A Randomized, Double-Blind, Vehicle-Controlled Study to Evaluate the Safety and Efficacy of BTX 1503 in Patients With Moderate to Severe Acne Vulgaris
Phase: PHASE2
Conditions: Acne Vulgaris
Sponsor: Botanix Pharmaceuticals

CLINICAL STUDY PROTOCOL 
 
Study Title:  
A Randomized, Double-Blind, Vehicle-Controlled Study to 
Evaluate the Safety and Efficacy of BTX 1503 in Patients with 
Moderate to Severe Acne Vulgaris 
 
Protocol Number: 
 
BTX.2018.001 
Version: 
 
 
2.4 
Phase:  
 
 
2 
 
Sponsor: 
 
 
Botanix Pharmaceuticals Ltd 
 
 
 
 
68 Aberdeen Street  
Northbridge WA 6003 
Australia 
 
 
Final Approval Date:  
07-June-2018  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This document is confidential communication of Botanix Pharmaceuticals Ltd.  Acceptance of 
this document constitutes the agreement by the recipient that no unpublished information 
contained within will be published or disclosed without prior written approval, except that this 
document may be disclosed to the appropriate Institutional Review Board/Ethics Committee 
under the condition that they are requested to keep it confidential. 
NCT03573518

 
 
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Protocol BTX.2018.001 Version 2.4 
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PROTOCOL SIGNATURE PAGE – SPONSOR 
 
Study Title:  
A Randomized, Double-Blind, Vehicle-Controlled Study to 
Evaluate the Safety and Efficacy of BTX 1503 in Patients with 
Moderate to Severe Acne Vulgaris 
 
Protocol Number: 
BTX.2018.001 
 
Version: 
 
 
2.4 
 
Signature: 
 
The undersigned acknowledges that he/she has received and read Protocol BTX.2018.001, 
Version 2.4, dated 07-June-2018. 
 
Sponsor Representative 
Signature 
Date 
VP, Clinical and Regulatory Affairs  
 
 
 
 
 
 
 
 
 
 
07 June 2018

 
 
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PROTOCOL SIGNATURE PAGE – INVESTIGATOR 
 
Study Title:  
A Randomized, Double-Blind, Vehicle-Controlled Study to 
Evaluate the Safety and Efficacy of BTX 1503 in Patients with 
Moderate to Severe Acne Vulgaris 
Protocol Number: 
BTX.2018.001 
 
Version: 
 
 
2.4 
 
Signature: 
 
The undersigned acknowledges that he/she has received and read Protocol BTX.2018.001, 
Version 2.4, dated 07-June-2018. 
 
Principal Investigator 
Signature 
Date 
 
 
 
 
 
 
By signing this protocol, the investigator has agreed to conduct this study in accordance with the 
requirements of this clinical protocol and in accordance with established principles of current Good 
Clinical Practice (GCP), Title 21 of the Code of Federal Regulations sections 50, 56, and 312 as 
applicable, and the ethical principles that have their origin in the Declaration of Helsinki. 
 
 
 
 
 
 

 
 
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DOCUMENT REVISION HISTORY 
 
Date 
Summary of changes 
Version 1.0 
12-FEB-2018 
Original document  
Version 2.0 
18-April-2018 
• Protocol was modified from a 28-day to 84-day treatment.  All 
sections wherein the length of treatment was specified have 
been updated.   
Note: No changes were made to the definitions for the IGA 
assessment or the cutaneous tolerability assessments. 
• A 2.5% daily dosing arm was added and randomization has 
been updated to 2:2:2:1:1 with 90 subjects in each active group 
and 45 subjects in each vehicle group for a total sample size of 
360 subjects. 
• Pediatric and adolescents were added for new age range of 9 – 
40 years with appropriate language for consent/assent 
requirements updated. 
• The primary and secondary endpoints have been changed from 
Day 28 to Day 84.   
• Exploratory endpoints of IGA and lesions counts on Day 14, 
Day 28, and Day 56 have been added. 
• Handling of missing data has been changed to use of last 
observation carried forward (LOCF) as the primary method 
with mixed model as sensitivity analysis. 
• Background and potential risks/benefits sections updated with 
data on 90-day minipig study, 28-day oral rat study, and 28-day 
clinical study in subjects with acne vulgaris. 
• Update of eligibility criteria: 
o Inclusion #9 and #10 clarification on concomitant use of 
moisturizers, sunscreens and makeup on the face,  
o Inclusion criterion #11, #13, and #14 to extend the use of 
contraception to 30 days after final study drug application, 
o Exclusion #6 clarification to exclude medications known 
to induce or exacerbate acne, 
o Exclusion #13 for use of testosterone, and 
o Exclusion #30 to clarify exclusion for drug screen 
findings. 

 
 
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• Section 6.1 and Section 10.1.6 changed for distribution of study 
drug from Pharmaceuticals Packaging Professionals (PPP) in 
Melbourne, Australia to The Coghlan Group (TCG) in Bastrop, 
Texas, USA. 
• Section 6.1.2 updated for new mode of delivery or study drug 
including weighing of study drug for compliance. 
• Section 7.1 added definition of comedones, papules, and 
pustules. 
• Section 7.3 moved IGA assessment prior to lesion counts. 
Section 7.4 and 7.5 added clarification on concomitant use of 
moisturizers, sunscreens and makeup on the face. 
Version 2.1 
10-May-2018 
• Section 5.1 Inclusion #14 updated criteria that subjects shall 
refrain from sperm donation from 60 days to 90 days after the 
trial. 
• Section 6.1.1 added TCG will provide study drug to the US sites 
and Pharmaceutical Packaging Professionals (PPP) will provide 
to the Australian sites. 
• Section 6.1.2 update to volume of study drug in each pump.  
30mL changed to approximately 39mL for BID dosing and 
20mL to approximately 21mL for QD dosing. Each kit will 
contain 4 pumps instead of 5.  
• Section 6.1.2 Label: update to study label to include 
investigational use only and Keep Out of Reach of Small 
Children. 
• Section 6.1.2 update to include bottle number on label and 
removal of back-up pump being dispensed as part of a kit. 
• Section 6.1.2 update from 50 mL bottle to 60mL bottle. 
• Section 6.1.2 Label – changed batch number to bottle number. 
• Section 6.1.3 removal of retest date included on the carton label. 
• Section 7.2.1 removal of culture from urinalysis. 
• Section 7.3.2 included weigh and dispense study drug. 
• Section 9.6.1 change of week number to bottle number on study 
label and update to fills on study drug pumps for each group, 
30mL changed to approximately 39mL for BID dosing and 
20mL to approximately 21mL for QD dosing. 
• 9.4.3 updated that total lesion counts will be presented as total 
and not just separate inflammatory and non-inflammatory, as 

 
 
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well as IGA scores and the frequency and percent distribution 
of the dichotomized IGA. 
Version 
2.2 
AUS 
22-May-2018 
Version 2.2 AUS is reserved for the protocol that is being 
conducted in Australia and tailored for local IRB requirements. 
Version 2.3 
27-May-2018 
• 
Section 5.1, #14 increased sperm donation restriction from 
60 days to 90 days after final study drug administration. 
• 
Section 5.1, #11 increased birth control requirements for 
males from 30 days to 90 days.  
• 
Section 6.1.2 Label: removed “Small” to state Keep Out of 
Reach of Children. 
Version 2.4 
07-June-2018 
• 
Removal of children 9-11 years of age from population being 
studied. 
 
 

 
 
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1. PROTOCOL SUMMARY 
Title: 
A Randomized, Double-Blinded, Vehicle-Controlled Study to Evaluate 
the Safety and Efficacy of BTX 1503 in Patients with Moderate to 
Severe Acne Vulgaris 
Study Phase: 
2 
Dose and Treatment 
Duration: 
There will be five dose groups.  All subjects will apply study drug for 
84 days. 
• BTX 1503 5% twice daily (BID),  
• BTX 1503 5% once daily (QD),  
• BTX 1503 2.5% once daily (QD), 
• Vehicle BID, or  
• Vehicle QD.   
Study Duration: 
The study will be a total of up to 17 weeks in duration; screening period 
up to 35 days (5 weeks) and 84 days (12 weeks) of treatment. 
Investigational 
Product: 
BTX 1503 5.0% (w/w) liquid formulation, or 
BTX 1503 2.5% (w/w) liquid formulation 
Concurrent Control: 
Vehicle without active ingredient 
Administration 
Route and Form:  
BTX 1503 or Vehicle will be applied topically to the entire face. 
Objective: 
The objective of this study is to assess safety and efficacy of various 
doses of BTX 1503 in subjects with moderate to severe acne vulgaris 
of the face. 
Study Design: 
This will be a multi-center, randomized, double-blinded, vehicle-
controlled, parallel group, dose-finding study in pediatrics, adolescents 
and adults (aged 12 to 40 years). 

 
 
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Outcome 
Measurements: 
The efficacy outcome measures are: 
Primary endpoint: 
The primary efficacy endpoint for the study is: 
• Absolute change from Baseline in inflammatory lesion counts 
at Day 84. 
Secondary endpoints:   
The secondary endpoints for the study are: 
• Absolute change from Baseline in non-inflammatory lesion 
counts at Day 84,  
• The percent change from Baseline in the inflammatory lesion 
counts at Day 84, 
• The percent change from Baseline in the non-inflammatory 
lesion counts at Day 84,  
• The proportion of subjects with at least a 2-grade reduction 
from the Baseline IGA score at Day 84,  
• The proportion of subjects with an IGA score of “clear” or 
“almost clear” at Day 84, and 
• The proportion of subjects with an IGA score of “clear” or 
“almost clear” at Day 84 and at least a 2-grade reduction from 
the Baseline IGA score. 
Exploratory endpoints: 
The exploratory endpoints are: 
• The change from Baseline in the total lesion count at Day 84,  
• The percent change from Baseline in the total lesion count at 
Day 84, 
• The change from Baseline in the IGA scores at Day 84, 
• The absolute and percent change from Baseline in 
inflammatory, non-inflammatory and total lesion counts at 
Day 14, Day 28 and Day 56, 
• The proportion of subjects with an IGA score of “clear” or 
“almost clear” at Day 14, Day 28 and Day 56, 

 
 
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• The proportion of subjects with at least a 2-grade reduction 
from the Baseline IGA score at Day 14, Day 28 and Day 56, 
and 
• The proportion of subjects with an IGA score of “clear” or 
“almost clear” at Day 14, Day 28 and Day 56 and at least a 2-
grade reduction from the Baseline IGA score. 
• The change from Baseline in the Acne-QoL at Day 84, and 
• Subject’s assessment of the change in their acne from Baseline 
to Day 84 (Patient Reported Outcome [PRO]).     
The safety outcome measures to be assessed are: 
• Adverse events (AEs) reported from time of consent/assent 
through the end of the study. 
• Complete blood count (CBC), chemistry, and urinalysis 
conducted at Baseline and at Day 84. 
Cutaneous tolerability (erythema, scaling, dryness, pruritus, and 
burning/stinging) will be assessed at the Baseline, Day 14, Day 28, Day 
56 and Day 84 Visits.  Cutaneous tolerability will be graded using the 
following scale: 0, None; 1, Slight; 2, Moderate; 3, Severe.   
Pregnancy testing will be conducted for women of child-bearing 
potential (WOCBP) at the Screening Visit, the Baseline Visit (if > 7 
days from Screening Visit) and at the Day 28, Day 56 and Day 84 
Visits. 
Total Sample Size:  
Subjects will be randomized 2:2:2:1:1 (BTX 1503 5% BID:BTX 1503 
5% QD:BTX 1503 2.5% QD:Vehicle BID:Vehicle QD) with 90 
subjects in each BTX 1503 group and 45 subjects in each vehicle group 
for a total of 360 subjects.    
Methods: 
Subjects will begin screening to determine eligibility to participate in 
the study. At the Screening Visit, informed consent/assent, medical 
history/review of systems, demographics, height and weight, 
tobacco/alcohol history, concomitant medications, and a urine 
pregnancy test (UPT) for WOCBP will be obtained.  A urine drug 
screen (UDS) will be performed.  In addition, lesion counts on the face 
(inflammatory and non-inflammatory lesions counted separately) and 
an IGA will be conducted to assess subject eligibility.  Subjects will be 
12 to 40 years of age with moderate to severe acne vulgaris of the face 

 
 
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(20 to 50 inflammatory lesions, 20 to 100 non-inflammatory lesions, 
and an IGA score of 3 or 4).  
If a subject is deemed eligible, they may be enrolled and begin Baseline 
assessments (within 35 days after the Screening Visit).  Assessments 
for safety (CBC, chemistry, and urinalysis) will be obtained at the 
Baseline Visit (Day 1). If the Screening and Baseline Visits are not 
conducted on the same day, lesion counts, IGA, UDS, and a review of 
concomitant medications will be repeated.  A UPT for WOCBP will be 
repeated if greater than 7 days from the Screening Visit.  Baseline 
photographs of the face (selected sites) will be obtained.  The Acne-
QoL will be administered.  Clinical site staff will apply the first dose of 
study drug.  Cutaneous tolerability assessments will be conducted prior 
to and approximately 15 minutes after the first application. Subjects 
will be given a diary and sufficient study drug to last until their Day 28 
Visit and instructed in the proper application to cover their entire face.  
Subjects will return to the clinic on Day 14 for a review of their diary 
to ensure compliance with study drug applications.  Lesion counts, IGA 
and cutaneous tolerability assessments will be conducted.  In addition, 
the subject will apply study drug during the visit for the clinical site to 
confirm correct application techniques.  AEs and concomitant 
medications will be reviewed.   
Subjects will return to the clinic on Day 28 and Day 56 for cutaneous 
tolerability assessments, UPT, lesion counts and IGA.  Subjects will 
also be queried for AEs and changes in concomitant medications.  
Diaries and study drug will be returned and reviewed for compliance.  
In addition, the subject will apply study drug during the visit for the 
clinical site to confirm correct application techniques.  Study drug will 
be dispensed along with the diary for the next 28 days of study drug 
treatment.       
Subjects will return to the clinic for their final visit on Day 84 for safety, 
tolerability and efficacy assessments, including lesion counts and IGA 
scoring of facial acne.  Safety labs (CBC, chemistry, and urinalysis) and 
a UPT for WOCBP will be obtained.  Photographs of the face will be 
obtained at selected sites.  Cutaneous tolerability assessments will be 
conducted, and concomitant medications and AEs will be reviewed. 
The Acne-QoL and a patient reported outcome (PRO) will be 
administered at Day 84, assessing the subject’s perception of the change 

 
 
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in their acne relative to Baseline.  See Table 3 for full Schedule of 
Assessments. 
Statistical Methods 
Analysis Sets: 
This study will be evaluated using 3 analysis sets: intent-to-treat (ITT), 
per protocol (PP), and safety.  Efficacy conclusions will be drawn from 
the ITT analysis set.  The PP analysis set will be used to support the 
efficacy findings in the ITT analyses.  Safety conclusions will be drawn 
from the safety analysis set. 
Demographics will be summarized using the safety analysis dataset by 
age, gender, race, ethnicity, height and weight.  The primary efficacy 
analysis will be conducted on the ITT population using last observation 
carried forward (LOCF) for missing data.  For continuous variables, the 
mean, standard deviation (SD), median, and range will be presented 
along with the 95% confidence interval (CI).   Categorical variables 
will be summarized by proportions along with the 95% CI. 
Vehicle QD and Vehicle BID groups may be combined for analyses. 
Handling of Missing Data: 
The primary method of handling missing efficacy data in the ITT 
analysis set will be based on LOCF.  Other imputation methods (e.g., 
mixed model for repeated measurement [MMRM]) may be used as a 
sensitivity analysis.  
All safety analyses will be conducted using the safety analysis set. No 
imputations will be made for missing safety data. 
Efficacy Analyses: 
The efficacy analyses will be performed using the ITT (primary) and 
PP (supportive) analysis sets. The efficacy variables include the IGA 
and lesion counts (inflammatory and non-inflammatory) collected at 
Screening/Baseline and all subsequent study visits. The primary 
efficacy endpoint is the absolute change in inflammatory lesion count 
at Day 84.   
Absolute and percent changes in lesion counts from Baseline will be 
calculated for each subject at Day 14, Day 28, Day 56 and Day 84.  The 
IGA will be dichotomized into “success” and “failure” at study Day 14, 
Day 28, Day 56, and Day 84 with a subject considered a “success” at 
each individual visit if the IGA at that visit is Clear (“0”) or Almost 

 
 
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Clear (“1”) and at least 2 grades less than the Baseline score.  
Exploratory efficacy assessments also include the Acne-QoL which 
will be scored according to the author’s scoring system (Martin 2001), 
and the subject’s assessment of improvement (PRO) using proportions 
by category. 
Descriptive statistics (including mean, median, standard deviation 
[SD], minimum, and maximum, unless otherwise stated) will be 
presented for the following parameters by study group using both the 
ITT and PP analysis sets: 
• Inflammatory, non-inflammatory, and total lesion counts at 
Baseline, Day 14, Day 28, Day 56, and Day 84, 
• Absolute and percent change from Baseline in inflammatory, 
non-inflammatory, and total lesion counts at study Day 14, Day 
28, Day 56, and Day 84, 
• IGA scores and frequency and percent distribution of the 
dichotomized IGA at study Day 14, Day 28, Day 56, and Day 
84. 
This Phase 2 study is designed to identify the response to two different 
dosing frequencies and two concentrations of BTX 1503. Statistical 
tests applied to the outcomes will be exploratory.  No adjustments for 
Type 1 error will occur. 
The change from Baseline in lesion counts (inflammatory and non-
inflammatory; separate and combined, and total) at Days 14, 28, 56, 
and 84 will be analyzed using ANCOVA with Baseline lesion count 
and treatment as covariates.  Success on IGA defined as a score of clear 
or almost clear and/or at least a 2-grade improvement from Baseline at 
Day 14, Day 28, Day 56, and Day 84 will be analyzed using logistic 
regression, adjusting for Baseline IGA.   
Safety Analyses:  
All subjects who receive at least one confirmed dose of study drug and 
have at least one post-Baseline assessment will be included in the safety 
analyses. Safety analyses will include summaries of treatment-
emergent adverse events (TEAEs), serious AEs (SAEs), and changes in 
laboratory assessments.  TEAEs and SAEs will be summarized by 
treatment group, the number of subjects reporting events, system organ 
class, preferred term, severity, relationship to study drug, and 

 
 
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seriousness. A list of subjects who prematurely discontinue from the 
study due to an AE and the reason for discontinuation will be provided. 
The number and percentage of subjects reporting each medication will 
be summarized.  Medications taken by each subject will be listed. 
Cutaneous Tolerability:  
Cutaneous tolerability (erythema, scaling, dryness, pruritus, and 
burning/stinging) will be summarized by treatment group at the 
Baseline, Day 14, Day 28, Day 56, and Day 84 Visits.  Cutaneous 
tolerability will be graded using the following scale: 0, None; 1, Slight; 
2, Moderate; 3, Severe. 
Sample Size: 
The sample size for this study is based on clinical considerations only. 
Subjects will be randomized 2:2:2:1:1 with 90 subjects in each active 
treatment group and 45 in each vehicle group for a total 360 subjects. 
This is considered adequate to evaluate the safety and tolerability of 
BTX 1503 in the treatment of acne vulgaris. 

 
 
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1.1. SCHEMATIC OF STUDY DESIGN  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs and concomitant medications collected at each visit. 
 
 
Enrollment Visit (Day 1) 
Safety labs, UPT, lesion counts, IGA, photos (select sites), Acne-
QoL, cutaneous tolerability  
N = 360: Screening Visit (Day -35 to Day 1) 
Assess eligibility and obtain demographics 
Day 28 Visit (Day 28 ± 5 days) 
UPT, lesion counts, IGA, cutaneous tolerability, and compliance 
Day 14 Visit (Day 14 ± 3 days) 
Assess compliance, lesion counts, IGA, cutaneous tolerability 
Randomize 
BTX 1503 
5% BID 
N=90 
BTX 1503 
5% QD 
N=90 
Vehicle 
BID 
N=45 
Vehicle 
QD 
N=45 
Day 56 Visit (Day 56 ± 5 days) 
UPT, lesion counts, IGA, cutaneous tolerability, and compliance 
Day 84 Visit/EOS (Day 84 ± 5 days) 
Safety labs, UPT, lesion counts, IGA, photos (select sites), 
cutaneous tolerability, Acne-QoL, PRO, and compliance 
BTX 1503 
2.5% QD 
N=90 

 
 
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TABLE OF CONTENTS 
1. 
PROTOCOL SUMMARY ...................................................................................................... 7 
1.1. 
SCHEMATIC OF STUDY DESIGN ............................................................................. 14 
TABLE OF CONTENTS .............................................................................................................. 15 
2. 
INTRODUCTION: BACKGROUND AND SCIENTIFIC RATIONALE .......................... 19 
2.1. 
Background Information ................................................................................................ 19 
2.2. 
Rationale......................................................................................................................... 19 
2.2.1. 
Mechanism of Action .............................................................................................. 19 
2.2.2. 
Nonclinical and Clinical Data ................................................................................. 21 
2.3. 
Rationale for Study......................................................................................................... 22 
2.4. 
Potential Risks and Benefits ........................................................................................... 23 
2.4.1. 
Known Potential Risks ............................................................................................ 23 
2.4.2. 
Known Potential Benefits ....................................................................................... 23 
3. 
OBJECTIVE ......................................................................................................................... 24 
4. 
STUDY DESIGN AND ENDPOINTS ................................................................................. 25 
4.1. 
Description of the Study Design .................................................................................... 25 
4.2. 
Study Endpoints ............................................................................................................. 25 
4.2.1. 
Primary Efficacy Endpoint ..................................................................................... 25 
4.2.2. 
Secondary Endpoints .............................................................................................. 25 
4.2.3. 
Exploratory Endpoints ............................................................................................ 25 
4.2.4. 
Safety Endpoints ..................................................................................................... 26 
4.2.5. 
Cutaneous Tolerability ............................................................................................ 26 
5. 
STUDY ENROLLMENT AND WITHDRAWAL .............................................................. 27 
5.1. 
Inclusion Criteria ............................................................................................................ 27 
5.2. 
Exclusion Criteria ........................................................................................................... 28 
5.3. 
Subject Withdrawal or Termination ............................................................................... 30 
5.3.1. 
Reasons for Withdrawal or Termination................................................................. 30 
5.3.2. 
Premature Termination or Suspension of Study ..................................................... 31 
6. 
STUDY DRUG ..................................................................................................................... 32 
6.1. 
Study Drug ..................................................................................................................... 32 
6.1.1. 
Acquisition .............................................................................................................. 32 

 
 
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6.1.2. 
Formulations, Appearance, Packaging, and Labeling ............................................ 32 
6.1.3. 
Product Storage and Stability.................................................................................. 33 
6.1.4. 
Preparation .............................................................................................................. 33 
6.1.5. 
Dosing and Administration ..................................................................................... 33 
6.1.6. 
Starting Dose ........................................................................................................... 34 
6.1.7. 
Dose Adjustments/Modifications/Delays ............................................................... 34 
6.1.8. 
Duration of Therapy ................................................................................................ 34 
6.1.9. 
Tracking of Dose..................................................................................................... 34 
6.2. 
Study Drug Accountability Procedures .......................................................................... 34 
7. 
STUDY PROCEDURES AND SCHEDULE ....................................................................... 35 
7.1. 
Study Specific Procedures/Evaluations .......................................................................... 35 
7.2. 
Laboratory Procedures/Evaluations ............................................................................... 38 
7.2.1. 
Clinical Laboratory Evaluations ............................................................................. 38 
7.2.2. 
Specimen Preparation, Handling, Shipment, and Storage ...................................... 39 
7.3. 
Study Schedule ............................................................................................................... 39 
7.3.1. 
Screening Visit ........................................................................................................ 39 
7.3.2. 
Baseline Visit .......................................................................................................... 39 
7.3.3. 
Study Drug Application Period ............................................................................... 40 
7.3.4. 
Day 14 Visit ............................................................................................................ 40 
7.3.5. 
Day 28 and Day 56 Visits ....................................................................................... 41 
7.3.6. 
Day 84/ End of Study Visit ..................................................................................... 41 
7.3.7. 
Early Termination Visit .......................................................................................... 42 
7.3.8. 
Schedule of Events Table – Subjects with Acne Vulgaris ...................................... 42 
7.4. 
Concomitant Medications, Treatment and Procedures .................................................. 44 
7.5. 
Prohibited Medication, Treatment, and Procedures ....................................................... 44 
7.6. 
Rescue Medication, Treatments and Procedures ............................................................ 45 
7.7. 
Subject Access to Study Agent at Study Closure ........................................................... 45 
8. 
ASSESSMENT OF SAFETY ............................................................................................... 46 
8.1. 
Specification of Safety Parameters ................................................................................ 46 
8.1.1. 
Definition of Adverse Events (AE)......................................................................... 46 
8.1.2. 
Definition of Serious Adverse Events (SAE) ......................................................... 46 

 
 
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8.2. 
Classification of Adverse Events ................................................................................... 47 
8.2.1. 
Relationship to Study Drug ..................................................................................... 47 
8.2.2. 
Severity of Event..................................................................................................... 48 
8.2.3. 
Expectedness ........................................................................................................... 48 
8.3. 
Time Period and Frequency for Event Assessment and Follow-up ............................... 48 
8.4. 
Reporting Procedures ..................................................................................................... 49 
8.4.1. 
Adverse Events Reporting ...................................................................................... 49 
8.4.2. 
Serious Adverse Event Reporting ........................................................................... 49 
8.4.3. 
Reporting of Pregnancy .......................................................................................... 49 
8.5. 
Safety Oversight ............................................................................................................. 50 
9. 
STATISTICAL CONSIDERATIONS.................................................................................. 51 
9.1. 
Statistical and Analytical Plans ...................................................................................... 51 
9.2. 
Statistical Hypotheses .................................................................................................... 51 
9.3. 
Analysis Datasets ........................................................................................................... 51 
9.4. 
Description of Statistical Methods ................................................................................. 52 
9.4.1. 
General Approach ................................................................................................... 52 
9.4.2. 
Safety Analyses ....................................................................................................... 52 
9.4.3. 
Efficacy Analyses ................................................................................................... 53 
9.4.4. 
Subset analyses ....................................................................................................... 55 
9.4.5. 
Adherence and Retention Analyses ........................................................................ 55 
9.4.6. 
Baseline Descriptive Statistics ................................................................................ 55 
9.4.7. 
Planned Interim Analyses ....................................................................................... 55 
9.4.8. 
Multiple Comparison/Multiplicity .......................................................................... 55 
9.4.9. 
Handling of Missing Data ....................................................................................... 55 
9.4.10. 
Tabulation of Individual Response Data ............................................................. 56 
9.5. 
Sample Size .................................................................................................................... 56 
9.6. 
Measures to Minimize Bias ............................................................................................ 56 
9.6.1. 
Enrollment/Randomization/Masking Procedures ................................................... 56 
9.6.2. 
Evaluation of Success of Blinding .......................................................................... 56 
9.6.3. 
Breaking the Study Blind/Subject Code ................................................................. 56 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .... 58 

 
 
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10.1. 
Regulatory, Ethical, and Study Oversight Considerations ......................................... 58 
10.1.1. 
Informed Consent/Assent Process ....................................................................... 58 
10.1.2. 
Institutional Review Board (IRB)/Ethics Committee (EC)................................. 58 
10.1.3. 
Subject and Data Confidentiality ........................................................................ 58 
10.1.4. 
Research Use of Stored Human Samples, Specimens or Data ............................ 59 
10.1.5. 
Future Use of Stored Specimens ......................................................................... 59 
10.1.6. 
Key Roles and Study Administration .................................................................. 59 
10.1.7. 
Clinical Monitoring ............................................................................................. 60 
10.1.8. 
Quality Assurance and Quality Control .............................................................. 61 
10.1.9. 
Data Handling and Record Keeping.................................................................... 61 
10.1.10. 
Protocol Deviations ............................................................................................. 63 
10.1.11. 
Publication and Data Sharing Policy ................................................................... 64 
10.2. 
Conflict of Interest Policy........................................................................................... 64 
10.3. 
List of Abbreviations .................................................................................................. 64 
11. 
REFERENCES .................................................................................................................. 66 
 
 
 
 
 

 
 
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2. INTRODUCTION: BACKGROUND AND SCIENTIFIC RATIONALE 
2.1. Background Information 
Botanix Pharmaceuticals' BTX 1503 containing the active pharmaceutical ingredient, cannabidiol 
(CBD; 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol) in a 
topical liquid formulation, is being developed for the treatment of acne vulgaris.  CBD is a member 
of a broader family of compounds known as cannabinoids, a class of compounds originally derived 
from the cannabis sativa plant.1 CBD is chemically synthesized under Good Manufacture Practices 
(GMP) for use in this study. 
Synthetic CBD is not psychoactive and clinical trials have demonstrated that CBD may 
successfully treat epilepsy, arthritis, pain, and even Fragile X Syndrome.2  Interest in CBD-based 
therapeutics has increased significantly in recent years, as published data has highlighted the 
potential efficacy and safety benefits of this compound.3  There are now more than 100 human 
clinical trials that have been completed, are underway, or pending recruitment around the world 
that are studying CBD in a range of diseases.4  
No known well-controlled, human clinical studies have ever been conducted using CBD to treat 
skin disease, and no CBD containing pharmaceuticals have been approved to treat skin disease. 
Researchers have found that CBD may play a beneficial role in regulating the cutaneous 
endocannabinoid system by decreasing unwanted skin cell growth, sebum production and skin 
inflammation associated with many human skin diseases.1   
2.2. Rationale 
2.2.1. Mechanism of Action 
This study is intended to establish preliminary safety and tolerability in subjects with acne vulgaris 
treated with BTX 1503.  The rationale for the use of BTX 1503 in acne is provided herein. 
Acne is the most common skin disease in the world and is characterized by partial obstruction of 
the pores and associated local skin lesions that can appear on the face, chest or back.5,6  Obstructed 
pores can become enlarged and inflamed as sebum and its breakdown products accumulate, 
resulting in visible lesions that can be unsightly and cause permanent scarring.5,6 Acne usually 
begins in puberty and affects many adolescents and young adults, but it can occur at any stage of 
life.  Approximately 85 percent of people between the ages of 12 and 24 experience at least minor 
acne.7 Acne often causes significant physical and psychological problems such as permanent 
scarring, poor self-image, depression and anxiety.8  
Acne lesions are believed to result from an interaction of four primary pathogenic factors: 
• the excessive production of sebum or lipids by sebaceous glands in the skin;  
• hyper-proliferation of keratinocytes that contribute to clogging of pores through which 
sebum is normally released to the skin surface;  

 
 
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• colonization of the area in and around the sebaceous gland by bacteria; and  
• inflammation, often associated with colonization by bacteria and their breakdown of sebum 
into irritating breakdown products.1  
For many years, treatment of acne has been dominated by the same four prescription 
pharmaceutical product classes:  
i. 
Antimicrobials.  Antimicrobials for acne treatment target bacterial colonization and 
inflammation and are widely used topically and, in more severe disease, orally.8  While 
antimicrobials have been shown to be effective, there is a growing interest in limiting the 
use of antibiotics in acne, because of concerns regarding bacterial resistance.9,10,6  
ii. 
Retinoids.  Topical retinoids address some of the changes in skin cells that contribute to 
clogging of the pores and are among the most commonly used prescription acne 
medications. Their limitations include skin irritation, photosensitization, and relatively 
modest efficacy in comparison with systemic therapies.10  
iii. 
Isotretinoin.  Oral isotretinoin (marketed initially as Accutane or Roaccutane) operates to 
significantly reduce sebum production and is indicated for the treatment of severe 
recalcitrant nodular acne.  Even in the case of very severe disease, the efficacy of oral 
isotretinoin can be significant, with large proportions of patients achieving partial or 
complete clearance, after one course of therapy.8,11 However, oral isotretinoin is associated 
with significant systemic toxicity, including liver damage and severe birth defects, which 
largely limit its use as second line treatment in  patients with severe disease who enroll in 
a monitoring program intended to restrict distribution of the drug. Mood disorders, 
depression, suicidal ideation and suicides have been reported in patients taking oral 
isotretinoin, but a causal relationship has not been established.8,12,13,14,15  
iv. 
Hormonal therapies.  Oral agents that reduce the activity of sex hormones (called 
androgens) are also highly effective, as these treatments also reduce sebum production.16 
Hormonal therapies have well-known systemic side effects, such as mood disturbance, loss 
of muscle mass and reduced sexual desire, that are related to their effects on sex hormones 
(they are most often used in the form of contraceptives). As such, they are not widely used 
in men or in women not seeking contraception.17  
No topical treatments are currently available which target all the above pathogenic factors.18  Acne 
treatment guidelines recommend that acne treatment be directed toward as many of the four 
primary pathogenic factors as possible.19  Accordingly, patients are often treated with combination 
regimens that incorporate multiple agents with complementary mechanisms of action targeting 
different pathogenic factors.20  While systemic therapies (such as isotretinoin) may inhibit sebum 
production, their use is limited by significant systemic side effects. An unmet need remains for 
effective therapies that are not associated with antibiotic resistance or treatment-limiting side 
effects, particularly therapies with novel mechanisms of action.9  

 
 
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BTX 1503 is focused on modulating the body's endocannabinoid system of receptors which 
regulate skin function, growth and renewal.21  It is understood that CBD may play a significant 
role in normalizing unwanted skin growth, reducing excessive production of oils and reducing 
inflammation and infection, amongst other functions.1  Botanix Pharmaceuticals is exploring 
whether endocannabinoid modulating drugs (such as synthetic CBD) can be exploited in the 
management of acne.  
BTX 1503 is a formulation of active synthetic CBD and inactive excipients designed to deliver a 
consistent dose of CBD to directly treat patients with acne. It is considered that CBD may: 
• normalize excessive lipid synthesis of human sebocytes  
• decrease proliferation (but not the viability) of these human sebocytes; 
• inhibit hyperproliferation of keratinocytes; 
• exert anti-inflammatory actions; and 
• have anti-bacterial effects.1,22  
2.2.2. Nonclinical and Clinical Data  
Nonclinical information on the safety pharmacology, pharmacokinetics and metabolism, and 
toxicology profiles of CBD has been extensively reported in the scientific literature.  The clinical 
safety of CBD has also been established and reviewed in the published scientific literature.  
Clinical investigations with CBD have been reported in both normal subjects and patients, 
including treatment of individuals with oral doses of up to 300 mg/day (5 mg/kg/day or 185 
mg/m2/day, for an individual with an average body weight of 60 kg).  Higher oral doses of up to 
1,500 mg/day (25 mg/kg/day or 925 mg/m2/day) have been reported to be well tolerated.  CBD 
formulated as a topical gel (Zynerba Pharmaceuticals) for treatment of epilepsy has also been 
shown to be safe and well-tolerated with only mild, transient application site AEs observed.  
Botanix Pharmaceuticals has conducted a Phase 1a single and multiple-ascending dose study (BTX 
2017.001) of BTX 1503 in normal healthy volunteers in Australia involving 20 subjects.  This 
study demonstrated that daily topical treatment with up to 3.75 mg/kg/day (225 mg CBD/day or 
0.398 mg/cm2/day1) applied as 3 mL of BTX 1503 5% (w/w) BID for 14 days was safe and well-
tolerated. Forty-two (42) AEs were reported in 18 of the 20 participants.  All AEs were reported 
as mild except one moderate vasovagal reaction to cannula insertion for blood draws (unrelated).  
Facial dryness and itchiness were the most frequently reported related AEs.  One subject reported 
application site stinging, and one subject reported stinging in the eyes after accidental transfer of 
BTX 1503 into the eyes.  
In a subsequent Australian Phase1b open-label study (BTX.2017.002) of BTX 1503 in subjects 
with moderate to severe acne involving 21 subjects, daily topical treatment with up to 3.75 
                                                 
1 Area of application assumed to be 565 cm2 (i.e., on the face), which is reported by the European Union Scientific Committee on 
Consumer Safety (SCCS) to be half of the surface area for a female head (SCCS Notes of Guidance for the Testing of Cosmetic 
Substances 
and 
Their 
Safety 
Evaluation, 
8th 
edition, 
2012; 
Table 2). 
Available 
at: 
http://ec.europa.eu/health/scientific_committees/consumer_safety/docs/sccs_s_006.pdf. 

 
 
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mg/kg/day (225 mg CBD/day or 0.398 mg/cm2/day) applied as 3 mL of BTX 1503 5% (w/w) BID 
for 28 days was shown to be safe and well-tolerated. There was only 1 AE associated with the 
study drug treatment; application site pain (sore eyes).  Slight to moderate erythema was reported 
most frequently in cutaneous tolerability assessments.  However, most subjects that reported 
erythema pre or post-study drug application had erythema at Baseline and treatment with BTX 
1503 did not exacerbate the erythema.  Only 1 subject had increased erythema from Baseline and 
this was reported at Day 35, seven days after their final application of study drug.  Slight scaling 
was reported in 2 subjects (9.5%), slight dryness was reported in 4 subjects (19.0%) and slight 
burning/stinging was reported in 5 subjects (23.4%).  Only 1 positive cutaneous tolerability 
assessment (slight dryness) was reported at more than a single visit.   
In support of this planned Phase 2 clinical study, dermal toxicology studies of 90 days in duration 
in minipigs with BTX 1503 have not revealed any clinically significant toxicities or laboratory 
abnormalities. Details on the results of these studies are provided in the Investigator’s Brochure. 
The published literature has suggested that CBD may be an inhibitor of human cytochrome P450 
CYP1A1 at concentrations that are 9.7-fold of observed maximum plasma concentrations (Cmax) 
in clinical studies with BTX 1503. 
The testes was the only target organ for toxicity identified in published studies in rats and monkeys: 
effects on sperm maturation were observed in a 25-day inhalation study in male rats [no-observed-
adverse-effect level (NOAEL) of less than 0.6 mg CBD/kg/day (< 3.6 mg/m2/day) and lower testis 
weights and inhibition of spermatogenesis were observed at a daily oral dose of 300 mg/kg 
CBD/kg/day (3,600 mg/m2/day) in male monkeys.  However, there were no changes in testis 
weight nor microscopic findings in the testes following 28 days of oral dosing in male rats at doses 
up to 400 mg/kg/day with the CBD to be used in the BTX 1503 formulations.  The Area Under the 
Concentration (AUC) exposures are over 1000-fold higher than reported in clinical studies 
involving BID dosing with BTX 1503.  In addition, there were no changes in testis weight nor 
microscopic correlates in the testes following 90 days of dermal dosing in minipigs using 
BTX 1503 at doses up to 150 mg/kg/day (AUC exposures in males at least 24-fold higher then 
observed in clinical studies with BTX 1503).  
2.3. Rationale for Study 
This study is designed to investigate the efficacy, safety and tolerability of BTX 1503 in subjects 
with moderate to severe acne.  In this study, BTX 1503 will be applied at 3 different dosage 
regimens and compared against a Vehicle control.  The treatment period will be 12 weeks to 
coincide with the FDA’s recommended minimum treatment duration to demonstrate efficacy. 

 
 
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2.4. Potential Risks and Benefits 
2.4.1. Known Potential Risks 
Based on studies conducted by Botanix Pharmaceuticals, the potential risks associated with BTX 
1503 include: 
• Ocular irritation 
• Local application site AE’s 
• Cutaneous reactions which may include erythema, dryness, scaling, and burning/stinging.   
Facial dryness and facial itchiness were reported as possible effects of study drug treatment in 
Botanix Pharmaceuticals’ healthy volunteer study (BTX.2017.001).  In the current study, subjects 
will be allowed to use their usual moisturizers.  Subjects in this study will be given instructions on 
what to do if BTX 1503 liquid accidentally gets into the eyes.   
In the BTX.2017.002 study, slight to moderate erythema was reported most frequently in 
cutaneous tolerability assessments.  However, most subjects that reported erythema pre-or post-
study drug application had erythema at Baseline and treatment with BTX 1503 did not exacerbate 
the erythema.  Only 1 subject had increased erythema from Baseline and this was reported at 
Day 35, seven days after their final application of study drug.  Slight scaling was reported in 2 
subjects (9.5%), slight dryness was reported in 4 subjects (19.0%) and slight burning/stinging was 
reported in 5 subjects (23.4%).  Only one positive cutaneous tolerability assessment (slight 
dryness) was reported at more than a single visit.      
In the published scientific literature, the only target organ for toxicity that has been identified was 
the testes in rat and monkey studies.  It is uncertain if the reduction in spermatogenesis noted in 
these animal studies has a clinical correlate.  In addition, this finding was not observed in the 28-
day oral rat study or in a 90-day dermal minipig study conducted with Botanix Pharmaceuticals’ 
BTX 1503.   
The other aspect of systemic exposure to CBD reported in the published scientific literature was 
the potential for competitive binding to CYP450 isozymes, indicating a potential for drug-drug 
interactions.  Given the limited systemic exposure observed in Botanix Pharmaceuticals’ healthy 
volunteer study, the potential for a drug-drug interaction is considered to be minimal.  
2.4.2. Known Potential Benefits 
Non-clinical data suggests BTX 1503 may target pathways relevant in pathogenesis of acne.  
Activity of BTX 1503 was observed in the BTX.2017.002 study in subject with moderate to severe 
acne.  Statistically significant improvements from Baseline in inflammatory and non-inflammatory 
lesion counts were observed.  Improvements were also observed in the IGA and in the PRO. 
Although improvements in acne were observed in this 28-day treatment study, the benefit of 
BTX 1503 in patients with 12 weeks of treatment is unknown.   

 
 
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3. OBJECTIVE 
The objective of this study is to assess safety and efficacy of various doses of BTX 1503 liquid 
formulation in subjects with moderate to severe acne vulgaris of the face. 

 
 
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4. STUDY DESIGN AND ENDPOINTS 
4.1. Description of the Study Design 
This is multi-center, randomized, double-blind, vehicle-controlled, parallel group, dose-finding 
study.  Approximately 360 subjects will be enrolled.   
4.2. Study Endpoints 
4.2.1. Primary Efficacy Endpoint 
The primary endpoint for the study is the absolute change from Baseline in inflammatory lesion 
counts at Day 84. 
4.2.2. Secondary Endpoints 
The secondary endpoints for the study are: 
• Absolute change from Baseline in non-inflammatory lesion counts at Day 84,  
• The percent change from Baseline in the inflammatory lesion counts at Day 84, 
• The percent change from Baseline in the non-inflammatory lesion counts at Day 84,  
• The proportion of subjects with an IGA score of “clear” or “almost clear” at Day 84, 
• The proportion of subjects with at least a 2-grade reduction from the Baseline IGA 
score at Day 84, and 
• The proportion of subjects with an IGA score of “clear” or “almost clear” at Day 84 
and at least a 2-grade reduction from the Baseline IGA score. 
4.2.3. Exploratory Endpoints 
The exploratory endpoints for the study are: 
• The change from Baseline in the total lesion count at Day 84,  
• The percent change from Baseline in the total lesion count at Day 84, 
• The change from baseline in the IGA scores and Day 84, 
• The absolute and percent change from Baseline in inflammatory, non-
inflammatory and total lesion counts at Day 14, Day 28 and Day 56. 
• The proportion of subjects with at least a 2-grade reduction from the Baseline 
IGA score at Day 14, Day 28 and Day 56,  
• The proportion of subjects with an IGA score of “clear” or “almost clear” at 
Day 14, Day 28 and Day 56, 

 
 
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• The proportion of subjects with an IGA score of “clear” or “almost clear” at 
Day 14, Day 28 and Day 56 and at least a 2-grade reduction from the Baseline 
IGA score. 
• The change from Baseline in the Acne-QoL at Day 84, and 
• Subject’s assessment of the change in their acne from Baseline to Day 84 (PRO). 
4.2.4. Safety Endpoints 
Safety for this study will be assessed by: 
• Collection of reported adverse events throughout the study, 
• Safety labs conducted at Baseline and Day 84, 
• Monitoring of concomitant medications throughout the study, 
• All women of childbearing potential (WOCBP) will have a urine pregnancy test 
(UPT) performed at the Baseline, Day 28, Day 56, and Day 84 Visits. 
4.2.5. Cutaneous Tolerability 
Cutaneous tolerability will be assessed at Baseline and each subsequent visit using a 4-point 
tolerability scale (0-3).  Erythema, scaling, and dryness will be assessed by the investigator at 
Baseline and at each visit.  Subjects will also be asked to rate symptoms of itching and 
burning/stinging over the preceding 24 hours at Baseline and subsequent visits using a 4-point 
(0-3) scale (see Table 1). 
 

 
 
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5. STUDY ENROLLMENT AND WITHDRAWAL 
5.1. Inclusion Criteria  
To be included in the study, subjects with acne vulgaris must meet the following inclusion criteria. 
1. Subject (or legal guardian) has the ability and willingness to sign a written informed 
consent/assent. 
2. Subject is of either gender and 12 to 40 years of age.  
3. Subject is in good general health without clinically significant haematological, cardiac, 
respiratory, renal, endocrine, gastrointestinal, psychiatric, hepatic, or malignant disease, as 
determined by the investigator. 
4. Subject has suitable venous access for blood sampling. 
5. Subject is able and willing to complete the study and to comply with all study instructions 
and attend the necessary visits. 
6. Subject has acne vulgaris of the face defined as: 
a. 20 to 50 (inclusive) inflammatory lesions on the face 
b. 20 to 100 (inclusive) non-inflammatory lesions on the face 
c. An Investigator’s Global Assessment (IGA) score for acne severity of 3 or 4 
(moderate or severe) assessed on the face. 
7. Subject has ≤ 2 nodular/cystic acne lesions (>5 mm in diameter). 
8. Subject must refrain from the use of other treatments for acne during the study. 
9. Subject must agree to not wash or shave their face, swim or otherwise get their face wet 
for at least 1 hour after application of study medication.   
10. Subject must agree to maintain their regular use of sunscreens, moisturizers, shaving 
cream, and facial make up throughout the entire course of the study.     
11. Male subjects and their partners must agree and commit to use a barrier method of 
contraception during the study and for 90 days after last study drug application. 
12. A negative UPT result for all WOCBP at the Screening Visit and Baseline Visit, if 
applicable.  A WOCBP is one who is not permanently sterilized or is not postmenopausal.  
Postmenopausal is defined as 24 months with no menses without an alternative medical 
cause. 

 
 
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13. Sexually active women must agree to use the following throughout the study and for 30 
days after last study drug application: 
a. One of these highly effective contraception methods 
i. Intrauterine device (IUD); hormonal (injections, implants, transdermal 
patch, vaginal ring; tubal ligation; partner vasectomy, OR 
b. Oral contraceptives WITH a barrier method (listed below), OR 
c. Two barrier forms of contraception (listed below) 
i. Male or female condom; diaphragm; cervical cap. 
14. Male subjects must refrain from sperm donation during the study treatment period until 90 
days after final study drug administration. 
15. Male subjects must agree to keep their face clean shaven (no moustache or goatee; short 
sideburns acceptable) throughout the study and use the same method for shaving as was 
used for the 4 weeks prior to the Screening Visit. 
5.2. Exclusion Criteria  
If a subject meets any of the following exclusion criteria, they may not participate in the study. 
1. People who would otherwise qualify for the study but are living in the same household as 
a study subject, are not allowed to participate in the study. 
2. Female subject who is breast feeding, pregnant, or planning to become pregnant any time 
during the course of the study.  
3. Subject with history of known or suspected intolerance to the drug product excipients.   
4. Subject has known HIV infection. 
5. Subject has acne conglobata, acne fulminans, secondary acne (chloracne), pseudo-
folliculitis, severe acne requiring systemic treatment, or is taking a medication known to 
induce or exacerbate acne. 
6. Subject has severe truncal acne. 
7. Subject has excessive facial hair that would interfere with the evaluation of safety or with 
the diagnosis or assessment of acne vulgaris.  
8. Subject has sunburns, unevenness in skin tones, tattoos, scars, excessive hair, freckles, 
birthmarks, moles, or other skin damage or abnormality that would result in the inability 
to evaluate the skin of the face. 
9. Subject has any skin condition of the face other than acne vulgaris.  
10. Subject has used oral retinoid (e.g. isotretinoin) within 6 months (180 days) prior to the 
Baseline Visit. 

 
 
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11. Subject has used Vitamin A supplements greater than 10,000 units/day within 6 months 
(180 days) prior to the Baseline Visit. 
12. Subject has used androgen receptor blockers (such as spironolactone or flutamide) within 
3 months (90 days) prior to the Baseline Visit. 
13. Subject has initiated treatment with hormonal therapy or changed dosing with hormonal 
therapy within 3 months (90 days) prior to the Baseline Visit.  Note: Dose and frequency 
of any hormonal therapy started more than 3 months (90 days) prior to the Baseline Visit 
must remain unchanged throughout the study.  Hormonal therapies include, but are not 
limited to, anabolic steroids and birth control pills.  Subjects taking testosterone therapy 
are excluded from participation. 
14. Subject has had facial procedures (chemical or laser peel, microdermabrasion, etc.) within 
8 weeks (56 days) prior to the Baseline Visit.   
15. Subject has had treatment with systemic antibiotics within 4 weeks (28 days) prior to the 
Baseline Visit. 
16. Subject has had treatment with systemic anti-acne drugs within 4 weeks (28 days) prior to 
the Baseline Visit. 
17. Subject has had treatment with systemic anti-inflammatory drugs within 4 weeks (28 days) 
prior to the Baseline Visit. 
Note: Occasional non-steroidal anti-inflammatory drugs (NSAIDs) and aspirin use on an 
as-needed basis, and if not used consecutively for >14 days prior to the Baseline Visit, is 
acceptable and does not require washout. Subjects receiving intranasal and inhaled 
corticosteroids may participate.  Low dose (81mg) aspirin taken daily is acceptable. 
18. Subject has had treatment with systemic (oral) corticosteroids other immunosuppressive 
medications within 4 weeks (28 days) prior to the Baseline Visit. 
19. Subject has had treatment with prescription topical retinoid use on the face (e.g. tretinoin, 
tazarotene) within 4 weeks (28 days) prior to the Baseline Visit. 
20. Subject has had treatment with topical prescription antibiotics (e.g. dapsone, clindamycin, 
erythromycin, or sulfacetamide) or combination products that include a topical antibiotic 
within 2 weeks (14 days) prior to the Baseline Visit.  
21. Subject has had treatment with over-the-counter (OTC) topical medications for the 
treatment of acne vulgaris including benzoyl peroxide, topical anti-inflammatory 
medications, corticosteroids, adapalene, α-hydroxy/glycolic acid on the face within 2 
weeks (14 days) prior to the Baseline Visit. 
22. Subject is currently using any medication that, in the opinion of the investigator, may affect 
the evaluation of the study product or place the subject at undue risk. 
23. Subject has had photodynamic therapy within 8 weeks (56 days) prior to the Baseline Visit.  

 
 
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24. Subject has used a tanning bed within 2 weeks (14 days) prior to the Baseline Visit. 
25. Subject has used home-based light treatment within 2 weeks (14 days) prior to the Baseline 
Visit. 
NOTE:  Use of the treatments listed in Exclusion Criteria 10 through 25 above are not permitted 
throughout the study. 
26. Subject has an underlying disease that requires the use of interfering topical or systemic 
therapy. 
27. Subject has other dermatological conditions that require the use of interfering topical or 
systemic therapy or that might interfere with study assessments such as, but not limited to, 
atopic dermatitis, psoriasis, perioral dermatitis, or rosacea. 
28. Subject has had excessive sun exposure (in the opinion of the investigator) within one week 
prior to the Baseline Visit and an unwillingness to refrain from excessive sun exposure 
during the study. 
29. Subject has a clinically relevant history or currently suffering from any disease or condition 
that, in the opinion of the investigator, may affect the evaluation of the study product or 
place the subject at undue risk. This may include respiratory (including chronic asthma 
requiring repetitive drug interventions), gastrointestinal, renal, hepatic, hematological, 
lymphatic, neurological, cardiovascular, psychiatric, musculoskeletal, genitourinary, 
immunological, dermatological, or connective tissue diseases or disorders. 
30. Subject has a clinically relevant history of, or current evidence of, abuse of alcohol or other 
drugs.  Subjects may be deemed eligible if the UDS identifies subject-reported, prescribed 
drugs or appropriate levels of alcohol, as determined by the investigator. 
31. Subject has participated in another investigational drug or device research study within 4 
weeks (28 days) of the Baseline Visit or five half-lives of the drug, whichever is longer. 
32. Any other reason that would make the subject, in the opinion of the investigator or sponsor, 
unsuitable for the study. 
5.3. Subject Withdrawal or Termination 
5.3.1. Reasons for Withdrawal or Termination 
If a subject is withdrawn from the study, the subject’s enrollment in the study will terminate and 
study drug application will be discontinued.  Efforts will be made to perform all assessments 
scheduled for the Day 84 Visit prior to subject withdrawal.  The Day 84 Visit should be scheduled 
for day 84 (±5 days), if possible. 
A subject may be withdrawn from further study participation under the following circumstances: 
• At the subject’s request. 

 
 
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• Noncompliance with protocol by the subject as determined by the study site staff and 
investigator. 
• Adverse Event (decision to be removed from study made by either the investigator or 
subject). The investigator must notify the sponsor immediately if a subject is withdrawn 
because of an AE. 
• Pregnancy. 
• Decision by the investigator or sponsor that termination is in the subject’s best medical 
interest or for an administrative decision for a reason other than that of an AE. 
• Lost to follow-up, as determined by failure to respond to at least 2 telephone calls followed 
by certified letter sent to the subject’s last known address. All attempts to contact the 
subject must be documented in the subject’s source documents. 
• Sponsor decision to halt the entire study. 
5.3.2. Premature Termination or Suspension of Study 
This study may be suspended or prematurely terminated if there is sufficient reasonable cause. 
Written notification, documenting the reason for study suspension or termination, will be provided 
by the suspending or terminating party to the investigator.  If the study is prematurely terminated 
or suspended by the sponsor, the PI will promptly inform the Institutional Review Board (IRB) or 
Ethics Committee (EC) and will provide the reason(s) for the termination or suspension.  
Circumstances that may warrant termination or suspension include, but are not limited to:  
• Determination of unexpected, significant, or unacceptable risk to subjects, 
• Insufficient compliance to protocol requirements,  
• Data that are not sufficiently complete and/or evaluable.  
The study may resume once concerns about safety, protocol compliance, or data quality are 
addressed and satisfy the sponsor and IRB/EC. 

 
 
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6. STUDY DRUG 
6.1. Study Drug  
6.1.1. Acquisition 
Study drug will be provided to the US study sites by The Coghlan Group (TCG) in Bastrop, Texas, 
USA and to the Australian sites by Pharmaceutical Packaging Professionals (PPP) in Port 
Melbourne, Victoria, Australia.  Initial shipments will be made to supply the study sites prior to 
enrollment of the first subject. Additional supplies will be made available as needed based on 
subject enrollment.  
6.1.2. Formulations, Appearance, Packaging, and Labeling 
Botanix Pharmaceuticals’ BTX 1503 contains the active pharmaceutical ingredient, cannabidiol 
(CBD).  CBD is a member of a broader family of compounds known as cannabinoids, a class of 
compounds originally derived from the cannabis sativa plant.1  CBD is chemically synthesized 
under Good Manufacturing Practices (GMP) for use in this study. 
The active study product is a clear to light yellow, slightly viscous liquid with a 2.5% or 5% (w/w) 
concentration of CBD in a formulation of excipients which have been used extensively in other 
topical products.  The liquid spreads easily and quickly evaporates, leaving the CBD and a small 
amount of excipients on the skin.  The Vehicle liquid is identical in appearance to the BTX 1503 
liquid.   
Each milliliter of the BTX 1503 5% liquid formulation contains 37.5 mg of CBD.  Each milliliter 
of the BTX 1503 2.5% liquid formulation contains 18.75 mg of CBD.  All subjects will apply 2.0 
mL, 4 pump actuations, of BTX 1503 BID or QD or Vehicle BID or QD based on their randomized 
treatment group.  Subjects will receive the following daily exposure to CBD. 
• Subjects randomized to BTX 1503 5% BID will apply 150.0 mg of CBD daily,    
• Subjects randomized to BTX 1503 5% QD will apply 75.0 mg of CBD daily,    
• Subjects randomized to BTX 1503 2.5% QD will apply 37.5 mg of CBD daily. 
Study drug will be supplied in 60 mL multi-dose, metered pumps delivering 0.5 mL per actuation.  
Each pump for BID dosing will contain approximately 39 mL of study drug and each pump for 
QD dosing will contain approximately 21 mL of study drug.  This will provide dosing for 7 days 
for all subjects.  Pumps for all groups will be labeled identically, except for kit number and bottle 
number, to maintain the blind.   
Study drug will be pumped into the palm of one hand and applied to the face using fingertips of 
the other hand.  Study drug will be applied to the entire face, regardless of location of acne lesions.   
Study drug will be provided in kits.  Each kit will contain adequate study drug for 4 weeks of daily 
applications (28 days).  Prior to distribution, pumps will be weighed by clinical site staff and the 
weights recorded in the source documents and the eCRF.  Each kit will contain 4 pumps, one for 

 
 
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each week of dosing.  When a subject is enrolled, the site will access the IWRS to receive a kit 
number for the first 28 days of dosing based on the IWRS randomization.  At the Day 28 and Day 
56 Visits, the site will access the IWRS to obtain the kit number for the following 28 days of 
dosing.  All distributed pumps will be returned by the subject at the Day 28, Day 56, and Day 84 
Visits and weighed to monitor compliance and document doses delivered.   
The study drug bottle may include the following information: 
Caution: New Drug--Limited by Federal (or United States) law to investigational use only. 
KEEP OUT OF REACH OF CHILDREN 
Drug Ingredient:  BTX 1503 or Vehicle 
Directions: Use in accordance with study drug application instructions. 
FOR TOPICAL APPLICATION ONLY.  
Protocol # BTX.2018.001 
 
 
 
Flammable.  Store between 15-30
oC. 
 
Bottle #  
Kit # 
Sponsor: Botanix Pharmaceuticals Ltd  
6.1.3. Product Storage and Stability 
The study drug will be stored at a controlled room temperature of 15°C to 30°C and should not be 
refrigerated.  Prior to dispensing to the subject, the study drug will be stored in a secured location 
with access only by authorized study personnel.  Study drug has been tested to ensure that there is 
adequate stability for the duration of the study.   Retest dates may be included on the carton 
labeling. 
6.1.4. Preparation 
No preparation of the study drug is required.   
6.1.5. Dosing and Administration 
Subjects will receive their initial application of study drug on Day 1 at the clinical sites 
administered by the clinical site staff.  When the subject is ready for study drug application, a 
pump is selected from the assigned study kit.  The clinical site staff will remove the cap and apply 
the first dose of the study drug to the subject’s entire face.   All subsequent applications will be 
completed by the subject.   To ensure that the entire face is covered, the study drug should be 
applied in a consistent manner for each application.   
Subjects will be instructed in how to apply study drug.  After their first application in the clinic 
subjects will apply their study drug at home.  Each application of study drug will occur at the 
approximately the same time in the morning with the second application (for BID dosing groups) 
approximately 8 to 12 hours later.  Subjects will apply study drug at the clinical site during the 
Day 14, Day 28, Day 56 and Day 84 Visits (final dose).  A diary will be maintained documenting 

 
 
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compliance with the self-administered applications.  All study drug bottles (used and unused) will 
be returned to the clinical site on the Day 28, Day 56, and Day 84 Visits. 
Study drug should not be applied to the eyes or mouth.   Subjects are to thoroughly wash their 
hands after study drug application.  The study drug must not be handled by a family member or 
caregiver for study drug application. 
6.1.6. Starting Dose  
The dose for all subjects will be 2.0 mL, 4 pump actuations, of study drug applied to the entire 
face.  No escalation of dose will occur.     
6.1.7. Dose Adjustments/Modifications/Delays 
There are no pre-planned dose adjustments, modifications, or delays.      
6.1.8. Duration of Therapy 
Subjects will apply study drug for 84 days with a final application on Day 84.  Subjects receiving 
BID dosing will apply 167 doses and subjects receiving QD dosing will apply 84 doses.   
6.1.9. Tracking of Dose 
All subjects will be required to maintain a diary documenting each application of study drug.  The 
subject will record that they applied each study dose.  Subjects will return the study drug bottles 
(used and unused) at each visit.  The clinical site staff will review the diary and count used/unused 
bottles to ensure subject compliance with dosing.   
6.2. Study Drug Accountability Procedures 
At each study visit the clinical site will weigh each pump dispensed to the subject and returned 
from the subject to calculate the amount (grams) of study drug used.  The investigator will keep a 
current and accurate inventory of all clinical supplies received.  These records will be reviewed at 
each monitoring visit performed by the CRA per SOPs.  

 
 
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7. STUDY PROCEDURES AND SCHEDULE 
7.1. Study Specific Procedures/Evaluations 
At the Screening Visit (Visit 1), all subjects/legal guardians will review and sign an informed 
consent/assent form attesting to their knowledge of the study requirements, risks, and benefits.  
The following study specific procedures will occur for all subjects at the Screening Visit: 
• Demographics, height, weight, and a medical history, including alcohol and tobacco use, 
will be obtained,   
• A review of systems will be conducted by the principal investigator or designee, 
• All WOCBP will have a UPT conducted.  The test must be negative for the subject to be 
enrolled,  
• A urine drug screen will be conducted to ensure that the subject is not taking drugs of 
abuse, 
• A count of inflammatory and non-inflammatory lesions on the face and an IGA will be 
collected, 
• The subjects will be queried for concomitant medications that they are currently taking.  
Concomitant medications include all prescribed and over the counter (OTC) medications 
and any supplements, and 
• Eligibility criteria will be reviewed to determine if subjects may proceed to study 
enrollment.   
If subjects are eligible upon screening, they may be enrolled into the study on the same day.   
At various visits throughout the study, the following will occur for all subjects to monitor the safety 
of the study drug treatment: 
• Blood draws will be conducted for CBC and chemistry analysis, 
• Collection of urine will occur for a urinalysis, 
• Cutaneous tolerability assessments will be conducted by the principal investigator or an 
appropriately trained designee.  Cutaneous tolerability will be graded using the following 
scale: 0, None; 1, Slight; 2, Moderate; 3, Severe.  Evaluation for, and grading of, the 
following will be done at each evaluation: 
o Erythema (investigator assessed),  
o Scaling (investigator assessed),  
o Dryness (investigator assessed),  
o Pruritus in last 24 hours (subject reported), and 
o Burning/Stinging in last 24 hours (subject reported). 
The definition for each level of grading for each tolerability assessment is provided in Table 1. 

 
 
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Table 1.  Cutaneous Tolerability Assessments Scale for Acne Vulgaris 
Tolerability Assessment 
Severity 
None = 0 
Mild = 1 
Moderate = 2 
Severe = 3 
Erythema 
No erythema 
Slight pinkness present 
Definite redness, easily 
recognized 
Intense redness 
Scaling 
No scaling 
Barely perceptible 
shedding, noticeable 
only on light scratching 
or rubbing 
Obvious but no profuse 
shedding 
Heavy scale production 
Dryness 
No dryness 
Slight but definite 
roughness 
Moderate roughness   
Marked roughness   
Pruritus (in last 24 hours) No itching 
Only aware of itching at 
times; only present when 
relaxing; not present 
when focused on other 
activities 
Often aware of itching; 
annoying; sometimes 
disturbs sleep and 
daytime activities 
Constant itching; 
distressing; frequent 
sleep disturbance; 
interferes with activities 
Burning/Stinging (in last 
24 hours) 
No Burning/Stinging 
Slight warm, 
tingling/stinging 
sensation; not really 
bothersome 
Definite warm, 
tingling/stinging 
sensation that is 
somewhat bothersome 
Hot, tingling/stinging 
sensation that has caused 
definite discomfort 
 
 
 
 
 

 
 
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• Subjects will be queried to report any AEs that have occurred since the last visit.   
• Subjects will be queried to report any new medications or changes in current medications. 
For all subjects, assessment of compliance with study drug application will be conducted through 
collection of a study diary on which subjects will record their daily administration.  Subjects will 
be required to bring all used and unused study drug to each visit where the study site will assess 
compliance. At each study visit the clinical site will weigh each pump dispensed to the subject and 
returned from the subject to calculate the amount (grams) of study drug used.   
The following efficacy assessments will be performed at the Screening, Baseline, Day 14, Day 28, 
Day 56, and Day 84 Visits: 
• Counting of inflammatory and non-inflammatory lesions of the face by the principal 
investigator (PI) or appropriately trained designee.  Thorough, documented, training will 
be provided to the PI and/or designee in the method for identifying and counting lesions.   
• Administration of the IGA by the PI or appropriately trained designee.  The IGA will be 
graded based on the scale provided in Table 2. 
Table 2.  Investigator’s Global Assessment Scale for Acne Vulgaris 
Grade 
Description 
0 
Clear 
No evidence of facial acne vulgaris 
1 
Almost Clear 
Few non-inflammatory lesions (comedones) are present; a few non-
inflamed papules (papules must be resolving and may be 
hyperpigmented, though not pink-red) may be present 
2 
Mild 
Several to many non-inflammatory lesions (comedones) are present; 
a few inflammatory lesions (papules/pustules) are present; no nodulo-
cystic lesions 
3 
Moderate 
Many 
non-inflammatory 
(comedones) 
and 
inflammatory 
(papules/pustules) are present; there may or may not be one small 
nodulo-cystic lesion 
4 
Severe 
Significant degree of inflammatory disease; papules/pustules are a 
predominant feature; a few nodulo-cystic lesions may be present; 
many comedones may be present.   
 
• Photographs of the subject’s face will be obtained at selected sites at the Baseline Visit and 
the Day 84 Visit.  Details on the methods for photography are provided in the Photography 
Manual. 
• At Baseline and at Day 84, the Acne-QoL will be administered. 

 
 
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• On Day 84, the subject will be asked to complete the Patient Reported Outcome (PRO) to 
assess the perception of their acne relative to their baseline.  The subject will complete the 
assessment to answer the following question: “Compared to the beginning of treatment, 
my acne is?” with a response of “Much better”, “Slightly better”, “The same”, “Slightly 
Worse”, or “Much worse”. 
For purposes of conducting IGA scoring, the following definitions will apply: 
• 
Open comedo - a widely dilated follicle, plugged with sebum and keratin (blackhead) 
• Closed comedo - a small, flesh-colored closed follicle, filled with sebum and firm to 
palpation  
• Papule - a small solid, inflamed, elevated lesion less than 5 mm in diameter 
• Pustule - a circumscribed, erythematous raised skin lesion containing white exudate or pus, 
less than 5 mm in diameter 
• Nodule - an erythematous, raised, firm, deep-seated papule equal to or greater than 5 mm 
in diameter 
7.2. Laboratory Procedures/Evaluations 
7.2.1. Clinical Laboratory Evaluations 
For all subjects, a CBC, chemistry, and urinalysis will be conducted at the Baseline and Day 84 
Visits.  Details are provided in the Laboratory Manual.  Blood samples will be taken per standard 
venipuncture techniques.  The following will be assessed: 
CBC: White blood cell (WBC) count (with automated differential for absolute neutrophils, 
lymphocytes, monocytes, eosinophils, and basophils), red blood cell (RBC) count, 
haemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular 
haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), and platelet 
count; 
Chemistry: Glucose, albumin, total protein, calcium, sodium, potassium, chloride, CO2 
(bicarbonate), blood urea nitrogen (BUN), creatinine, alkaline phosphatase, alanine amino 
transferase (ALT), aspartate amine transferase (AST), and total bilirubin; 
Urinalysis: Color, clarity, specific gravity, pH, protein, glucose, and leukocyte esterase.  If 
the results are abnormal or further analysis is requested by the site, the sample will undergo 
microscopic analysis for red blood cells, white blood cells, and squamous epithelial cells. 
For all WOCBP, a UPT will be conducted at the Screening Visit, Baseline Visit (if > 7 days from 
Screening Visit), and the Day 28, Day 56, and Day 84 Visits.  Details for collecting and testing 
urine for the UPT are provided in the Laboratory Manual.   

 
 
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7.2.2. Specimen Preparation, Handling, Shipment, and Storage 
Specimen preparation, handling, shipment, and storage for the CBC, chemistry and urinalysis are 
described in the Laboratory Manual.   
7.3. Study Schedule 
7.3.1. Screening Visit 
At the Screening Visit (Day -35 to Day 1), the following will be conducted: 
• Obtain written informed consent/assent 
• Conduct medical history and review of systems 
• Obtain subject demographics  
• Obtain subject’s height and weight 
• Obtain smoking and alcohol history and current use 
• Conduct UPT for all WOCBP 
• Collect urine sample to test for drugs of abuse 
• Perform IGA 
• Count inflammatory and non-inflammatory lesions (separately) on the face 
• Review eligibility criteria 
• Query subject for concomitant medications 
If the subject is found to be eligible for participation in the study, the Baseline Visit procedures 
may then be conducted.  If the subject requires any washout period, this period must be completed 
within 35 days prior to the Baseline Visit.  Subjects found to be ineligible will be screen failed and 
the reason for screen failure will be recorded. 
7.3.2. Baseline Visit  
If the subject is deemed eligible and proceeds to enrollment on the same day as the Screening Visit, 
in addition to the screening assessments the following will be conducted: 
• Collect blood sample for CBC and chemistry 
• Collect urine sample for urinalysis  
• Take photographs of face (selected sites) 
• Administer Acne-QoL prior to first application of study drug 
• Assess cutaneous tolerability prior to application of study drug 
• Apply study drug on subject’s face (see Section 6.1.5) 
• Assess cutaneous tolerability approximately 15 minutes after the application of study drug 
• Monitor subject for adverse events 
• Train subject in proper application of study drug.  Dispense study drug 
• Dispense study diary and train the subject in diary completion 
• Weigh and dispense study drug 

 
 
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If the subject is not enrolled on the same day as the Screening Visit, the following will be 
conducted at the Baseline Visit: 
• Review eligibility criteria 
• Query subject for changes in concomitant medications  
• Collect blood sample for CBC and chemistry 
• Collect urine sample for urinalysis 
• Conduct UPT (WOCBP only) (if > 7 days from Screening Visit) 
• Collect urine sample to test for drugs of abuse 
• Perform IGA 
• Count inflammatory and non-inflammatory lesions (separately) on the face  
• Take photographs of face (selected sites) 
• Administer Acne-QoL prior to first application of study drug 
• Assess cutaneous tolerability prior to application of study drug 
• Apply study drug on subject’s face (see Section 6.1.5) 
• Assess cutaneous tolerability approximately 15 minutes after the application of study drug 
• Monitor subject for adverse events 
• Train subject in proper application of study drug.   
• Weigh and dispense study drug 
• Dispense study diary and train the subject in diary completion 
7.3.3. Study Drug Application Period 
At the Day 1 Visit, subjects will receive their first study drug application at the clinical site during 
the visit.  Subjects will be trained in the correct application of the study drug.   Application of 
study drug should occur at approximately the same time each day.  For subjects receiving BID 
dosing, the evening application should take place approximately 8 to 12 hours after the morning 
application.  A diary will be maintained documenting compliance with the self-administered 
applications.  At the Baseline, Day 28, and Day 56 Visits, the subject will be provided an ample 
supply of study drug to complete dosing for the next 28 days.  Study drug will be applied at the 
clinical site during the Day 14, Day 28, Day 56 and Day 84 Visits (final dose) to ensure compliance 
with application instructions. Subjects will be instructed to not apply their study drug prior to the 
study visit.      
7.3.4. Day 14 Visit 
At the Day 14 Visit ± 3 days, the following will be conducted. 
• Query subject for changes in concomitant medications since the Baseline Visit 
• Query subject for adverse events that occurred since the Baseline Visit  
• Review subject dosing diary and the number of used/unused bottles to ensure compliance   
• Perform IGA  

 
 
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• Count facial inflammatory and non-inflammatory lesions (separately) on the face  
• Assess cutaneous tolerability prior to application of study drug 
• Study drug application by the subject   
• Assess cutaneous tolerability approximately 15 minutes after the application of study drug 
7.3.5. Day 28 and Day 56 Visits 
At the Day 28 Visit ± 5 days and the Day 56 Visit ± 5 days, the following will be conducted. 
• Query subject for changes in concomitant medications  
• Query subject for adverse events that occurred since the previous visit  
• Conduct UPT for WOCBP 
• Perform IGA  
• Count inflammatory and non-inflammatory lesions (separately) on the face  
• Collect and weigh study drug  
• Collect study diary and dispense new diary for next 28 days 
• Assess for cutaneous tolerability prior to application of the study drug 
• Subject will apply dose of study drug in front of clinical site staff 
• Assess cutaneous tolerability approximately 15 minutes after application of the study drug 
• Weigh and dispense study drug for next 28 days of dosing 
7.3.6. Day 84/ End of Study Visit 
The final application of study drug will occur during the Day 84 Visit.  Subjects will be instructed 
to not apply their final application of study drug until they are seen in the clinic.  At the Day 84 
Visit (Day 84 ± 5 days) the following will be conducted.  
• Query subject for changes in concomitant medications  
• Query subject for adverse events that occurred since the Day 56 Visit  
• Conduct UPT for WOCBP 
• Collect blood sample for CBC and chemistry 
• Collect urine sample for urinalysis  
• Perform IGA  
• Count inflammatory and non-inflammatory lesions (separately) on the face  
• Take photography of face (selected sites) 
• Administer Acne-QoL 
• Administer PRO 
• Collect and weigh study drug  
• Collect study diary 
• Assess for cutaneous tolerability prior application of the final dose 
• Subject will apply final dose of study drug in front of clinical site staff 
• Assess cutaneous tolerability approximately 15 minutes after application of the final dose 

 
 
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• Discharge subject from study 
7.3.7. Early Termination Visit 
If a subject terminates the study early for reasons other than an AE, attempts will be made to 
complete the assessments required for the Day 84 Visit on Day 84 (± 5 days), if possible.   
7.3.8. Schedule of Events Table – Subjects with Acne Vulgaris 
The Schedule of Events is provided in Table 3. 
 

 
 
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Table 3: Time and Events Schedule  
Parameter 
 
Screening Visit 
(-35 to Day 1) 
Baseline Visit 
(Day 1)a 
Day 14 Visit 
(Day 14 ±3 days) 
Day 28 Visit  
(Day 28 ±5 days) 
Day 56 Visit 
(Day 56 ±5 days) 
Day 84 Visitc 
(Day 84 ±5 days) 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Written informed consent/assent 
X 
 
 
 
 
 
Medical history/ review of systems 
X 
 
 
 
 
 
Demographics with Height and Weight  
X 
 
 
 
 
 
Tobacco and Alcohol History 
X 
 
 
 
 
 
Urine pregnancy test (WOCBP only) 
X 
X 
 
X 
X 
X 
Eligibility criteria review 
X 
X 
 
 
 
 
Safety Laboratory (CBC, chemistry and urinalysis) 
 
X 
 
 
 
X 
Urine drug screening 
X 
X 
 
 
 
 
Investigator’s Global Assessment  
X 
X 
X 
X 
X 
X 
Inflammatory and non-inflammatory lesion count 
X 
X 
X 
X 
X 
X 
Photography of Face (selected sites) 
 
X 
 
 
 
X 
Administer Acne-QoL 
 
X 
 
 
 
X 
Administer PRO  
 
 
 
 
 
X 
Ensure compliance with study drug administration 
 
 
X 
X 
X 
X 
Study drug administration by site personnel (am) 
 
X 
 
 
 
 
Study drug administration by subject 
 
Day 1 pm to Day 84d; Day 14, 28, 56, and 84 doses applied in clinic 
Concomitant medications  
X 
X 
X 
X 
X 
X 
Adverse events  
 
X 
X 
X 
X 
X 
Cutaneous tolerability assessmentsb 
 
X 
X 
X 
X 
X 
Dispense study drug and diary 
 
X 
 
X 
X 
 
Collect diary and study drug 
 
 
 
X 
X 
X 
a Screening and Baseline Visit may occur on the same day.    
b Assess cutaneous tolerability prior to and approximately 15 min after initial dose on Day 1 and the subject applications on Day 14, Day 28. Day 56, and Day 84   
c If subject discontinues treatment early, Day 84 evaluations will be performed when possible. 
d Subjects randomized to BID dosing will apply study drug in the morning and evening, 8 to 12 hours apart.

 
 
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7.4. Concomitant Medications, Treatment and Procedures 
All concomitant medications taken during study participation will be recorded on the case report 
forms (eCRFs). For this protocol, a prescription medication is defined as a medication that can be 
prescribed only by a properly authorized/licensed clinician. Medications to be reported in the 
eCRF are concomitant prescription medications, OTC medications, and non-prescription 
medications.  In addition, vitamins, supplements and other non-pharmaceuticals products that are 
taken orally are to be reported in the eCRF.  Any use of marijuana products will be reported. 
Subjects will use their normal facial cleansers throughout the study.  The face will be washed daily 
with these cleansers.  Subjects will be instructed to wash their face prior to the Baseline, Day 14, 
Day 28, Day 56, and Day 84 Visits.  The face will not be washed within 5 minutes prior to, or 
within 1 hour after application of study drug.  Subjects must agree to maintain their regular use of 
sunscreens, moisturizers, and facial makeup throughout the entire course of the study.  Sunscreens, 
moisturizers and makeup may be applied to the face after study drug has adequate time to dry.  
Detailed dosing instruction will be provided to the subjects. 
7.5. Prohibited Medication, Treatment, and Procedures 
The following medications, treatments, and procedures are prohibited for all subjects during the 
study.   
• Use of topical acne treatments or other topical medication on the face  
• Shaving cream and cleansers cannot be used within 5 minutes prior to, or for 1 hour after 
application of study medication 
• Participation in a clinical study of any investigational product or procedure 
• Use of any medications, other than the study drug, for treatment of acne vulgaris 
• Use of any medication that, in the opinion of the investigator, may affect the evaluation of 
the study product (e.g., tetracycline or macrolide for > 7 days for URI) or place the subject 
at undue risk 
• Use of oral retinoids (e.g., isotretinoin) or high dose (> 10,000 IU) Vitamin D  
• Use of systemic corticosteroids (inhaled or intranasal corticosteroid ≤ 1000 µg daily dose 
is acceptable), oral antibiotics, or anti-inflammatory drugs (occasional NSAIDs to treat 
ailments other than acne are permitted) 
• Use of hormonal therapy solely for the control of acne 
• Use of an androgen receptor blocker (e.g., spironolactone)  
• Facial procedures (e.g., microdermabrasion, chemical or laser peel) 
• Photodynamic therapy 
• Use of home-based light therapies 
• Use of tanning beds 
Subjects should avoid swimming and heavy exercise for 1 hour after application of study drug.  

 
 
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Subjects are to avoid contact of their face with other persons (e.g. kissing and hugging) for 1 hour 
after application of study drug.   
Subjects will wash their hands directly after application of study drug.   
7.6. Rescue Medication, Treatments and Procedures 
This section is not applicable. 
7.7. Subject Access to Study Agent at Study Closure 
Subjects will not have access to the study drug after completion of their participation until the 
product is available commercially. 

 
 
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8. ASSESSMENT OF SAFETY 
8.1. Specification of Safety Parameters 
8.1.1. Definition of Adverse Events (AE) 
An AE is defined as any untoward medical occurrence in a study subject which does not 
necessarily have to have a causal relationship with the study treatment.  An AE can therefore be 
any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of study drug treatment, whether or not considered 
related to the study drug.   
Any events involving illnesses or injuries with onset during the study or any events involving 
exacerbations of pre-existing illnesses should be recorded.  All clearly related signs and symptoms 
should be grouped together and recorded as a single diagnosis in the eCRF.  A pre-existing 
condition will not be reported as an AE unless the condition worsens during the trial.  The 
condition, however, must be reported in the Medical History section of the eCRF. Scheduled or 
planned diagnostic and therapeutic procedures such as surgery will not be reported as AEs.   
8.1.2. Definition of Serious Adverse Events (SAE) 
Each AE will be independently judged by the investigator in terms of seriousness.  A serious AE 
(SAE) is defined as any untoward medical occurrence that: 
• Results in death,  
• Is life-threatening, 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the subject was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Results in permanent impairment of a body function or permanent damage to a body 
structure,  
• Is a congenital anomaly/birth defect,  
• Necessitates medical or surgical intervention to preclude any one of the outcomes listed in 
this definition. 

 
 
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8.2. Classification of Adverse Events 
8.2.1. Relationship to Study Drug 
The investigator will review each event and assess its relationship (unrelated, unlikely, possibly, 
probably, definitely) to drug treatment.  The following definitions will be used for these causality 
assessments. 
Unrelated 
• The AE must clearly be caused by the subject’s clinical state, or the 
study procedure/conditions. 
• Definitely not related to drug. 
• Temporal sequence of an AE onset relative to administration of drug 
not reasonable. 
• Another obvious cause of an AE. 
Unlikely 
• Time sequence is unreasonable. 
• There is another more likely cause for an AE. 
Possibly 
• Corresponds to what is known about the drug. 
• Time sequence is reasonable. 
• Could have been due to another equally, likely cause. 
Probably 
• Is a known effect of the drug. 
• Time sequence from taking drug is reasonable. 
• Ceases on stopping the drug. 
• Cannot be reasonably explained by the known characteristics of the 
subject’s clinical state. 
Definitely 
• Is a known effect of the drug (e.g., listed in Investigator’s Brochure). 
• Time sequence from taking drug is reasonable. 
• Event stops upon stopping drug, event returns upon restarting drug. 
NOTE: Re-challenge will only be considered after consultation with 
the medical monitor and the sponsor. 
 

 
 
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8.2.2. Severity of Event 
Each sign or symptom reported will be graded on a 5-point severity scale (Grade 1, 2, 3, 4 and 5). 
The following definitions for rating maximum severity will be used: 
Grade 1 
 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2 
 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living.* 
Grade 3  
 
Severe or medically significant but not immediately life-threatening; 
hospitalisation or prolongation of hospitalisation indicated; disabling; 
limiting self-care activities of daily living.** 
Note: An experience may be severe but may not be serious, (e.g., severe 
headache). 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
Note:  A semi-colon indicates ‘or’ within the description of the grade. 
*Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
**Self-care activities of daily living refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
8.2.3. Expectedness 
For this study, all AEs will be recorded.   
The safety and tolerability of BTX 1503 5% was evaluated in a Phase 1a study in healthy 
volunteers and in a Phase 1b study in subjects with moderate to severe acne vulgaris.  These studies 
demonstrated that BTX 1503 5% was safe and well tolerated with up to 3 mL applied BID (225 
mg CBD daily) for up to 28 days.  Adverse events reported as related to study drug treatment were 
facial dryness and itchiness. Mild cutaneous reactions included erythema, dryness, scaling, and 
burning/stinging.   
Studies of the active ingredient (CBD) administered orally in multiple therapeutic settings has 
described no consistent findings for systemic AEs.  Based on findings in a cumulative irritation 
study of the BTX 1503 vehicle, mild skin irritation may occur. 
8.3. Time Period and Frequency for Event Assessment and Follow-up 
All AEs occurring after signing of the consent/assent form through completion of the Day 84 Visit 
will be recorded.  AEs arising after the time of initiation of first treatment with study drug will be 

 
 
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considered treatment emergent AEs (TEAEs).  At each contact with the subject, the investigator 
or designee will seek information on AEs by non-leading specific questioning and, as appropriate, 
by examination.  All observed or volunteered AEs, regardless of suspected causal relationship to 
study drug, must be recorded on the AE page of the eCRF. 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits 
and interviews of a study subject presenting for medical care, or upon review by a study monitor. 
All AEs including local and systemic reactions will be recorded. All AEs occurring while on study 
must be documented appropriately regardless of relationship. All AEs will be followed to 
resolution or considered stable by the investigator.  
Changes in the severity of an AE will be documented to allow an assessment of the duration of the 
event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
8.4. Reporting Procedures 
8.4.1. Adverse Events Reporting 
All AEs will be recorded on the AE eCRF.  For each AE, the name of the event, date of onset, 
relationship to study drug, severity, seriousness (Y/N), whether a medication was used to treat the 
event, date of resolution (or ongoing), and outcome (fatal, recovered/resolved, recovered/resolved 
with sequelae, ongoing) will be noted. 
8.4.2. Serious Adverse Event Reporting 
Each AE will be independently judged by the investigator in terms of seriousness.  A SAE is 
defined in Section 8.1.2.  
All SAEs will be reported to the sponsor via fax or e-mail within 24 hours of becoming aware of 
the event, whether or not the serious events are deemed drug-related.  All serious event reporting 
will adhere to 21 CFR 312.32 for Investigational New Drugs (IND) and to the Guidance for 
Industry 
and 
Investigators: 
Safety 
Reporting 
Requirements 
for 
INDs 
and 
Bioavailability/Bioequivalence, dated December 2012. The IRB/EC will be notified of the Alert 
Reports. 
All AEs will be followed until resolution or until the investigator determines that the subject’s 
status has returned to normal or has stabilized. 
8.4.3. Reporting of Pregnancy 
As part of the eligibility criteria, WOCBP must agree to use appropriate contraception methods to 
avoid pregnancy during the study.  If a subject does become pregnant, or is suspected of being 

 
 
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pregnant, the subject will be immediately withdrawn from any further treatment with the study 
drug.  The pregnancy, or suspected pregnancy will be immediately reported to the medical monitor. 
Any subject that becomes pregnant during the study will be followed to term to collect pregnancy 
outcomes pending acquisition of the subject’s permission.   
8.5. Safety Oversight 
Oversight of the safety of the study will be the responsibility of the medical monitor.  Safety data 
will be regularly reviewed (monthly at a minimum).  If unexpected safety signals are observed, 
the medical monitor and the sponsor will determine if the enrollment or the study should be 
discontinued, or the protocol amended to include additional safety monitoring.    
 

 
 
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9. STATISTICAL CONSIDERATIONS 
9.1. Statistical and Analytical Plans 
A separate Statistical Analysis Plan (SAP) will be prepared for this study.  The statistical 
approaches to analysis of the data are described in this protocol.  Further detail on the structure of 
tables, listings, and figures is provided in the SAP.   
9.2. Statistical Hypotheses 
The purpose of this Phase 2 study is to describe the safety and efficacy of treatment with the BTX 
1503 5% liquid formulation or 2.5% liquid formulation vs Vehicle liquid formulation with QD or 
BID dosing in subjects with acne vulgaris.  P-values for selected variables will be presented to 
assist in evaluating the outcome of the study. Failure to achieve a statistically significant result 
does not imply a failed study; results from this study will be used to inform statistical approaches 
for registration studies.   
The primary efficacy endpoint of the study is the change from Baseline in inflammatory lesion 
counts.  The study will evaluate the superiority of active study drug over vehicle based on the 
following hypotheses:  
H0: µactive - µvehicle = 0  
H1: µactive - µvehicle > 0. 
Where H0 is the null hypothesis, H1 the alternative hypotheses, µactive is the absolute change in the 
number of inflammatory lesions counts from Baseline to Day 84, and µvehicle is the absolute change 
in the number of inflammatory lesions counts from Baseline to Day 84.   
Secondary and exploratory endpoints do not have a priori hypotheses but will be evaluated using 
appropriate statistical methods to inform statistical approaches for future studies. 
9.3. Analysis Datasets 
This study will be evaluated using 3 analysis sets: intent-to-treat (ITT), per protocol (PP), and 
safety.  Efficacy conclusions will be drawn from the ITT analysis set.  The PP analysis set will be 
used to support the efficacy findings in the ITT analyses. Safety conclusions will be drawn from 
the safety analysis set. 
The ITT analysis set includes all subjects who are randomized and is based on randomized study 
group, regardless of study drug received.  The safety analysis set includes all subjects who are 
randomized, receive at least 1 confirmed dose of study drug, and have at least 1 post-Baseline 
assessment.  The safety analysis set will be assessed based on study drug received, regardless of 
group to which subject was randomized.  The PP analysis set includes all subjects in the ITT 
analysis set who complete the Day 84 visit without noteworthy study protocol violations, including 
compliance with study drug application, Day 84 visit window, and completion of efficacy 

 
 
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evaluations on Day 84.  The full definition of the PP population is given in the SAP which will be 
approved prior to database lock. 
Subjects who have a documented lack of treatment effect or who are discontinued from the study 
due to an AE that was considered by the investigator to be study drug related will be included in 
the PP analysis set.  Specific criteria for identifying the PP analysis set will be determined prior to 
breaking the blind.    
Vehicle QD and Vehicle BID groups may be combined for analyses. 
9.4. Description of Statistical Methods 
9.4.1. General Approach 
All statistical processing will be performed using SAS® 9.3 or higher. Demographics will be 
summarized by age, gender, race, ethnicity, height and weight.  Summary statistics will be 
presented for change from Baseline in lesion counts (inflammatory and non-inflammatory separate 
and combined) and IGA.  For continuous variables, the mean, standard deviation (SD), median, 
and range will be presented.   Categorical variables will be summarized by frequency counts and 
percentages.  
9.4.2. Safety Analyses 
All subjects who receive at least one confirmed dose of study drug and have at least one post-
Baseline assessment will be included in the safety analyses.  
All treatment-emergent adverse events (TEAEs) reported during the study will be recorded and 
classified based on MedDRA terminology. Treatment-emergent adverse events are those AEs with 
an onset on or after the first application of study medication. All reported TEAEs will be 
summarized by treatment group, the number of subjects reporting events, system organ class, 
preferred term, severity, relationship to study drug, and seriousness. When summarizing events by 
causality and severity, each subject will be counted only once within a system organ class or a 
preferred term by using the event with the greatest relationship and highest severity within each 
classification. 
Serious adverse events (SAEs) will be summarized by cohort, system organ class, preferred term, 
severity, outcome and relationship to study drug; and all SAEs will be listed by subject. In addition, 
a list of subjects who prematurely discontinue from the study due to an AE and the reason for 
discontinuation will be provided. 
Concomitant medication will be mapped to ATC Level 2 using the WHODrug dictionary.  The 
number and percentage of subjects reporting each medication will be summarized.  Medications 
taken by each subject will be listed. 

 
 
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Changes from Baseline in safety laboratory assessments (CBC, chemistry and urinalysis) at 
Day 84 will be summarized using shift tables.  Abnormal values will be summarized.  Laboratory 
values will be listed by subject.   
Cutaneous tolerability will be assessed at the Baseline, Day 14, Day 28, Day 56 and Day 84 Visits.  
Summaries will present frequencies and percentages for the grading of each of the signs/symptoms 
that was performed at each scheduled visit/time point combination.  The summary of cutaneous 
tolerability assessment scores table will present summary statistics for the scores (‘None’=0, 
‘Slight’=1, ‘Moderate’=2 and ‘Severe’=3) and the change from Baseline values at each scheduled 
post-Baseline visits/time point for each of the signs/symptoms.  Listings will be provided by 
subject.   
9.4.3. Efficacy Analyses 
The efficacy analyses will be performed using the ITT (primary) and PP (supportive) analysis sets. 
The efficacy variables include the IGA and lesion counts (inflammatory and non-inflammatory) 
collected at Screening/Baseline and the Day 14, Day 28, Day 56, and Day 84 Visits.  Absolute and 
percent changes in lesion counts from Baseline will be calculated for each subject.  The IGA will 
be dichotomized into “success” and “failure”, with a subject considered a “success” at each 
individual visit if the IGA at that visit is Clear (“0”) or Almost Clear (“1”) and at least 2 grades 
less than the Baseline score.  Efficacy variables also include the Acne-QoL assessed at Baseline 
and Day 84 which will be scored according to the author’s scoring system (Martin 2001), and the 
subject’s assessment of improvement (PRO) using proportions by category. 
Descriptive statistics (including mean, median, standard deviation [SD], minimum, and maximum, 
unless otherwise stated) will be presented for the following parameters by study group using both 
the ITT and PP analysis sets: 
• Inflammatory, non-inflammatory, and total lesion counts at Baseline and study Day 14, 
Day 28, Day 56, and Day 84, 
• Absolute and percent change from Baseline in inflammatory, non-inflammatory, and total 
lesion counts at study Day 14, Day 28, Day 56, and Day 84, and 
• IGA scores and frequency and percent distribution of the dichotomized IGA at study Day 
14, Day 28, Day 56, and Day 84. 
Primary endpoint: 
The primary efficacy endpoint for the study is: 
• Absolute change from Baseline in inflammatory lesion counts at Day 84. 
Secondary endpoints:   
The secondary endpoints for the study are: 
• Absolute change from Baseline in non-inflammatory lesion count at Day 84,  

 
 
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• The percent change from Baseline in the inflammatory lesion count at Day 84,  
• The percent change from Baseline in the non-inflammatory lesion count at Day 84,  
• The proportion of subjects with at least a 2-grade reduction from the Baseline IGA score 
at Day 84, 
• The proportion of subjects with an IGA score of “clear” or “almost clear” at Day 84, and 
• The proportion of subjects with an IGA score of “clear” or “almost clear” at Day 84 and 
at least a 2-grade reduction from the Baseline IGA score. 
Exploratory endpoints: 
The exploratory endpoints are: 
• The change from Baseline in the total lesion count at Day 84,  
• The percent change from Baseline in the total lesion count at Day 84, 
• The change from baseline in the IGA scores and Day 84, 
• The absolute and percent change from Baseline in inflammatory, non-inflammatory and 
total lesion counts at Day 14, Day 28 and Day 56. 
• The proportion of subjects with at least a 2-grade reduction from the Baseline IGA score 
at Day 14, Day 28 and Day 56, and 
• The proportion of subjects with an IGA score of “clear” or “almost clear” at Day 14, 
Day 28 and Day 56, 
• The proportion of subjects with an IGA score of “clear” or “almost clear” at Day 14, 
Day 28 and Day 56 and at least a 2-grade reduction from the Baseline IGA score. 
• The change from Baseline in the Acne-QoL at Day 84, and 
• Subject’s assessment of the change in their acne from baseline to Day 84 (PRO). 
Tests of superiority for the primary and secondary endpoints of absolute change from Baseline in 
lesion counts will be based on either parametric or nonparametric 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 the respective Baseline lesion count as 
covariates, or on ranked data submitted to an ANCOVA with factors of treatment, analysis center, 
and the respective Baseline lesion count as a covariate.   
Data will be reviewed for skewedness (details in the SAP).  If a parametric analysis is indicated, 
the results of the parametric analysis will be considered the primary analysis.  If a nonparametric 
analysis is indicated, the absolute or percent changes in inflammatory lesion counts will be rank-
transformed prior to submitting them to the ANCOVA. Results of the rank-transformed analyses 

 
 
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will then be considered the primary analysis; results of the nonrank-transformed analyses will be 
also presented. 
The dichotomized IGA will be analyzed with logistic regression, adjusting for baseline IGA and 
site.  Pairwise tests will be conducted comparing the treated groups to vehicle.  The lesion count 
and IGA analyses employ the methods for handling missing data described in Section 9.4.9. 
9.4.4. Subset analyses  
Subset analyses will be conducted for the primary efficacy endpoint. These analyses will be 
summarized using descriptive statistics.  The specific subsets within the ITT analysis set that will 
be evaluated include: Baseline lesion counts, Baseline IGA, sex, age, ethnicity, race, and for the 
group less than the median age and greater than or equal to the median age. 
9.4.5. Adherence and Retention Analyses 
Compliance with study drug administration will be summarised based on dosing information from 
the clinical sites along with diary information obtained from subjects self-administering the study 
drug.  Subjects who drop-out from the study for any reason will be summarised.   
9.4.6. Baseline Descriptive Statistics 
Demographics will be summarised by age, gender, race, ethnicity, height, and weight.  Alcohol 
and tobacco history will be summarised, 
9.4.7. Planned Interim Analyses 
No interim analysis is planned.   
9.4.8. Multiple Comparison/Multiplicity 
This Phase 2 study is designed to identify the response to two different concentrations and dosing 
frequencies of BTX 1503. Statistical tests applied to the outcomes will be exploratory for 
establishing the dose and sample size for Phase 3 studies.   No adjustments for Type 1 error will 
occur. 
9.4.9. Handling of Missing Data 
All efforts will be made to minimize the occurrence of missing data. It is not expected that dropout 
rates will differ between groups.  Therefore, the primary method of handling missing efficacy data 
in the ITT analysis set will be based on last observation carried forward (LOCF). 
Other imputation methods (e.g., MMRM) may be used as a sensitivity analysis to the LOCF 
method.  

 
 
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All safety analyses will be conducted using the safety analysis set. No imputations will be made 
for missing safety data.   
Additional details on imputation and sensitivity analyses are provided in the SAP. 
9.4.10. Tabulation of Individual Response Data 
Individual response data will be presented in data listings.     
9.5. Sample Size 
The sample size for this study is based on clinical considerations only.  Subjects will be 
randomized 2:2:2:1:1 with 90 subjects in each active treatment group and 45 subjects in each 
vehicle group for a total 360 subjects. This is considered adequate to evaluate the safety and 
tolerability of BTX 1503 in the treatment of acne vulgaris. 
9.6. Measures to Minimize Bias 
9.6.1. Enrollment/Randomization/Masking Procedures 
 A randomization code will be prepared by an unblinded statistician at the CRO.  This statistician 
will be the only person aware of the randomization code.  Randomization will be 2:2:2:1:1 (90 
subjects in each active group and 45 in each vehicle group) and done by site.  Once a subject is 
deemed eligible to enroll, randomization will occur.  The site will contact the IVRS/IWRS to 
receive the kit number to be used for that subject throughout the study.   
Study drug, active or vehicle, will be labelled identically except for the kit number and bottle 
number.  Study drug pumps will contain approximately 39 mL for BID dosing groups and 
approximately 21 mL for QD dosing groups. There is no double-dummy in this study for BID vs 
QD dosing, so knowledge of volumes (during study drug accountability) will not unmask treatment 
groups (active vs vehicle). The vehicle study drug is indistinguishable from the active study drug.     
9.6.2. Evaluation of Success of Blinding 
For this Phase 2 study, no analyses to evaluate the success of the blinding will be conducted.  
Subjects known to have been unblinded during the study will be addressed in the final analysis as 
described in the SAP.    
9.6.3. Breaking the Study Blind/Subject Code 
During the study, the randomization code will not be broken except in the case of a safety concern, 
either for an individual subject or for the entire study. 
If a subject has an adverse event that may necessitate unblinding of the randomization code, the 
site will contact the CRO and sponsor to discuss if there are options other than unblinding.  If the 
site and sponsor agree that unblinding is in the best interests of the subject, the unblinded 
statistician will be contacted to conduct the unblinding.  For circumstances where the CRO or 

 
 
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sponsor cannot be contacted, and the subject is in imminent danger without knowledge of their 
treatment, unblinding can be done through the IVRS/IWRS system.     
At the completion of the study, the blind will be broken only after all data on all subjects has been 
entered into the database and the database is locked.  Database lock procedures will follow the 
CRO’s SOPs. 
 

 
 
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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
This research will be carried out in accordance with the protocol, the ICH harmonized tripartite 
guideline regarding GCP (E6 Consolidated Guidance, June 1996), the National Statement on 
Ethical Conduct in Human Research (updated May 2015), and the ethical principles set forth in 
the Declaration of Helsinki. 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations 
10.1.1. Informed Consent/Assent Process 
It is the responsibility of the investigator, or a person designated by the investigator (if acceptable 
by local regulations), to obtain written informed consent/assent from each subject participating in 
this study after adequate explanation of the aims, methods, objectives and potential hazards of the 
study.  It must also be explained to the subjects that they are completely free to refuse to enter the 
study or to withdraw from it at any time for any reason.  In states or institutions where permission 
is required from a legal guardian and the child is required to assent to participate, the appropriate 
assent-permission process will be followed according to the relevant local and/or state laws.  
Appropriate IRB/EC-approved forms for obtaining written informed consent/assent will be 
provided by the investigator or by the sponsor or its designee.   
The case report forms for this study contain a section for documenting informed consent/assent 
and this must be completed appropriately.  If new safety information results in significant changes 
in the risk/benefit assessment, the consent/assent form will be reviewed and updated if necessary.  
All subjects (including those already being treated) will be informed of the new information, given 
a copy of the revised form and be re-consented/assented to continue in the study. 
10.1.2. Institutional Review Board (IRB)/Ethics Committee (EC) 
This protocol, the informed consent/assent form and any accompanying material provided to the 
subject (such as subject information sheets or descriptions of the study used to obtain informed 
consent/assent) as well as any advertising or compensation given to the subject, will be reviewed 
by the IRB/EC, and the study will not start until the IRB/EC has approved the protocol or a 
modification thereof.  The IRB/EC is constituted and operates in accordance with the principles 
and requirements described in 21 CFR 56, ICH E6, and the National Statement on Ethical Conduct 
in Human Research (updated May 2015).  
Protocol modifications to this study must be made only after consultation between an appropriate 
representative of the sponsor and the investigator.  Protocol amendments must be prepared and 
approved by the sponsor and reviewed and approved by the IRB/EC prior to implementation. 
10.1.3. Subject and Data Confidentiality 
Subject confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their agents. This confidentiality is extended to cover testing of biological samples 

 
 
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in addition to the clinical information relating to subjects. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence. No 
information concerning the study or data will be released to any unauthorized third party without 
prior written approval of the sponsor.  
The study monitor, other authorized representatives of the sponsor, or representatives of the 
IRB/EC may inspect all documents and records required to be maintained by the investigator, 
including but not limited to, medical records (office, clinic, or hospital) and pharmacy records for 
the subjects in this study. The clinical study site will permit access to such records.  
The study subject’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location 
as described in Section 10.1.9.  
Study subject research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored at the CRO. This will not include the subject’s contact or 
identifying information. Rather, individual subjects and their research data will be identified by a 
unique study identification number. The study data entry and study management systems used by 
clinical sites and by the clinical sites’ research staff will be secured and password protected. At 
the end of the study, all study databases will be de-identified and archived at the CRO and 
ultimately with the sponsor. 
10.1.4. Research Use of Stored Human Samples, Specimens or Data 
Samples and data collected under this protocol will be used to study the safety of the study drug, 
BTX 1503 liquid formulation. No genetic testing will be performed.  Samples and data will be 
stored using codes assigned by the clinical study site, the CROs, and/or the laboratories assessing 
the samples. Data will be kept in password-protected computers. Only those entities participating 
in the study will have access to the samples and data.  
The study involves taking digital photographs of the subject’s face at selected sites. The subject or 
subject’s parent/guardian will consent/assent, in advance of any photographs being taken, to the 
taking, copyright, publication, and use of their photographs.  The subject’s eyes will be masked to 
conceal their identity. The photographs will be part of the study record and will be sent to the 
sponsor and regulatory agencies. The photographs will only be linked to the subject’s study code 
and not the subject’s name.   
10.1.5. Future Use of Stored Specimens 
All blood and urine samples used for assessment or study drug safety will be destroyed after 
analysis.  No specimens will be stored for future use. 
10.1.6. Key Roles and Study Administration 
The sponsor of this study is Botanix Pharmaceuticals Ltd (Botanix).  Botanix has engaged Premier 
Research (Durham, North Carolina, US) to oversee the conduct of the study.  Premier will conduct 

 
 
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the data management, clinical monitoring and statistical management of the study.  The medical 
monitor for this study will be provided by Premier.  His/her responsibility will be to oversee the 
safety of subjects in the study.   
The IRB/EC, which protects the rights and welfare of subjects, will be either local or centralized 
based on the study site.  Central IRBs will be preferentially used when possible.  Clinical sites 
outside of the US, will have IRB/EC oversight based on local and national requirements. 
Photography of facial acne at selected sites will be performed utilizing equipment from a 
photography vendor.  The vendor will provide a Photography Manual describing correct 
techniques for photographing subjects.  Photographs from the study are the property of Botanix 
and will become part of the study record.   
Study drug will be manufactured in the United States.  The Coghlan Group (TCG; Bastrop, Texas, 
USA) is responsible for packaging, labeling, and distribution of the study drug.  
A qualified vendor will act as the central lab for analysis of the blood and urine samples.  Results 
will be provided to the sites for their subject management and to Premier for data analysis.   
There will be no DSMB for this study.  Blinded safety data will be reviewed in real-time by the 
medical monitor to assure subject safety. 
10.1.7. Clinical Monitoring 
Clinical site monitoring is conducted to ensure that the rights and well-being of human subjects 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct 
of the study is in compliance with the currently approved protocol/amendment(s), with GCP, and 
with applicable regulatory requirement(s).  
Monitoring for this study will be performed by a CRO contracted by the sponsor to conduct this 
activity.  
On-site monitoring will occur for initial site assessment and training throughout the study and at a 
frequency adequate to assess the above based on the number of subjects enrolled at each site and 
the time from enrollment of the subjects.  The monitor should have access to laboratory test reports 
and other subject records needed to verify the entries on the Case Report Form.  The investigator 
(or his/her designee) agrees to cooperate with the monitor to ensure that any problems detected 
during these monitoring visits are resolved. 
A site visit monitoring report will be prepared for each visit.  Details of clinical site monitoring 
are documented in the Clinical Monitoring Plan (CMP). The CMP describes in detail who will 
conduct the monitoring, at what frequency monitoring will be done, at what level of detail 
monitoring will be performed, and the preparation and distribution of monitoring reports.  
Independent audits may be conducted by auditors from the sponsor or its designee or regulatory 
agencies.  

 
 
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10.1.8. Quality Assurance and Quality Control 
Each clinical site, CRO, and laboratory participating in this study will have SOPs for quality 
management that describe: 
• How data will be evaluated for compliance with the protocol, ethical standards, regulatory 
compliance, and accuracy in relation to source documents.  
• The documents to be reviewed (e.g., eCRFs, clinic notes, product accountability records, 
specimen tracking logs, questionnaires, audio or video recordings), who is responsible, and 
the frequency for reviews.  
• Who will be responsible for addressing QA issues (e.g., correcting procedures that are not 
in compliance with protocol) and QC issues (e.g., correcting errors in data entry).  
• Staff training methods and how such training will be tracked.  
• If applicable, calibration exercises conducted prior to and during the study to train 
examiners and maintain acceptable intra-and inter-examiner agreement.  
QC procedures will be implemented beginning with the data entry system and data QC checks that 
will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution.  
Following written SOPs, the clinical study monitors will verify that the clinical trial is conducted, 
and data are generated, documented (recorded), and reported in compliance with the protocol, 
GCP, and the applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good 
Manufacturing Practices (GMP)).  
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for monitoring and auditing by the sponsor, and inspection by local and regulatory 
authorities. 
10.1.9. Data Handling and Record Keeping 
The investigator shall supply the sponsor or its designee on request with any required background 
data from the study documentation or clinic records.  This is particularly important when data on 
the electronic Case Report Forms requires clarification.  In case of special problems/and or 
governmental queries or requests for audit inspections, it is also necessary to have access to the 
complete study records, provided that subject confidentiality is protected.  
All source data forms should be typed or filled out using indelible ink and must be legible.  Errors 
should be crossed out with a single line, but not obliterated, the correction inserted, and the change 
initialed and dated by the investigator or his/her authorized delegate.   
The investigator should understand that source documents for this trial should be made available 
to appropriately qualified personnel from the sponsor or its designees or to health authority 
inspectors after appropriate notification.  The verification of the eCRF Data must be by direct 
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For each subject enrolled, an eCRF must be completed by an authorized delegate from the study 
staff and signed by the principal investigator.  If a subject withdraws from the study, the reason 
must be noted on the eCRF.  If a subject is withdrawn from the study because of a treatment-
limiting adverse event, thorough efforts should be made to clearly document the outcome.  The 
investigator should ensure the accuracy, completeness, and timeliness of the data reported to the 
sponsor in the eCRF’s and in all required reports. 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with ICH E6 and regulatory and institutional requirements for the protection of 
confidentiality of subjects.  
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Examples 
of these original documents and data records include, but are not limited to, hospital records, clinic 
and office charts, laboratory notes, memoranda, subjects’ memory aids or evaluation checklists, 
subject diaries, pharmacy dispensing records, recorded audio tapes of counseling sessions, 
recorded data from automated instruments, copies or transcriptions certified after verification as 
being accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, 
x-rays, and subject files and records kept at the pharmacy, at the laboratories, and medico-technical 
departments involved in the clinical trial.  
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the 
site principal investigator. The investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported.  
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. Black ink is required to ensure clarity of reproduced copies. When making 
changes or corrections, cross out the original entry with a single line, and initial and date the 
change. DO NOT ERASE, OVERWRITE, OR USE CORRECTION FLUID OR TAPE ON THE 
ORIGINAL.  
Source documents will be maintained for recording data for each subject enrolled in the study. 
Data reported in the eCRF derived from source documents should be consistent with the source 
documents or the discrepancies should be explained and captured in a progress note and 
maintained in the subject’s official study record.  
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and 
clinical laboratory data will be entered into the electronic data capture (EDC) system, a 21 CFR 
Part 11-compliant data capture system provided by the CRO. The data system includes password 
protection and internal quality checks, such as automatic range checks, to identify data that appear 
inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the source 
documents. 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified.  These documents should 

 
 
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be classified into two different separate categories (1) Investigator’s Study File, and (2) Subject 
clinical source documents. The Investigator’s Study File will contain the protocol/amendments, 
Case Report and Query Forms, IRB/EC and governmental approval (as appropriate) with 
correspondence, sample informed consent/assent, study drug records, staff curriculum vitae and 
authorization forms and other appropriate documents/correspondence. All records defined in 21 
CFR 312.57 will be kept on file. 
The investigator must keep these two categories of documents on file for at least 2 years after the 
latest of the following: completion, discontinuation of the study, or the regulatory submission for 
which the study is being performed is no longer under review.  After that, the documents may be 
destroyed, subject to local regulations. 
Should the investigator wish to assign the study records to another party or move them to another 
location, the sponsor must be notified in advance. 
If the investigator cannot guarantee this archiving requirement at the investigational site for any or 
all of the documents, special arrangements must be made between the investigator and the sponsor 
to store these in a sealed container(s) off-site so that they can be returned sealed 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 of the site. 
The investigator shall supply the sponsor on request with any required background data from the 
study documentation or clinic records.  This is particularly important when data on the eCRFs 
requires clarification.  In case of special problems/and or governmental queries or requests for 
audit inspections, it is also necessary to have access to the complete study records, ensuring that 
subject confidentiality is protected. 
10.1.10. 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or other study 
requirements (e.g., SOPs, Laboratory Manuals, etc). The noncompliance may be either on the part 
of the subject, the investigator, or the study site staff.  As a result of deviations, corrective actions 
are to be developed by the site and implemented promptly.  
These practices are consistent with ICH E6:  
• 4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 5.1 Quality Assurance and Quality Control, section 5.1.1  
• 5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
It is the responsibility of the site to use continuous vigilance to identify and report deviations within 
5 working days of identification of the protocol deviation, or within 5 working days of the 
scheduled protocol-required activity. All deviations must be addressed in study source documents 
and reported to the clinical study monitor or to the CRO.  Protocol deviations must be sent to the 
IRB/EC per their guidelines. The site investigator/study staff is responsible for knowing and 
adhering to their IRB/EC requirements.  

 
 
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It is not anticipated that waivers of eligibility requirements will be granted for any subjects.  
However, if eligibility requirements are waived in special circumstances, waivers must be 
approved by the medical monitor and the sponsor before a subject may be enrolled.  
Documentation of granted waivers will be maintained in the investigator’s and sponsor’s files. 
10.1.11. 
Publication and Data Sharing Policy 
The results of this study may be published or presented at scientific meetings.  The investigator 
agrees to submit all manuscripts or abstracts to Botanix Pharmaceuticals at least 30 days prior to 
submission.  This allows Botanix Pharmaceuticals to protect proprietary information and to 
provide comments based on information from other studies that may not yet be available to the 
investigator. 
In accordance with standard editorial and ethical practice, Botanix Pharmaceuticals will generally 
support publication of multicenter trials in their entirety.  In this case, a coordinating investigator 
will be designated by mutual agreement.  Authorship will be determined by mutual agreement. 
10.2. 
Conflict of Interest Policy 
The independence of this study from any actual or perceived influence is critical.  Therefore, any 
actual conflict of interest of persons who have a role in the design, conduct, analysis, publication, 
or any aspect of this trial will be disclosed and managed.  Furthermore, persons who have a 
perceived conflict of interest will be required to have such conflicts managed in a way that is 
appropriate to their participation in the study. The study leadership has established policies and 
procedures for all study group members to disclose all conflicts of interest and will establish a 
mechanism for the management of all reported dualities of interest. 
10.3. 
List of Abbreviations 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
BID 
Twice Daily 
CBC 
Complete Blood Count 
CBD 
Cannabidiol 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CMP 
Clinical Monitoring Plan 
CRA 
Clinical Research Assistant / Associate 
CRO 
Clinical Research Organization 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
FDA 
Food & Drug Administration 

 
 
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GCP 
Good Clinical Practices 
GMP 
Good Manufacturing Practices 
IGA 
Investigator’s Global Assessment 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
MCH 
Mean Corpuscular Haemoglobin 
MCHC 
Mean Corpuscular Haemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
NSAID 
Non-Steroidal Anti-inflammatory Drug 
OTC 
Over the Counter 
PK 
Pharmacokinetics 
QA 
Quality Assurance 
QC 
Quality Control 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SD 
Standard Deviation 
SOP 
Standard Operating Procedure 
TEAE 
Treatment Emergent Adverse Event 
THC 
Tetrahydrocannabinol 
UDS 
Urine Drug Screen 
UPT 
Urine Pregnancy Test 
WBC 
White Blood Cell 
WHO 
World Health Organization 
WOCBP 
Women of Child-Bearing Potential 
 

 
 
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