a p plyi n g  
 
 
 
 
 
1 2. H o w  w ell  t h e pr o d uct  fits i nt o 
m y  d ail y  s ki n c ar e r o uti n e 
 
 
 
 
 
 

SAP_001.pdf: 
CONFIDENTIAL 
 
 
 
Statistical Analysis Plan for Dermira, Inc. 
Page 1 
Protocol Number: DRM01B-ACN04 
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STATISTICAL ANALYSIS PLAN 
Protocol Number: DRM01B-ACN04 
 
 
 
Study Title: A Randomized, Double-Blind, Vehicle-Controlled, Efficacy and Safety Study 
of Olumacostat Glasaretil Gel in Subjects with Acne Vulgaris 
 
 
 
Development Phase of Study: 3 
 
 
 
Sponsor: Dermira, Inc. 
 
Sponsor Contact: Beth Zib 
 
 
 
Statistical Analysis Plan based on Protocol Version: 06 October 2016 
 
 
 
Statistical Analysis Plan Date: 20 September 2017 
 
Statistical Analysis Plan Version: v1.0 
 
 
 




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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................5 
2. 
INTRODUCTION .................................................................................................................6 
3. 
STUDY OBJECTIVES .........................................................................................................6 
4. 
STUDY DESIGN ...................................................................................................................7 
4.1 Overall Study Design ......................................................................................................7 
4.1.1 
Schedule of Visits and Assessments .................................................................7 
4.1.2 
Method of Assigning Subjects to Treatment Groups ........................................7 
4.1.3 
Blinding .............................................................................................................8 
4.2 Determination of Sample Size ........................................................................................8 
5. 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES .........9 
6. 
EFFICACY AND SAFETY ENDPOINTS .........................................................................9 
6.1 Efficacy Endpoints ..........................................................................................................9 
6.1.1 
Primary Efficacy Endpoints ..............................................................................9 
6.1.2 
Secondary Efficacy Endpoints ........................................................................10 
6.2 Safety Endpoints ...........................................................................................................10 
7. 
STATISTICAL METHODS AND ANALYSIS ................................................................10 
7.1 General Methodology ...................................................................................................10 
7.2 Adjustments for Covariates ..........................................................................................11 
7.3 Handling of Dropouts or Missing Data .........................................................................11 
7.3.1 
MCMC Multiple Imputation ...........................................................................12 
7.3.1.1 
Lesion Count Variable Missing Data Imputation ........................12 
7.3.1.2 
IGA Missing Data Imputation .....................................................12 
7.3.2 
Sensitivity Analyses ........................................................................................13 
7.3.2.1 
Lesion Count Variable Missing Data Imputation ........................13 
7.3.2.2 
IGA Missing Data Imputation .....................................................13 
7.4 Interim Analyses and Data Monitoring ........................................................................13 
7.5 Multicenter Studies .......................................................................................................14 
7.6 Multiple Comparisons/Multiplicity ..............................................................................16 
7.7 Examination of Subgroups ............................................................................................16 
7.8 Analysis Populations .....................................................................................................17 
7.8.1 
Randomized Population ..................................................................................17 
7.8.2 
Intent-to-Treat (ITT) Population .....................................................................17 
7.8.3 
Safety Population.............................................................................................17 


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7.8.4 
Per-Protocol (PP) Population ..........................................................................17 
7.9 Statistical Analysis ........................................................................................................18 
7.9.1 
Baseline Definition ..........................................................................................18 
7.9.2 
Visit Windowing .............................................................................................18 
7.9.3 
Subject Disposition ..........................................................................................19 
7.9.4 
Protocol Deviations .........................................................................................19 
7.9.5 
Demographic and Baseline Characteristics .....................................................19 
7.9.6 
Prior and Concomitant Medications ................................................................20 
7.9.7 
Efficacy Analyses ............................................................................................20 
7.9.7.1 
Primary Efficacy Analyses ..........................................................20 
7.9.7.2 
Secondary Efficacy Analyses ......................................................21 
7.9.7.3 
Other Supportive Efficacy Analyses ............................................22 
7.9.8 
Safety Analyses ...............................................................................................22 
7.9.8.1 
Extent of Exposure .......................................................................22 
7.9.8.2 
Adverse Events ............................................................................24 
7.9.8.3 
Clinical Laboratory Evaluations ..................................................25 
7.9.8.4 
Local Skin Reactions ...................................................................25 
7.9.8.5 
Other Observations Related to Safety ..........................................25 
7.9.8.5.1 
ECG Measurements ..............................................25 
7.9.8.5.2 
Vital Signs ............................................................26 
7.9.8.5.3 
Physical Examination ...........................................26 
8. 
REFERENCES ....................................................................................................................26 
 
 


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1. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE(s) 
Adverse event(s) 
ANCOVA 
Analysis of covariance 
ATC 
Anatomical therapeutic chemical 
ECG 
Electrocardiogram 
ET 
Early termination 
IGA 
Investigator Global Assessment 
ITT 
Intent-to-treat 
IWRS 
Interactive web-based randomization system 
LSMean 
Least squares mean 
LSR 
Local skin reactions 
LSSD 
Least squares standard deviation 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
n 
Number of observations 
N 
Number of subjects (sample size) 
PP 
Per-protocol 
Q1 
25th percentile 
Q3 
75th percentile 
QST 
QST Consultations, Ltd. 
QTc 
QT interval corrected for heart rate 
QTcB 
QT interval corrected for heart rate using Bazett’s formula 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
SAE(s) 
Serious adverse event(s) 
SAP 
Statistical Analysis Plan 
SAS® 
Statistical Analysis System (SAS® Institute Inc., Cary, NC) 
SD 
Standard deviation 
TEAE 
Treatment-emergent adverse event 
TESAE 
Treatment-emergent serious adverse event 
TOFA 
5-(tetradecyloxy)-2-furancarboxylic acid 
WHO-DDE 
World Health Organization Drug Dictionary 
 
 


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2. INTRODUCTION 
Acne arises from a combination of physiological changes in the skin including altered sebaceous 
gland cell differentiation, heightened sebum production, localized bacterial colonization and 
inflammation. Although acne is generally viewed as a benign dermatological disease of 
adolescence, more severe forms may lead to permanent scar formation, with some of these 
patients suffering from psychological injury and significant loss of self-worth. Recent scientific 
advances in the understanding of the complex multi-factorial nature of this common disease offer 
great opportunity for scientific innovation through selective targeting of key elements of the 
disease process. 
Topical agents routinely prescribed for acne, including antibiotics, retinoids and combinations 
thereof, often produce only modest therapeutic benefits and do not affect sebum production. A 
locally-delivered medication that selectively inhibited sebum formation would represent a 
breakthrough advance in reducing the pathogenic influences of sebum overproduction in acne. 
Dermira, Inc. is pursuing the development of olumacostat glasaretil, previously referred to as 
DRM01B, a pro-drug of TOFA (5-(tetradecyloxy)-2-furancarboxylic acid), sarcosine ester, as a 
topically applied sebum inhibitor for the treatment of acne vulgaris. Olumacostat glasaretil is a 
new chemical entity and has been formulated for clinical development as Olumacostat Glasaretil 
Gel, 5.0%. 
Data from the completed Phase 2 dose ranging study, DRM01B-ACN02, and data from study 
DRM01B-ACN01, have shown that Olumacostat Glasaretil Gel was well tolerated at multiple 
concentrations. Olumacostat Glasaretil Gel at a strength of 5.0% has been selected as the 
concentration to take forward in Phase 3 development. Two Phase 3 pivotal trials are planned as 
part of the Phase 3 development program and will include adults and adolescents (ages 9 years 
and older) in order to confirm the efficacy and safety of Olumacostat Glasaretil Gel, 5.0% for the 
treatment of acne vulgaris. 
This study, DRM01B-ACN04, is one of the two confirmatory Phase 3 trials being conducted to 
assess the efficacy and safety of Olumacostat Glasaretil Gel, 5.0% in subjects with acne vulgaris. 
3. STUDY OBJECTIVES 
The objective of this study will be to assess the efficacy and safety of Olumacostat Glasaretil Gel 
at a concentration of 5.0%, compared to Olumacostat Glasaretil Gel, Vehicle when applied twice 
daily for 12 weeks in subjects with acne vulgaris. 


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4. STUDY DESIGN 
4.1 
Overall Study Design 
This study is a randomized, double-blind, vehicle-controlled, parallel group study, designed to 
assess the efficacy and safety of Olumacostat Glasaretil Gel, 5.0% compared to Olumacostat 
Glasaretil Gel, Vehicle in subjects with acne vulgaris on the face. All subjects will provide 
informed consent or assent (pediatric subjects) and undergo screening for study eligibility. 
Approximately 700 eligible subjects ≥ 9 years of age will be randomized, in a 2:1 fashion, to 
Olumacostat Glasaretil Gel, 5.0% or Olumacostat Glasaretil Gel, Vehicle treatment, respectively. 
Study drug will be applied twice daily to the face for 12 weeks. Subjects will return to the study 
clinic at Weeks 1, 4, 8 and 12 (Study Exit). A follow-up phone call at Week 2 will be made to 
assess safety (adverse events [AEs]) only. 
Primary efficacy will be assessed through acne lesion counts (inflammatory and non-
inflammatory lesions) and investigator global assessment of acne (IGA). All efficacy endpoints 
will be assessed as the change from Baseline to Week 12. 
Safety will be assessed through AEs, local skin reactions (LSRs), serum chemistry, hematology 
and urinalysis laboratory testing, electrocardiogram (ECG) testing, physical examination and 
vital signs. 
4.1.1 
Schedule of Visits and Assessments 
The schedule of assessments can be found in Appendix 1 of the protocol. 
4.1.2 
Method of Assigning Subjects to Treatment Groups 
A randomization schedule will be generated by a member of the Statistical Services department 
at QST Consultations, Ltd. (QST) who is not associated with the conduct or analysis of the 
study, using a validated system.  The randomization list will not be stratified but stratification by 
site will be completed within the Interactive Web-based Randomization System (IWRS).   
At the Baseline/Day 1 visit, qualified subjects will be randomized to treatment using the IWRS. 
The IWRS will assign a study drug kit number based on the subject’s treatment assignment and 
available inventory at the investigational site. The kit number will be recorded in the electronic 
case report form. Approximately 467 subjects will be randomized to active treatment and 
approximately 233 subjects will be randomized to vehicle treatment for a total of approximately 
700 subjects. Subjects will be randomized to treatment groups in such a manner to balance 
treatment allocation within study sites in a 2:1 fashion. 


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4.1.3 
Blinding 
The Sponsor, the contract research organization, the investigator, study site personnel and 
subjects will be blinded to the treatment assignment.  The randomization schedule will be kept 
strictly confidential and accessible only to authorized persons.  Only when the study has been 
completed, the protocol violations determined and the study database locked will the 
randomization schedule be made available for analysis. 
The integrity of this clinical study must be maintained by observing the treatment blind. If an AE 
occurs which cannot be managed without knowing whether the subject is receiving active study 
drug or vehicle solution, the IWRS will be used to obtain treatment assignment information. The 
Medical Monitor must be notified whenever study medication is unblinded, preferably prior to 
unblinding a subject. 
4.2 
Determination of Sample Size 
The sample size for this study was based on estimates from the DRM01B-ACN02 study 
observed Week 12 results. Estimates were combined for all three active treatment groups as well 
as for the two vehicle groups. All power calculations were performed with nQuery Advisor 
Version 7.0 for a two-sided test at alpha = 0.05. 
For inflammatory lesion change a sample size of 300 Olumacostat Glasaretil Gel and 150 
Olumacostat Glasaretil Gel, Vehicle subjects has at least 95% power to detect a statistically 
significant difference with a significance level of 0.05 using the estimated absolute change from 
Baseline in treatment means of -15.21 and -9.7 for Olumacostat Glasaretil Gel versus its vehicle, 
respectively, with a standard deviation (SD) of 11.00. 
For non-inflammatory lesion change a sample size of 450 Olumacostat Glasaretil Gel and 225 
Olumacostat Glasaretil Gel, Vehicle subjects has 95% power to detect a statistically significant 
difference with a significance level of 0.05 using the estimated absolute change from Baseline in 
treatment means of -14.73 and -9.70 for Olumacostat Glasaretil Gel versus its vehicle, 
respectively, with a SD of 16.72. 
The success rate for dichotomized IGA is estimated to be 20.5% in the Olumacostat Glasaretil 
Gel subjects and 9.6% in vehicle subjects. A sample size of 444 Olumacostat Glasaretil Gel and 
222 Olumacostat Glasaretil Gel, Vehicle will have 95% power to detect a statistically significant 
difference in proportions of successes. These calculations were performed with nQuery Advisor 
Version 7.0 for a two-sided continuity corrected chi-square test at alpha = 0.05. 
To allow for a slight loss in power due to dropouts and withdrawals as well as to accommodate 
sufficient power in all three co-primary variables, a sample of 700 subjects randomized to 2 to 1 
for Olumacostat Glasaretil Gel (n=467) and vehicle (n=233), respectively, will be enrolled in the 
trial. 


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5. CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES 
There are no changes in the conduct of the study, but there are minor changes to the planned 
analyses. 
The pooling analysis described in the protocol is updated in the statistical analysis plan (SAP) to 
reflect the intended analysis. The protocol discusses pooling sites with five or fewer subjects 
enrolled in each treatment arm. Taking into consideration the randomization ratio, the SAP 
requires ten subjects in the active treatment arm and five subjects in the vehicle group. The SAP 
also clarifies the pooling of sites will be performed for each country separately. 
As part of the pooling analysis, the treatment effect within investigational site must be 
investigated. The protocol states the site main effect will be examined by using a one-way 
analysis of variance (for lesion count variables) or a logistic regression analysis (for 
dichotomized IGA) with a factor of site. The SAP instead explains site will be incorporated into 
the primary analysis models. Change from Baseline in lesion counts will be analyzed with an 
analysis of covariance (ANCOVA) (unranked or ranked) with factors of treatment group, 
investigational site and treatment group by investigational site interaction, and the respective 
baseline lesion count variable as a covariate. The dichotomized primary endpoint will be 
analyzed with a logistic regression with factors of treatment group, investigational site and the 
interaction term of treatment group by investigational site. 
The protocol describes repeated measures sensitivity analyses for the primary efficacy endpoints. 
Treatment group, analysis center and visit are listed as factors for the repeated measures 
analyses. In addition to these factors, the SAP includes a factor of treatment group by visit 
interaction. 
The seed values pre-specified in the protocol are the same values as in the parallel executed 
Phase 3 (DRM01B-ACN03). The seed values were updated to be unique. 
6. EFFICACY AND SAFETY ENDPOINTS 
6.1 
Efficacy Endpoints 
Primary and secondary efficacy endpoints will be assessed as the change from Baseline to Week 
12. 
6.1.1 
Primary Efficacy Endpoints 
The primary efficacy endpoints are as follows: 
• Mean absolute change in acne lesion counts (inflammatory and non-inflammatory 
lesions) from Baseline to Week 12; 


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• Proportion of subjects who achieved ≥2-grade improvement and a grade of 0 or 1, in the 
IGA from Baseline to Week 12. 
6.1.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are as follows: 
• Percent change in acne lesion counts (inflammatory and non-inflammatory lesions) from 
Baseline to Week 12; 
• Proportion of subjects who achieved ≥ 2-grade improvement in the IGA from Baseline to 
Week 12. 
6.2 
Safety Endpoints 
Safety will be assessed through AEs, LSRs, serum chemistry, hematology and urinalysis 
laboratory testing, ECG testing, physical examination and vital signs. 
7. STATISTICAL METHODS AND ANALYSIS 
7.1 
General Methodology 
All analyses will be performed using SAS® Version 9.3 or later. No interim analyses are 
planned. Except where noted, all statistical tests will be two-sided and will be performed at the 
0.05 level of significance.  
Descriptive statistics will be used to provide an overview of the efficacy and safety results. For 
categorical parameters, the number and percentage of subjects in each category will be 
presented. For continuous parameters, descriptive statistics will include n (number of 
observations), mean, SD, median, minimum and maximum. Appropriate inferential statistics will 
be used for the primary, secondary and exploratory efficacy variables.  
The primary method of handling missing efficacy data will be the method of Markov Chain 
Monte Carlo (MCMC) multiple imputation.  
The primary method of dichotomizing the IGA score will be to consider a subject a “success” if 
the IGA at a post-baseline visit is 0 or 1 and 2 or more grades lower than at Baseline; otherwise 
the subject will be considered a treatment “failure”. 
Reported AEs, medical history terms, prior and concomitant procedures and therapies and 
washout procedures will be classified on the basis of Medical Dictionary for Regulatory 
Activities (MedDRA) terminology, Version 19.1. Prior and concomitant medications and 
washout medications will be classified on the basis of World Health Organization Drug 
Dictionary (WHO-DDE) terminology, Format B2, Version March 1, 2016. 


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7.2 
Adjustments for Covariates 
Baseline inflammatory lesion count will be a covariate for the primary efficacy endpoint for 
inflammatory acne lesion counts. Similarly, baseline non-inflammatory lesion count will be a 
covariate for the primary efficacy endpoint for non-inflammatory lesion counts. No other 
covariates are planned to be used in the analyses for this study.  
7.3 
Handling of Dropouts or Missing Data 
Missing 12 week efficacy data will be imputed and subsequently analyzed. The primary method 
of handling missing efficacy data will be the method of MCMC multiple imputation which does 
not rely on the assumption of data missing at random. Additionally, the pattern of missing 
observations in each treatment group will not influence the missing value estimation in the other 
because the imputation will be conducted independently for each treatment group. 
The multiple imputation process for imputing missing lesion count and IGA data and subsequent 
analysis will involve 4 distinct phases with these principal tasks: 
1. Calculate the number of missing 12-week values for each treatment group to be estimated 
by MCMC. Let nmiss be the maximum number of missing between the two treatment 
groups. 
2. Create a data set of subjects, one for each treatment group, with observed values and 
those needing estimation by MCMC. The missing values in each data set will be filled in 
using the MCMC method ‘5 x nmiss’ times to generate ‘5 x nmiss’ data sets. The 
resulting data sets for each treatment arm will be combined into one complete data set for 
each imputation. 
3. For each complete data set, compute the necessary derived variables. Each complete data 
set will be analyzed with the appropriate analysis model. See Sections 7.3.1.1 and 7.3.1.2 
for details. 
4. The results from these analyses will be combined into a single inference using SAS 
PROC MIANALYZE. 
Sensitivity analyses will be performed on the primary efficacy endpoints to investigate the 
impact of the method of imputation. The first set of sensitivity analyses will use repeated 
measures. See Sections 7.3.2.1 and 7.3.2.2 for details.  
The second set of sensitivity analyses will use model-based multiple imputation. The model-
based multiple imputation process requires the data to have a monotone missing pattern. 
However, the imputation model will include treatment group and analysis center, and for lesion 
counts will include a covariate of baseline lesion count. Since treatment group, analysis center 
and baseline lesion count will be non-missing, the data will have a monotone missing pattern. 
The model-based multiple imputation process will involve 4 principal tasks: 


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1. Calculate the number of missing 12-week values to be imputed (nmiss). 
2. Missing values will be filled in ‘5 x nmiss’ times to generate ‘5 x nmiss’ complete data 
sets. The imputation model used will be the analysis model.  
3. For each complete data set, compute the necessary derived variables. Each complete data 
set will be analyzed with the appropriate analysis model. See Sections 7.3.2.1 and 7.3.2.2 
for details. 
4. Results from these analyses will be combined into a single inference using SAS PROC 
MIANALYZE. 
7.3.1 
MCMC Multiple Imputation 
7.3.1.1 
Lesion Count Variable Missing Data Imputation 
A total of 4 random seeds will be needed to use PROC MCMC to impute inflammatory lesion 
counts and non-inflammatory lesion counts for the two treatment groups. Those 4 random seeds 
have been pre-specified by using a random number generator: 
• Inflammatory Lesion Counts; Olumacostat Glasaretil Gel, 5.0%: Seed= 1367270369;  
• Inflammatory Lesion Counts; Olumacostat Glasaretil Gel, Vehicle: Seed= 197172559;  
• Non-Inflammatory Lesion Counts; Olumacostat Glasaretil Gel, 5.0%: Seed= 453193225;  
• Non-Inflammatory Lesion Counts; Olumacostat Glasaretil, Vehicle: Seed= 1120886549. 
After imputing with PROC MCMC, the absolute change in lesion counts will be computed. Each 
complete data set will be analyzed with an ANCOVA with factors of treatment group and 
analysis center and the respective baseline lesion count as a covariate. A factor of treatment 
group by analysis center will be added if necessary, and appropriate modifications will be made 
should the analysis be based on a non-parametric method. The results from these analyses will be 
combined using SAS PROC MIANALYZE. 
7.3.1.2 
IGA Missing Data Imputation 
A total of 2 random seeds will be needed to impute IGA for the two treatment groups. Those 
2 random seeds have been pre-specified by using a random number generator: 
• IGA; Olumacostat Glasaretil Gel, 5.0%: Seed= 1249913374;  
• IGA; Olumacostat Glasaretil Gel, Vehicle: Seed= 1524754873. 
After imputing with PROC MCMC, the dichotomous success rate (clear or almost clear with at 
least a 2-point change from Baseline) will be computed. The 12-week estimated IGA values will 
be rounded to the nearest integer value prior to evaluating the success rate. Each complete data 


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set will be analyzed with a logistic regression with factors of treatment group and analysis center. 
The results from these analyses will be combined using SAS PROC MIANALYZE. 
7.3.2 
Sensitivity Analyses 
7.3.2.1 
Lesion Count Variable Missing Data Imputation 
The first sensitivity analysis for absolute change in lesion count will use a repeated measures 
ANCOVA, with factors of treatment group, analysis center, visit (i.e., Week 4, Week 8) and 
treatment group by visit interaction and a covariate of baseline lesion count. In this analysis, data 
from all post-baseline visits will be included with no imputation for missing data. 
The second sensitivity analysis will use the model-based multiple imputation method to impute 
missing data for the absolute change in lesion counts at Week 12. The imputation model will 
include treatment group, analysis center, and baseline lesion count. A total of 2 random seeds 
will be needed to impute inflammatory lesion counts and non-inflammatory lesion counts for the 
two treatment groups. Those 2 random seeds have been pre-specified by using a random number 
generator: 
• Inflammatory Lesion CountsSeed= 1342565113;  
• Non-Inflammatory Lesion Counts: Seed= 974836051. 
7.3.2.2 
IGA Missing Data Imputation 
The first sensitivity analysis for the dichotomized IGA success will use a repeated measures 
logistic regression model (generalized estimating equations), with dichotomized IGA success as 
the dependent variable and treatment group, analysis center, visit (i.e., Week 4, Week 8) and 
treatment by visit interaction. In this analysis, data from all post-baseline visits will be included 
with no imputation for missing data. 
The second sensitivity analysis will use the model-based multiple imputation method to impute 
missing data for the dichotomized IGA data at Week 12. The imputation model used will be a 
logistic regression with factors of treatment group and analysis center. One random seed will be 
needed to impute IGA for the two treatment groups. The random seed has been pre-specified by 
using a random number generator: 
• IGA: Seed= 318176687. 
7.4 
Interim Analyses and Data Monitoring 
No interim analysis or data monitoring is planned for this study. 


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7.5 
Multicenter Studies 
The clinical study will be conducted under a common protocol for each investigational site with 
the intention of pooling the data for analysis. Every effort will be made to promote consistency 
in study execution at each study site. The study is intended to be conducted in a manner such that 
a minimum of 15 subjects will be randomized and included in the ITT population (i.e., at least 
ten subjects in the active treatment arm and five subjects in the vehicle treatment arm) for any 
investigator. In the event that there are too few subjects in a treatment arm for an investigational 
site, then the site’s data will be combined with other site’s data to achieve the desired sample size 
minimum per treatment arm. Country will be considered when pooling sites, such that sites from 
the United States will be combined with other sites from only the United States, and similarly for 
sites from Canada and sites from Australia. The combining of investigator data will be 
accomplished by taking the investigator with the smallest enrollment and combining it with the 
investigator with the largest enrollment, restricted to investigational sites who did not meet 
minimum enrollment. If there is a further need to combine data, then the data of the investigator 
with the second smallest enrollment will be combined with the investigator's data which had the 
second largest enrollment (restricted to investigational sites who did not meet minimum 
enrollment), and so on. This process will continue for all investigators who did not have a 
minimum of 15 subjects enrolled. The process of combining investigator data that have 
insufficient subjects per treatment arm will result in redefining the groups of investigators for the 
purposes of statistical analyses. These combined groups will be referred to as "analysis centers" 
in the statistical analyses. 
The consistency of treatment response will be investigated across the analysis centers subsequent 
to combining the data as described above. Statistical tests will be conducted to identify if there 
are extreme analysis centers that could affect the interpretation of common statistical and clinical 
conclusions. An analysis center by treatment interaction will be included in the primary and 
secondary variable analyses to test for parallel treatment effect at an alpha level of 0.10. Change 
from baseline in inflammatory lesions and non-inflammatory lesions will be analyzed with an 
ANCOVA (unranked or ranked) with factors of treatment group, analysis center and treatment 
group by analysis center interaction and the respective baseline lesion count variable as a 
covariate. For the purpose of testing consistency of treatment response, the dichotomized IGA 
will be analyzed with a logistic regression with factors of treatment group, analysis center, and 
the interaction term of treatment group by analysis center. Further examination will follow for 
any variables that have a significant ANCOVA or logistic regression interaction term. 
In the event that the ANCOVA or logistic regression interaction (referred to henceforth as the 
"appropriate test") p-value is ≤0.10, a sensitivity analysis that excludes analysis centers with the 
extreme efficacy result will be performed to determine the robustness of the treatment effect. On 
the other hand, if all three analyses result in interaction terms with p-values >0.10, then the 


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conclusions from the pooled data will be considered to be free of the impact of extreme analysis 
centers. 
The first step in conducting a sensitivity analysis is to identify the extreme analysis center or 
centers that contribute to the statistical significance of the interaction term of the appropriate test. 
The process involves submitting subsets of analysis centers to the appropriate test and observing 
the interaction p-value for the subset. Subsets producing interaction p-values >0.10 are 
considered homogeneous. 
The search for an extreme analysis center begins by analyzing all subsets that can be created by 
excluding one analysis center. If one or more of the subsets result in an interaction p-value 
>0.10, then the analysis center excluded from the subset with the largest interaction p-value is 
deemed to be the extreme analysis center. 
If all subset interaction p-values are ≤ 0.10, then the process will analyze the interaction for all 
subsets that can be created by excluding two analysis centers. If one or more of these subsets 
generate interaction p-values > 0.10, then the analysis centers excluded from the subset with the 
largest interaction p-value are deemed the extreme analysis centers. 
Thus, the process of identifying the extreme analysis centers will continue in a stepwise manner 
by first excluding one, then two, then three, etc., analysis centers until the appropriate test 
interaction p-value is > 0.10. 
Once the extreme analysis center or centers have been identified, then the treatment p-values of 
the remaining analysis centers will be computed. Inferences will be drawn from the treatment p-
value, as well as any pertinent observations regarding the extreme analysis center or centers. 
Additionally, it is noted that this process excludes subjects from the analysis in a nonrandom 
manner and has an unpredictable impact on the power of the treatment effect test. In the event 
that the treatment effect of the remaining subset is not statistically significant, due consideration 
of the post hoc aspects of the process will be given when the results are interpreted. Conclusions 
will be presented by the Sponsor as appropriate to the findings of the sensitivity analysis.  
Prior to investigating the treatment effect within the analysis centers, the treatment effect within 
investigational site will be investigated to determine if the site-to-site variability is such that it 
could mask the analysis center effects. Thus, prior to pooling, change from baseline in 
inflammatory lesions and non-inflammatory lesions will be analyzed with an ANCOVA 
(unranked or ranked) with factors of treatment group, investigational site, and treatment group by 
investigational site interaction, and the respective baseline lesion count variable as a covariate. 
The dichotomized primary endpoint will be analyzed with a logistic regression with factors of 
treatment group, investigational site, and the interaction term of treatment group by 
investigational site. If any of the analyses are not computationally feasible due to some 
investigational sites having very few subjects enrolled, the low-enrolling investigational sites 
will be excluded from the analysis. 


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7.6 
Multiple Comparisons/Multiplicity 
The following stepwise process will be conducted for testing the secondary efficacy endpoints in 
order to control for multiplicity. These tests will be performed for only the intent-to-treat (ITT) 
population. The testing process will terminate whenever a statistical test for a step is not 
significant. All subsequent tests for the remaining steps will be considered not significant. The 
order of testing is percent change in inflammatory lesion count from Baseline to Week 12, 
percent change in non-inflammatory lesion count from Baseline to Week 12 and the proportion 
of subjects who are dichotomized to success (minimum 2-grade improvement from Baseline). 
7.7 
Examination of Subgroups 
Subset analyses will be conducted for the ITT population for subgroups based on the following: 
• Baseline IGA; 
o Categorized as Baseline IGA = 3 (Moderate) and Baseline IGA = 4 (Severe); due 
to the inclusion criteria requiring subjects to have either a 3 or 4 IGA score at 
study entry other IGA response categories will not be presented; 
• Gender; 
• Age: 
o Dichotomized as less than the median age of ITT subjects and greater than or 
equal to the median age of ITT subjects; 
o Categorized as less than 18, 18 to less than the median age of ITT subjects and 
greater than or equal to the median age of ITT subjects;  If the median age of ITT 
subjects is less than 18 then the subgroup will be <18 and >= 18 
• Ethnicity; 
• Race: 
o Categorized as White and Non-White; subjects indicating more than one race 
category which includes both white and a non-white race will be summarized 
under the Non-White subgroup. 
Subset analyses will be conducted on the variables absolute change from Baseline in 
inflammatory lesions and non-inflammatory lesions at Week 12 as well as the dichotomized IGA 
score at Week 12. These analyses will contain descriptive statistics only. 


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7.8 
Analysis Populations 
7.8.1 
Randomized Population 
All subjects who are randomized to study treatment will be included in the randomized 
population and will be analyzed according to the treatment group they were randomized.   
7.8.2 
Intent-to-Treat (ITT) Population 
All subjects in the randomized population who are dispensed study drug will be included in the 
ITT population and will be analyzed according to the treatment group they were randomized.  
All efficacy analyses will be presented using the ITT population. 
7.8.3 
Safety Population 
All subjects in the randomized population who receive at least one confirmed dose of study drug 
and have at least one post-baseline safety assessment will be included in the safety population 
and will be analyzed according to the treatment they received.  All safety analyses will be 
performed using the safety population. 
7.8.4 
Per-Protocol (PP) Population 
All subjects in the safety population who complete the Week 12 evaluation without any 
significant protocol violations will be included in the PP population and analyzed according to 
the treatment group they received.  The PP population will include subjects in the safety 
population who do not meet any of the following criteria: 
• Violated the inclusion/exclusion criteria; 
• Have taken any interfering concomitant medication; 
• Did not attend the Week 12 visit; 
• Have missed both the Week 4 and Week 8 study visits; 
• Have not been compliant with the dosing regimen (i.e. subjects must apply 80-120% of 
the expected applications of study medication during participation in the study); 
• Out of visit window at the Week 12 visit by ±5 days. 
Subjects that discontinue treatment or from the study due to an AE related to study treatment or 
documented lack of treatment effect will be included in the PP population.  Prior to breaking the 
blind, other additional criteria may be added to the list to accommodate for unforeseen events 
that occurred during the conduct of the trial that result in noteworthy study protocol violations.   
All efficacy analyses will be performed on the PP population. 


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7.9 
Statistical Analysis 
All analyses will be performed by QST.  All summary tables and data listings will be prepared 
utilizing SAS® software. The standard operating procedures of QST will be followed in the 
creation and quality control of all data displays and analyses. 
All data collected at scheduled time points will be summarized, regardless of treatment with 
study drug. Post-treatment assessments for subjects who discontinue treatment but continued to 
be followed in the study will be included in summaries. 
7.9.1 
Baseline Definition 
Baseline is defined as the last non-missing assessment prior to the first dose of study drug.   
7.9.2 
Visit Windowing 
Data will be summarized based on nominal visit indications with the exception of data captured 
at early termination and unscheduled visits. Data from early termination and unscheduled visits 
will be summarized based on mapped visit values.  The analysis windows for early termination 
and unscheduled visits are presented in the following table.  
Analysis Windows for Efficacy and Safety Assessments 
Scheduled Visit 
Target Study Day 
Window (Days) 
Week 1 
8 
5 to 18 
Week 4 
29 
19 to 42 
Week 8 
57 
43 to 70 
Week 12 
85 
71 to 98 
Data collected at early termination and unscheduled visits prior to study day 5 will not be 
analyzed, with the exception of those identified as baseline values. Data collected at early 
termination and unscheduled visits after study day 98 will not be included in analyses. 
The definition for the study day included in each study window is defined as below: 
Study Day Prior to Day 1 = Visit Date – Day 1 Date 
 
Study Day On or After Day 1 = Visit Date – Day 1 Date + 1. 
If an assessment’s mapped visit is a visit at which the subject has data from a scheduled visit 
present, or if no analyses are planned for the assessment at the mapped visit, the data collected at 
the early termination or unscheduled visit will not be included in analyses.   
In the event of multiple values from unscheduled or early termination assessments within an 
analysis window, the value closest to the scheduled visit target study day will be used for 


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analyses.  If two values tie as closest to the time point (for example, one value is before and the 
other value is after the time point), then the later value will be selected.  
Data collected at all visits will be included in the data listings with visit presented as reported by 
the site. 
7.9.3 
Subject Disposition 
The number of subjects included in each analysis population (randomized, ITT, safety and PP) 
will be summarized by treatment group, by treatment group within analysis center and by 
treatment group within investigational site.  The number of subjects completed and discontinued 
(including the primary reason for discontinuation) will be summarized for each treatment group. 
Subjects who are excluded from an analysis population will be summarized by the reasons for 
exclusion. Reasons subjects were not randomized will be summarized for subjects who did not 
enroll in the study. 
7.9.4 
Protocol Deviations 
Protocol deviations will not be entered into the database. Only deviations leading to exclusion 
from analysis populations will be identified and summarized. 
7.9.5 
Demographic and Baseline Characteristics 
All baseline summaries will be performed on the ITT, PP and safety populations. 
Sex, race, ethnicity and Fitzpatrick skin type will be summarized by counts and percentages.  
Age will be summarized with descriptive statistics. Summaries of dichotomized age (less than 
median and greater than or equal to median) and categorized age (less than 18, 18 to less than 
median and greater than or equal to median) will also be included. 
Subjects’ baseline characteristics related to efficacy analyses will be summarized and compared 
between treatment groups to evaluate baseline balance between the treatment arms.  Baseline 
inflammatory lesion count and baseline non-inflammatory lesion count will be compared using a 
two-way analysis of variance with factors of treatment group and analysis center.  Baseline IGA 
will be compared using a Cochran-Mantel-Haenszel test of row means scores, stratified by 
analysis center. 
Acne vulgaris history, including number of years since onset, anatomical areas affected and prior 
acne treatments, will be summarized by counts and percentages.  If only the year is known for 
start of acne vulgaris the number of years since onset will be calculated by using January for 
month and “01” as day.  If only the year and month are known for start of acne vulgaris then 
onset will be calculated by using “01” as day. 


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Medical histories will be coded using the MedDRA dictionary and presented in a by-subject 
listing. 
7.9.6 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded to preferred name and anatomical therapeutic 
chemical (ATC) classification of ingredients using the WHO-DDE. 
Counts and percentages will be provided to summarize the use of prior and concomitant 
medications other than the study drug reported throughout the study.  The number and percent of 
subjects reporting medications will be summarized by ATC level 2 term and preferred name.  
Medications which start prior to first dose will be considered prior medications. Ongoing 
medications and medications ending after the date of first dose will be considered concomitant 
medications. Medications which are both prior and concomitant will be included in both 
summaries. Incomplete start and end dates which could be prior to first dose or after first dose 
will be considered prior to first dose. 
7.9.7 
Efficacy Analyses 
All efficacy analyses will be presented by treatment group for both ITT and PP populations. 
7.9.7.1 
Primary Efficacy Analyses 
Absolute change from Baseline to Week 12 in inflammatory and non-inflammatory lesion counts 
will be analyzed using either parametric or non-parametric methods consistent with the statistical 
assumptions required to support the analyses. Specifically, the tests of superiority will be based 
on an ANCOVA with factors of treatment group and analysis center and the respective baseline 
lesion count as a covariate or on ranked data submitted to an ANCOVA with factors of treatment 
group and analysis center and the respective baseline lesion count as a covariate. If the treatment 
group by analysis center interaction effect is significant at an alpha less than 0.10, then the effect 
will be included in the model; otherwise it will be omitted. 
A skewness test, based on the methods presented by J.H. Zar (1984) [1], will be applied to the 
residuals resulting from an ANCOVA. A two-sided p-value for the skewness test significant at 
0.01 will imply the use of the non-parametric method. If a parametric analysis is indicated, the 
results of the parametric analysis will be considered the primary analysis. Should a non-
parametric analysis be indicated, the absolute or percent changes in inflammatory and non-
inflammatory lesions will be rank-transformed prior to submitting them to the ANCOVA. 
Results of the rank-transformed analyses then will be considered the primary analysis; however, 
results of the non-ranked transformed analyses will also be presented. That is, the primary 
analyses for inflammatory and non-inflammatory lesion counts will be determined by the 
treatment group by analysis center interaction p-value and the skewness p-value as described in 
the table below: 


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Determination of Model for Primary Analyses 
Interaction P-Value 
Skewness P-Value 
Analysis Model 
< 0.10 
< 0.01 
Ranked ANCOVA with factors of treatment, 
analysis center and treatment by analysis center 
interaction and the respective baseline lesion 
count as a covariate 
≥ 0.10 
< 0.01 
Ranked ANCOVA with factors of treatment 
and analysis center and the respective baseline 
lesion count as a covariate 
< 0.10 
≥ 0.01 
ANCOVA with factors of treatment, analysis 
center and treatment by analysis center 
interaction and the respective baseline lesion 
count as a covariate
≥ 0.10 
≥ 0.01 
ANCOVA with factors of treatment and 
analysis center and the respective baseline 
lesion count as a covariate 
Note that interaction and skewness p-values will be computed for each imputation of multiply-
imputed data. Model determination will depend on averaged p-values, computed by finding the 
mean p-values across all imputations. 
The proportion of subjects who are dichotomized to success at Week 12 will be analyzed using a 
logistic regression with factors of treatment group and analysis center. 
The sensitivity analysis for absolute change in lesion count will include a skewness test, based on 
the methods presented by J.H. Zar (1984) [1].  A ranked repeated measures analysis of 
covariance with factors of treatment group, visit, analysis center and treatment by visit 
interaction, and the respective baseline lesion count as covariate will also be included.  Values 
will be ranked across all visits (i.e. visit will be ingored when ranking) and the baseline covariate 
will not be ranked.  
7.9.7.2 
Secondary Efficacy Analyses 
The percent change from Baseline to Week 12 in inflammatory and non-inflammatory lesion 
counts will be analyzed using the same ANCOVA method described for the primary endpoint. 
The proportion of subjects who are dichotomized to success (minimum 2-grade improvement 
from Baseline) at Week 12 will be analyzed using the same logistic analysis method described 
for the primary endpoint. A stepwise process will be conducted for testing the secondary efficacy 
endpoints in order to control for multiplicity, refer to Section 7.6 for details. 


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7.9.7.3 
Other Supportive Efficacy Analyses 
The percent change and absolute change from Baseline to Weeks 4 and 8 inflammatory and non-
inflammatory lesion counts will be analyzed using the same ANCOVA method described for the 
primary endpoint of absolute change in lesion counts from Baseline to Week 12. The inclusion of 
p-values in these efficacy analyses is to assist in characterizing the therapeutic efficacy of the 
active formulation and dosage regimen. No adjustments will be made for multiple comparisons 
for the supportive efficacy analyses. 
Descriptive statistics will be presented for the following parameters by treatment group for both 
the ITT and PP populations:  
• Frequency and percent distributions of the IGA Score at Baseline and Weeks 4, 8 and 12; 
• Frequency and percent distributions of the dichotomized IGA Score at Baseline and 
Weeks 4, 8 and 12; 
• Descriptive statistics will be used to summarize inflammatory and non-inflammatory 
lesion counts at Baseline and Weeks 4, 8 and 12; 
• Descriptive statistics will be used to summarize the absolute and percent change in 
inflammatory and non-inflammatory lesion counts at Weeks 4, 8 and 12; 
• Descriptive statistics will be used to summarize the Acne Patient Self-Questionnaire 
assessments at Weeks 4, 8 and 12. Satifasction questions answered at Week 12 will be 
summarized with frequency and percent distributions. 
7.9.8 
Safety Analyses 
7.9.8.1 
Extent of Exposure 
The extent of exposure to study drug in each treatment group will be summarized by amount of 
study drug used (computed from study drug tube weights) and anatomical areas treated. Facial 
exposure will be summarized by total number of days of exposure, total number of applications, 
number of missed applications and number and percentage of subjects who are compliant. A 
subject will be considered compliant with the dosing regimen if the subject applied 80% to 120% 
of the expected number of applications while enrolled in the study. Total number of days of 
exposure will be computed as follows: 
Total Exposure = Date of Last Application – Date of First Application + 1. 
Dosing deviations reported for areas other than the face will not be considered in compliance 
calculations. On the date of first application and the date of last application, some subjects were 
to apply one dose and others were to apply two doses, depending on the time of the study visit. 
After the date of first application and before the date of last application subjects were expected to 


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apply two doses. Missed applications will be calculated from dosing deviations which report zero 
or one application on a given date. Extra doses will be calculated from dosing deviations which 
report more than the expected number of applications on a given date. The total number of 
applications will be calculated as follows: 
If the Date of First Application is not equal to Date of Last Application, then 
Total Applications = 2*(Date of Last Application – Date of First Application – 1)  
 
 + Expected Applications on Date of First Application  
 
 + Expected Applications on Date of Last Application  
 
 – Missed Applications + Extra Applications. 
If the Date of First Application = Date of Last Application, then  
Total Applications =  Expected Applications on Date of First Application  
 
 – Missed Applications + Extra Applications. 
Treatment compliance will be based on the expected number of doses given the treatment period 
duration. Treatment period duration will be computed from the Baseline/Day 1 visit date and the 
Week 12/Early Termination (ET) visit date. If a subject does not have a Week 12/ET visit, 
treatment period duration will be calculated based on the date of last dose or last completed visit 
date, whichever is later. That is, treatment period duration will be computed from the 
Baseline/Day 1 date and the end of treatment period date, where the end of treatment period date 
is given by  
• If the subject completed the Week 12/ET visit, the end of treatment period date will be: 
o The date of the Week 12/ET visit if the expected number of applications on the 
date of last application is one; 
o The day prior to the Week 12/ET visit if the expected number of applications on 
the date of last application is two; 
• If the subject did not complete the Week 12/ET visit, the end of treatment period date 
will be the date of last dose or last completed visit, whichever is later. 
Then treatment period duration may be calculated as: 
 
Treatment Period Duration = End of Treatment Period Date – Day 1 Date + 1. 
If the treatment period duration exceeds 88 days, treatment period duration will be considered 88 
days. In addition to treatment period duration, missed applications due to treatment-related AEs 
will be considered when determining the expected number of doses for each subject. If a 
treatment-related AE (regardless of location) requires interruption of study drug during the 


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treatment period, missed applications during the AE (onset date to resolution date) will be 
deducted from the expected number of doses. Therefore, the expected number of applications 
will be calculated as:  
Expected Applications = 2*(Treatment Period Duration – 2) 
 
 + Expected Applications on Date of First Application  
 
 + Expected Applications on Date of Last Application  
 
 – Applications Missed Due to a Treatment-Related AE. 
If Treatment Period Duration = 1, then  
Expected Applications= Expected Applications on Date of First Application  
 
 – Applications Missed Due to a Treatment-Related AE. 
Percent compliance will be calculated from total number of applications and total number of 
expected applications as follows: 
Percent Compliance = 100*(Total Applications/Expected Applications). 
Percent compliance will not be calculated for subjects who are lost to follow-up.   
7.9.8.2 
Adverse Events 
All AEs that occur during the study will be recorded and classified on the basis of MedDRA 
terminology. Treatment-emergent AEs (TEAEs) are defined as AEs with an onset on or after the 
date of the first study drug application. AEs noted prior to the first study drug administration that 
worsen after Baseline will also be reported as AEs and included in the summaries.  
All information pertaining to an AE noted during the study will be listed by subject, detailing 
verbatim term given by the investigator or designee, preferred term, system organ class, onset 
date, resolution date, severity, seriousness, action taken, outcome and drug relatedness. The 
event onset will also be shown relative (in number of days) to date of first application.  
Treatment-emergent AEs will be summarized by treatment group, the number of subjects 
reporting a TEAE, system organ class, preferred term, severity, relationship to study drug 
(causality) and seriousness. When summarizing AEs by severity and relationship, each subject 
will be counted once within a system organ class or a preferred term by using the event with the 
highest severity and greatest relationship within each classification. 
Serious AEs (SAEs) will be summarized by treatment group, severity and relationship to study 
drug, and individual SAEs will be listed by subject. In addition, a summary of AEs leading to 
discontinuation from the study due will be provided. 
No statistical inference between treatment groups will be performed on AEs. 


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Listings will be presented for all AEs as well as for SAEs and AEs leading to discontinuation 
from the study. 
7.9.8.3 
Clinical Laboratory Evaluations 
Laboratory test results will be summarized descriptively at Baseline and Week 12. Additionally, 
shifts from Baseline to Week 12 in laboratory test results based on normal ranges will be 
summarized with descriptive statistics. Individual laboratory test results will be presented in a 
by-subject listing.  
7.9.8.4 
Local Skin Reactions 
LSRs include erythema, peeling, dryness, burning/stinging and pruritus. These will be scored as 
0 (None), 1 (Mild), 2 (Moderate) or 3 (Severe). LSRs will be summarized by treatment group 
and visit using descriptive statistics. Each subject’s worst post-baseline grade for each LSR will 
also by summarized. Additionally, the number of subjects who experience mild, moderate or 
severe LSRs post-baseline will be presented. By-subject listing of all LSRs, as well as subjects 
with any severe LSRs will be included.  
7.9.8.5 
Other Observations Related to Safety 
7.9.8.5.1 
ECG Measurements 
Descriptive statistics by treatment group and visit will be provided for the following ECG 
parameters: heart rate (HR), PR duration, RR duration, QRS duration, QT duration, QT interval 
corrected for heart rate using Bazett’s formula (QTcB) and QT interval corrected for heart rate 
using Fridericia’s formula (QTcF). Change from Baseline in ECG abnormalities will be 
summarized using shift tables at the Week 12 visit. Shift tables will be based on the following 
categories: 
• PR Interval: < 100 msec, 100 – 220 msec and > 220 msec; 
• QRS Interval: < 50 msec, 50 – 110 msec and > 110 msec; 
• QTcF Interval: < 450 msec, 450 – 500 msec and > 500 msec. 
The following treatment-emergent ECG abnormalities will be summarized for subjects in the 
safety population with at least one post-application ECG: 
• PR Interval 
o > 220 msec; 
o > 220 msec and Change from Baseline > 25%; 
• QRS Interval 


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o > 110 msec; 
o > 110 msec and Change from Baseline > 25%; 
• QTcF Interval 
o > 450 – 480 msec; 
o > 480 – 500 msec; 
o > 500 msec; 
o Change from Baseline > 30 - 60 msec; 
o Change from Baseline > 60 msec; 
o > 450 - 480 msec and Change from Baseline > 30 - 60 msec; 
o > 450 - 480 msec and Change from Baseline > 60 msec; 
o > 480 - 500 msec and Change from Baseline > 30 - 60 msec; 
o > 480 - 500 msec and Change from Baseline > 60 msec; 
o > 500 msec and Change from Baseline > 30 - 60 msec; 
o > 500 msec and Change from Baseline > 60 msec. 
7.9.8.5.2 
Vital Signs 
Vital signs will be presented by treatment group and visit as observed values and changes from 
Baseline using descriptive statistics. 
7.9.8.5.3 
Physical Examination 
Physical examination data will be presented in a by-subject listing.  
8. REFERENCES 
1. Zar, JH (1984), Biostatistical Analysis, 2nd 
 ed. Englewood Cliffs, New Jersey: P 118-119.