Clinical trial NCT03627468
Conditions: Primary Axillary Hyperhidrosis
Sponsor: Botanix Pharmaceuticals
Start date: 2018-09-05; Completion date: 2020-01-27
Enrollment: 300 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Hyperhidrosis is a disorder of abnormal excessive sweating. Primary hyperhidrosis (armpits, hands, and feet) affects approximately 4.8% of the US population and is believed to be caused by an overactive cholinergic response of the sweat glands. Current therapies have limited effectiveness, significant side effects, and can be invasive and costly. Sofpironium bromide (BBI-4000) is a novel soft-drug in development for the topical treatment of hyperhidrosis. This Phase 3 study will assess the long-term safety, tolerability, and efficacy of sofpironium bromide gel applied topically to subjects with axillary hyperhidrosis.

Detailed description:
This is a randomized, open-label, phase 3 long-term study designed to evaluate the safety, local tolerability and efficacy of sofpironium bromide gel when applied topically to the axillae.

Subjects will apply the gel once daily at bedtime, to both axillae.

A maximum of 300 subjects, will be randomized to receive one of two sofpironium bromide gel concentrations.

Adverse events, vital signs, and local tolerability assessments will be collected at each visit. Urine pregnancy tests will be taken throughout the course of the study for women of child bearing potential. Blood and urine samples will be collected and analyzed for routine hematology, chemistry, and urinalysis parameters at specified visits. Patient-reported outcome assessments will be recorded during the study at predefined time points.

The study will be comprised of a total of 17 scheduled visits to take place over a 52 week period.

Arms: arm 1: Sofpironium Bromide Gel, 5%, applied topically to each axilla once daily for 48 weeks arm 2: Sofpironium Bromide Gel, 15%, applied topically to each axilla once daily for 48 weeks
Interventions: intervention 1: Sofpironium Bromide Gel, 5% intervention 2: Sofpironium Bromide Gel, 15%
Intervention descriptions: intervention 1: Sofpironium Bromide Gel, 5% intervention 2: Sofpironium Bromide Gel, 15%

Protocol documents:
Prot_000.pdf: 
Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 1 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
 
CONFIDENTIAL 
A Multicenter, Randomized, Open-label, Phase 3 Long-term Safety Study of 
Topically Applied Sofpironium Bromide (BBI-4000) Gel, 5% and 15% in 
Subjects with Axillary Hyperhidrosis 
PROTOCOL NUMBER:  
BBI-4000-CL-303 
NAME OF INVESTIGATIONAL PRODUCT: 
Sofpironium Bromide (BBI-4000)  
ORIGINAL PROTOCOL: 
March 7, 2018 
AMENDMENT 01: 
May 15, 2018 
SPONSOR: 
 
Brickell Biotech, Inc. 
5777 Central Ave., Suite 102 
Boulder, CO 80301 
PHASE: 
3 (Long-term Safety Study; the Argyle Study) 
IND NUMBER: 
121,256 
MEDICAL MONITOR: 
Brandon Kirsch, MD 
Brickell Biotech, Inc. 
5777 Central Avenue, Suite 102 
Boulder, CO 80301 
Phone: 720-619-4966 
Fax: 1 (866) 666-7392 
Email: safety@brickellbiotech.com 
 
Copyright 2018 Brickell Biotech, Inc.  All rights reserved.  Unauthorized copying or use of this information is 
prohibited. 
NCT03627468


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 2 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
SPONSOR SIGNATORY: 
 
 
 
 
 
Patricia Walker, MD, PhD 
President and Chief Scientific Officer 
 
Date 
 
May 16 2018


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 3 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
INVESTIGATOR SIGNATURE PAGE 
I agree to: 
 
• Implement and conduct this study diligently and in strict compliance with the protocol, good clinical 
practices (GCPs), and all applicable laws and regulations. 
 
• Maintain all information supplied by Brickell Biotech, Inc. in confidence and, when this information is 
submitted to an Institutional Review Board (IRB) or another group, it will be submitted with a designation 
that the material is confidential. 
 
 
I have read this protocol in its entirety and I agree to all aspects. 
 
 
 
 
___________________________________________________________________________ 
Investigator Printed Name  
 
 
Signature  
 
 
Date 
 
 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 4 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
TABLE OF CONTENTS 
SPONSOR SIGNATORY ............................................................................................................... 2 
INVESTIGATOR SIGNATURE PAGE........................................................................................ 3 
TABLE OF CONTENTS ................................................................................................................ 4 
SYNOPSIS ........................................................................................................................................ 8 
ABBREVIATIONS ........................................................................................................................ 13 
1 BACKGROUND AND CLINICAL RATIONALE .............................................................. 16 
2 STUDY DESIGN ...................................................................................................................... 20 
3 STUDY OBJECTIVES AND ASSESSMENTS .................................................................... 21 
3.1 
Study Objectives .................................................................................................................. 21 
3.2 
Study Assessments ............................................................................................................... 21 
4 STUDY POPULATION .......................................................................................................... 22 
4.1 
Number of Subjects ............................................................................................................. 22 
4.2 
Inclusion Criteria ................................................................................................................ 22 
4.3 
Exclusion Criteria ............................................................................................................... 23 
5 INVESTIGATIONAL PRODUCT (IP) ................................................................................. 24 
5.1 
Storage of Investigational Product .................................................................................... 24 
5.2 
Instructions for Use and Administration of Investigational Product ............................. 25 
5.3 
Instructions for the Subjects .............................................................................................. 25 
6 CONCOMITANT MEDICATIONS/TREATMENTS ......................................................... 26 
6.1 
Permissible Medications/Treatments ................................................................................ 26 
6.2 
Prohibited Medications/Treatments .................................................................................. 26 
7 PROCEDURES ........................................................................................................................ 27 
7.1 
Time and Events Table ....................................................................................................... 28 
7.2 
Visit-Specific Procedures .................................................................................................... 29 
7.2.1 
Visit 1 (Screening; Days -31 to 0) ................................................................................... 29 
7.2.2 
Visit 2: Baseline (Day 1).................................................................................................. 29 
7.2.3 
Visits 3-6 (Weeks 2, 4, 6, and 8) ±3 Days........................................................................ 30 
7.2.4 
Visits 7-16 (Weeks 12-48) ±5 Days ................................................................................. 31 
7.2.5 
Visit 17 (End of Study) ±5 Days ...................................................................................... 32 
7.3 
Unscheduled Visits .............................................................................................................. 32 
7.4 
Early Discontinuation of Subjects ..................................................................................... 32 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 5 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
8 RESPONSE MEASURES AND SUMMARY OF DATA COLLECTION METHODS ... 33 
8.1 
Safety Measures ................................................................................................................... 33 
8.1.1 
Physical Exam ................................................................................................................. 33 
8.1.2 
Adverse Events ................................................................................................................. 33 
8.1.3 
Local Tolerability Assessments ....................................................................................... 34 
8.1.4 
Recommendations for Dose Interruption ....................................................................... 34 
8.1.5 
Vital Signs ........................................................................................................................ 34 
8.1.6 
Clinical Laboratory Assessments .................................................................................... 35 
8.1.7 
Subject Assessments ........................................................................................................ 35 
8.2 
Summary of Methods of Data Collection .......................................................................... 36 
8.3 
Efficacy Measures ............................................................................................................... 36 
8.4 
Additional Efficacy Measure .............................................................................................. 36 
9 ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE) ......................... 36 
9.1 
Safety Evaluations ............................................................................................................... 36 
9.2 
Adverse Events .................................................................................................................... 36 
9.2.1 
Definitions of Adverse Events ......................................................................................... 36 
9.3 
Serious Adverse Events ...................................................................................................... 39 
9.3.1 
Definition and Reporting Procedures ............................................................................. 39 
9.4 
Follow-up of Adverse Events and Laboratory Test Abnormalities................................ 40 
9.5 
Pregnancy Reporting .......................................................................................................... 41 
9.5.1 
Time period for collecting pregnancy information ........................................................ 41 
9.5.2 
Action to be taken if pregnancy occurs .......................................................................... 41 
9.6 
Other Safety Measures ....................................................................................................... 42 
10 STATISTICAL PROCEDURES ............................................................................................ 42 
10.1 Analysis Populations ........................................................................................................... 42 
10.2 Endpoints ............................................................................................................................. 43 
10.3 Safety Analyses .................................................................................................................... 44 
10.4 Efficacy Analyses ................................................................................................................. 44 
10.5 Exploratory Analysis .......................................................................................................... 44 
10.6 Sample Size .......................................................................................................................... 44 
11 STUDY ADMINISTRATION PROCEDURES .................................................................... 45 
11.1 Subject Entry Procedures .................................................................................................. 45 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 6 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
11.1.1 
Overview of Entry Procedures ........................................................................................ 45 
11.1.2 
Informed Consent and Subject Privacy .......................................................................... 45 
11.1.3 
Method for Assignment to Study Product Groups ......................................................... 45 
11.2 Compliance with Protocol .................................................................................................. 46 
11.3 Study Termination .............................................................................................................. 46 
12 ADMINISTRATIVE ISSUES ................................................................................................. 46 
12.1 Posting of Information on Clinicaltrials.gov .................................................................... 46 
12.2 Protection of Human Subjects ........................................................................................... 46 
12.2.1 
Compliance with Informed Consent Regulations (US 21 CFR Part 50) and  
Relevant Country Regulations ........................................................................................ 46 
12.2.2 
Compliance with IRB Regulations ................................................................................. 46 
12.2.3 
Compliance with Good Clinical Practice........................................................................ 46 
12.3 Changes to the Protocol ...................................................................................................... 47 
12.4 Subject Confidentiality ....................................................................................................... 47 
12.4.1 
Subject Privacy ................................................................................................................ 47 
12.5 Documentation .................................................................................................................... 47 
12.5.1 
Source Documents ........................................................................................................... 47 
12.5.2 
Electronic Case Report Form Completion ..................................................................... 47 
12.5.3 
Retention of Documentation ........................................................................................... 47 
12.6 Labelling, Packaging, Storage, and Return or Disposal of Investigational Product .... 48 
12.6.1 
Labeling/Packaging ......................................................................................................... 48 
12.6.2 
Storage of Investigational Product ................................................................................. 48 
12.6.3 
Clinical Supply Inventory................................................................................................ 48 
12.6.4 
Return or Disposal of Investigational Product............................................................... 48 
12.7 Monitoring by the Sponsor ................................................................................................. 48 
12.8 Publications .......................................................................................................................... 49 
13 REFERENCES ......................................................................................................................... 50 
14 APPENDICES .......................................................................................................................... 51 
APPENDIX 1:  HYPERHIDROSIS DISEASE SEVERITY MEASURE-AXILLARY  
(HDSM-AX) .............................................................................................................................. 52 
APPENDIX 2: DERMATOLOGY LIFE QUALITY INDEX-AXILLA; FOR SUBJECTS  
17 YEARS OF AGE............................................................................................................... 55 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 7 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
APPENDIX 3:  HYPERHIDROSIS QUALITY OF LIFE INDEX (HIDROQOL©);  
FOR SUBJECTS 17 YEARS OF AGE ................................................................................ 57 
APPENDIX 4:  TOLERABILITY ASSESSMENTS .................................................................. 59 
APPENDIX 5:  STUDY DRUG APPLICATION & SUBJECT INSTRUCTIONS ................ 60 
APPENDIX 6:  EXAMPLE POTENT INHIBITORS OF CYP3A AND CYP2D6 ................. 62 
APPENDIX 7:  EXAMPLE POTENT INHIBITORS OF  OCT-2/MATE1/MATE2  
TRANSPORTERS ................................................................................................................... 63 
APPENDIX 8:  PROTOCOL AMENDMENTS ......................................................................... 64 
 
 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 8 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
SYNOPSIS 
Protocol Title 
A Multicenter, Randomized, Open-label, Phase 3 Long-term Safety Study of Topically Applied 
Sofpironium Bromide (BBI-4000) Gel, 5% and 15% in Subjects with Axillary Hyperhidrosis 
Study Objectives 
Primary: 
To evaluate the long-term safety and local tolerability of sofpironium bromide gel, 5% and 15% when 
applied topically in subjects with axillary hyperhidrosis. 
Secondary: 
• To evaluate the long-term effect of topically applied sofpironium bromide gel, 5% and 15% on 
Hyperhidrosis Disease Severity Measure-Axillary (HDSM-Ax©) in subjects with axillary 
hyperhidrosis. 
• To evaluate the long-term effect of topically applied sofpironium bromide gel, 5% and 15% on 
patient reported Dermatology Life Quality Index (DLQI) in subjects with axillary hyperhidrosis. 
Other: 
• To evaluate the effect of topically applied sofpironium bromide gel, 5% and 15% on the 
Hyperhidrosis Quality of Life Index (HidroQoL©) in subjects with axillary hyperhidrosis. Only the 
first 100 subjects enrolled will complete this assessment. 
Study Population 
Subjects aged ≥12 years with a diagnosis of axillary hyperhidrosis.  
Inclusion Criteria 
Subjects must fulfill all the following criteria to be eligible for study admission: 
1. Male or female subject ≥12 years of age in good general health. 
2. Diagnosis of primary axillary hyperhidrosis in the opinion of the Investigator that meets all the following 
criteria: 
a. HDSM-Ax of 3 – 4 inclusive at both the Screening Visit (Visit 1) and Baseline Visit (Visit 2). 
b. Symptoms of axillary hyperhidrosis for 6 months’ duration prior to Baseline Visit (Visit 2). 
3. The ability to understand and sign a written informed consent form (ICF), which must be obtained prior 
to any study-related procedures (including medication wash-out, if required) and treatment. Subjects less 
than the age of consent must sign an Assent for the study and a parent or a legal guardian must sign the 
informed consent (if the subject reaches age of consent during the study they should be re-consented at the 
next study visit). 
4. The ability to understand and sign a Health Insurance Portability and Accountability Act (HIPAA) 
authorization form which shall permit the use and disclosure of the subject’s individually identifiable health 
information. 
5. The ability to understand and follow all study-related procedures including study drug administration. 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 9 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
6. Sexually active females of childbearing potential (FOCBP)* must agree to periodic pregnancy testing 
and use a medically acceptable method of contraception while receiving protocol-assigned product. 
Acceptable contraceptive methods include the following: 
a. Abstinence for the duration of the study, or where partner is sterile (e.g., vasectomy), is an acceptable 
form of contraception; 
b. Hormonal contraception, including oral, injectable, or implantable methods started 2 months prior to 
screening; OR 
c. Two forms of non-hormonal contraception, including intrauterine devices (1-week status post 
placement), or properly used barrier methods (e.g., male or female condoms, cervical cap/diaphragm, 
spermicidal agents). 
* FOCBP for this study includes any premenopausal female capable of becoming pregnant who has not 
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation [6 months prior to 
baseline] or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea >12 consecutive 
months in women 55 years of age). 
Exclusion Criteria 
The following criteria will exclude a subject from participating in this study: 
1. In the Investigator’s opinion, any skin or subcutaneous tissue conditions of the axilla(e), (i.e., the axillary 
area should be deemed otherwise “normal”, besides the hyperhidrosis diagnosis, and free of blisters, large 
boils or sinus tracts, significant scarring or open wounds). 
2. Prior use of any prohibited medication(s) or procedure(s) within the specified timeframe for the treatment 
of axillary hyperhidrosis: 
a. Botulinum toxin to the axillary area within 6 months of the Baseline Visit (Visit 2). 
b. Axillary thermolysis, sympathectomy or surgical procedures of the axillary area at any time in the past. 
c. Serotonergic agonist (or drugs that increase serotonin activity including SSRIs), beta-blocker, alpha-
adrenergic agonist (clonidine), dopamine partial agonist or tricyclic antidepressant treatment within 28 days 
of the Baseline Visit (Visit 2). However, if a subject has been on a stable dose (in the opinion of the PI) of 
any of these medications and has not had a recent change in hyperhidrosis frequency or severity for  
3 months prior to the Baseline Visit; they may be included. Doses of these agents should not be altered 
during the course of the study. 
d. Any topical treatment for hyperhidrosis, requiring a prescription, within 15 days of Baseline Visit (Visit 
2). 
3. Anticholinergic agents used to treat conditions such as, but not limited to, hyperhidrosis, asthma, 
incontinence, gastrointestinal cramps, and muscular spasms by any route of administration (e.g., IV, oral, 
inhaled, topical) within 28 days of the Baseline Visit (Visit 2). 
4. Use of potent oral inhibitors of cytochrome P450 CYP3A & CYP2D6 and transporter inhibitors 
(OCT2/MATE1/MATE2) 14 days prior to the Baseline Visit (Visit 2). The use of topical antifungal 
medications is permitted if not applied in the treatment area. See Appendices 6 and 7. 
5. Any oral or topical homeopathic or herbal treatment (i.e., alternative therapies such as sage tablets, 
chamomile, valerian root and St. John’s Wort) within 7 days of the Baseline Visit (Visit 2). 
6. Use of any cholinergic drug (e.g., bethanechol) within 15 days of the Baseline Visit (Visit 2). 
7. Use of any anti-anxiety and/or anti-depressant, amphetamine product or drugs with known 
anticholinergic side effects is prohibited with the following exceptions: 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 10 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
a. If a subject has been on a stable dose of an anti-anxiety and/or anti-depressant drug and has not had a 
recent change in hyperhidrosis frequency or severity for 3 months; they may be included. 
b. An amphetamine product may be allowed if the dose has been stable for 6 months without change in 
hyperhidrosis frequency or severity. 
c. Drugs with known anticholinergic side effects (taken within the last 28 days), including dry mouth, 
blurred vision, may be allowed based on the Principal Investigator’s assessment. 
NOTE: If anticholinergic side effect(s) are experienced on these medications prior to starting study 
medication; document the side effect(s) and severities in the source document and the eCRF. The doses of 
these agents should not be altered during the course of the study. 
8. Known causes of hyperhidrosis or known history of a condition that may cause hyperhidrosis (i.e., 
hyperhidrosis secondary to any known cause such hyperthyroidism, diabetes mellitus, medications, etc.). 
9. Subjects with hyperhidrosis symptoms initiated or exacerbated with menopause. 
10. Subjects with unstable type 1 or type 2 diabetes mellitus or thyroid disease, history of renal impairment, 
hepatic impairment, malignancy, glaucoma, intestinal obstructive or motility disease, obstructive uropathy, 
myasthenia gravis, benign prostatic hyperplasia (BPH), neurological conditions, psychiatric conditions, 
Sjögren’s syndrome, Sicca syndrome, or cardiac abnormalities that may alter normal sweat production or 
may be exacerbated by the use of anticholinergics in the Investigator’s opinion. 
11. Known hypersensitivity to glycopyrrolate, anticholinergics, or any of the components of the topical 
formulation. 
12. Subject is pregnant, lactating or is planning to become pregnant during the study. 
13. Participating in a study of or used an investigational drug or device within 28 days prior to the Baseline 
Visit (Visit 2). 
14. Any major illness within 28 days before the screening examination. 
15. Any other condition, including psychiatric illness (depression and/or anxiety) that would interfere with 
study participation and/or evaluation of study endpoints or laboratory abnormality that, in the opinion of the 
Investigator, would put the subject at unacceptable risk for participation in the study or may interfere with 
the assessments included in the study. 
16. History or presence of supraventricular tachycardia, ventricular arrhythmias, atrial fibrillation or atrial 
flutter. 
17. Employees of Brickell Biotech, Inc., the Investigator, or contract research organization (CRO) involved 
in the study, or an immediate family member (partner, offspring, parents, siblings, or sibling’s offspring) of 
an employee involved in the study. 
Study Design 
A maximum of 300 subjects, at approximately 30 clinical sites, will be randomized to receive either 
sofpironium bromide gel, 5% or 15% in a 1:2 ratio to obtain approximately 150 subjects (50 subjects dosed 
with 5% gel and 100 subjects dosed with 15% gel) who have completed 48 weeks of dosing and 52 weeks 
of clinical assessments. 
Subjects will apply the Investigational Product (sofpironium bromide gel, 5% or 15%); once daily at 
bedtime, to both axillae for 48 weeks. 
Vital signs, local tolerability assessments (including burning, itching, dryness, scaling and erythema 
assessed using standardized scales), and adverse events will be collected at each visit. Urine pregnancy tests 
(UPT) for FOCBP will be taken throughout the course of the study and blood and urine samples will be 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 11 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
collected and analyzed at the Screening Visit and at Visit 5 (Week 6), Visit 10 (Week 24), and Visit 16 
(Week 48) for routine hematology, chemistry, and urinalysis parameters. Patient-reported outcomes: 
HDSM-Ax and DLQI will be recorded during the study at predefined time points. Patient Global 
Impression of Severity (PGI-S) will be administered with each administration of the HDSM-Ax and the 
Patient Global Impression of Change (PGI-C) will be administered at the 24 Week and 48 Week (EOT) 
visits. HidroQoL will be recording during the study at baseline, Visit 3 (Week 2), and Visit 5 (Week 6); 
only the first 100 subjects enrolled will complete this asessment. 
A total of 17 scheduled visits will take place over approximately 52 weeks. 
Test Product, Dose, and Mode of Administration 
5% or 15% sofpironium bromide (BBI-4000) gel topically applied to the axillae 
Duration of Treatment 
48 weeks (11 months) followed by a 4-week post-treatment visit (52 weeks) 
Safety Assessments 
• Adverse events  
• Local tolerability assessments including burning, itching, dryness, scaling and erythema 
• Vital signs (blood pressure, pulse rate, respiratory rate, and temperature) 
• Laboratory tests (hematology, chemistry, and urinalysis) and pregnancy testing in FOCBP 
Efficacy Assessments 
The following assessment measures will be conducted to evaluate the long-term efficacy of sofpironium 
bromide gel, 5% and 15%: 
• HDSM-Ax as measured by the subject  
• DLQI as measured by the subject (for subjects ≥17 years of age) 
• Patient Global Impression Scales; Severity (PGI-S) and Change (PGI-C) 
Additionally, HidroQoL assessment will be conducted as an exploratory analysis, as measured by the 
subject (for subjects ≥17 years of age). This assessment will be performed at baseline, Visit 3 (Week 2), and 
Visit 5 (Week 6) for only the first 100 subjects enrolled in the study.  
Statistical Methods 
Safety Analyses 
Treatment emergent adverse event (TEAE) descriptions will be mapped to standard terms, i.e., MedDRA 
System Organ Class and Preferred Term.  At each post-baseline visit, the number and proportion of subjects 
reporting any given TEAE will be tabulated by severity; each subject will be counted only once according 
to the worst severity reported up to the current visit. Separate tables will be constructed for (a) all reported 
TEAEs, (b) protocol treatment-related TEAEs, (c) serious TEAEs, and (d) TEAEs leading to protocol 
treatment discontinuation.   
At each visit, local tolerability (burning, itching, scaling, dryness and erythema at either axilla) will be 
described by severity. At each post-baseline visit, local tolerability will be summarized as cumulative shift 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 12 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
tables vs. baseline. Subject counts for each symptom will be cross-tabulated with baseline severity 
according to the maximum post-baseline severity reported for either axilla up to the current visit. 
Laboratory parameters will be descriptively summarized (mean, standard deviation [SD], median, 
minimum, maximum) for values at each specified visit and for changes from screening at each subsequent 
measurement. In addition, for each post-baseline measurement, parameter status (low, normal, high) will 
also be summarized as shift tables vs. screening status. 
Vital signs will be summarized similarly as for laboratory parameters but without shift tables. 
Efficacy Analyses 
For HDSM-Ax the mean of the items in sections No. 1, 2, and 3 (11 sub-items in total) will be used for 
analysis. The HDSM-Ax total score will be descriptively summarized (mean, SD, median, minimum, 
maximum) for values at each visit and for changes from baseline (average of screening and Day 0) at each 
subsequent visit. In addition, at each post-baseline visit, the proportions of subjects with a ≥1.0 point,  
≥1.5-point, and ≥2-point decrease from baseline will be reported.  
Change in the DLQI from baseline to Week 2, Week 6, Week 24, and Week 48 (EOT). 
Exploratory Analysis 
Change in the HidroQoL from baseline to Week 2 and Week 6 will be assessed. Only the first 100 subjects 
enrolled in the study will complete this assessment, and an interim analysis will be performed. 
 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 13 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
ABBREVIATIONS 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BBI-4000 
Sofpironium bromide 
BP 
Blood pressure 
BPH 
Benign prostatic hyperplasia 
Bpm 
Beats per minute 
BUN 
Blood urea nitrogen 
C 
Celsius 
Chem. 
Chemistry 
CFR 
Code of Federal Regulations 
Conmeds 
Concomitant medications 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
DB20 
Dimethiconol Blend 20 
DLQI 
Dermatology Life Quality Index 
DLQI-Palm 
Dermatology Life Quality Index-Palm 
ECG 
Electrocardiogram 
eCOA 
Electronic Clinical Outcome Assessment 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EOT 
End of Treatment 
F 
Fahrenheit 
FDA 
Food and Drug Administration 
FOCBP 
Female of Childbearing Potential 
G 
Grams 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transpeptidase 
GSP 
Gravimetric Sweat Production 
HDSM-Ax 
Hyperhidrosis Disease Severity Measure-Axillary 
HDSM-Palm 
Hyperhidrosis Disease Severity Measure-Palm Scale 
HDSS 
Hyperhidrosis Disease Severity Scale 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 14 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
Heme. 
Hematology 
HidroQoL 
Hyperhidrosis Quality of Life Index 
HIPAA 
Health Insurance Portability and Accountability Act 
Hr 
Hour 
HR 
Heart rate 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
I/E 
Inclusion and Exclusion Criteria 
IEC 
Institutional Ethics Committee 
IND 
Investigational New Drug 
IP 
Investigational product 
IPM 
Isopropyl myristate 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IUD 
Intrauterine device 
IV 
Intravenous  
Kg 
Kilogram 
LLOQ 
Lower limit of quantification 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram 
min 
Minute 
mL 
Milliliter 
mm 
Millimeter 
mmHg 
Millimeter of mercury 
mo. 
Months 
MUPK 
Maximum use pharmacokinetics 
NF 
National Formulary 
Ng 
Nanogram 
nM 
Nanomolar 
PGI-C 
Patient Global Impression of Change 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 15 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
PGI-S 
Patient Global Impression of Severity 
PHIS 
Palmar Hyperhidrosis Impact Scale 
PK 
Pharmacokinetics 
PP 
Per-Protocol 
PT 
Preferred term 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SC 
Subcutaneous 
SD 
Standard deviation 
SOC 
System organ class 
SSRI 
Selective serotonin re-uptake inhibitors 
Temp 
Temperature 
US 
United States of America 
UPT 
Urine Pregnancy Test 
USP 
United States Pharmacopeia 
WBC 
White blood cell 
 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 16 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
1 
BACKGROUND AND CLINICAL RATIONALE 
Sofpironium bromide (BBI-4000) is a novel soft-anticholinergic ester analog of glycopyrrolate in development 
for the topical treatment of hyperhidrosis. Sofpironium bromide is a competitive inhibitor of acetylcholine 
receptors located on certain peripheral tissues, including sweat glands. Sofpironium bromide gel is expected to 
inhibit the action of acetylcholine in sweat glands thereby reducing the extent of sweating. Please refer to the 
sofpironium bromide (BBI-4000) Investigator’s Brochure for more information. 
Hyperhidrosis is a disorder of excessive sweating beyond what is expected for thermoregulatory needs and 
environmental conditions. Primary hyperhidrosis (armpits, hands, and feet) affects approximately 4.8% of the US 
population (Doolittle, 20161) and is believed to be caused by an overactive cholinergic response of the sweat 
glands. Current therapies have limitation in their efficacy, significant side effects, and/or are invasive and costly.  
Oral and topical anticholinergic drugs, such as glycopyrrolate, have been used to treat hyperhidrosis, although 
they are not currently approved for this indication in the US. Their main limitations are systemic anticholinergic 
side effects (blurred vision, dizziness, dry mouth, constipation, urinary retention, and tachycardia). 
“Soft-drugs” are designed to provide maximal therapeutic effect with minimal side effects. The synthesis of a 
soft-drug is achieved by starting with a known inactive or minimally active metabolite of a known active drug 
(e.g., glycopyrrolate). The inactive metabolite is then structurally modified to an active form that will undergo a 
predictable one-step transformation back to the inactive or less active metabolite in vivo. Thus, the soft-drug 
concept is based upon predictable metabolic deactivation by enzymatic and hydrolytic processes, which occur 
predominately in the systemic circulation.  
Sofpironium bromide was designed as a structural analog of glycopyrrolate, a well-known, potent anticholinergic. 
The ester structure of sofpironium bromide allows for a rapid conversion via enzymatic and hydrolytic processes 
into a less active metabolite (carboxylic acid metabolite, referred to as BBI-4010). The predicted metabolite 
(BBI-4010) is highly polar and ionized at physiological pH, and thus is predicted to be subject to rapid 
elimination from the systemic circulation. This drug design is expected to result in the reduction of undesirable 
systemic anticholinergic effects while maintaining intended topical efficacy. 
The initial nonclinical and clinical programs were conducted with a gel formulation consisting of sofpironium 
bromide dissolved in an anhydrous base of hydroxypropyl cellulose, hexylene glycol, citric acid anhydrous, 
dehydrated alcohol, and the novel excipient dimethiconol blend 20 (DB20), which was used in the formulation to 
improve the product's aesthetic properties. The DB20 gel formulation was evaluated in nonclinical studies with 
sofpironium bromide concentrations up to 20% and in clinical studies with sofpironium bromide concentrations 
of 0% (placebo), 5%, 10%, and 15% applied topically to the axillae or palms.  
Although these studies demonstrated that the sofpironium bromide DB20 gel at these concentrations was safe and 
well tolerated, sofpironium bromide gel was reformulated by replacing DB20 with isopropyl myristate (IPM, a 
generally recognized as safe [GRAS] ingredient) due to concerns about physical instability of DB20 during 
process transfer and scale up. Please refer to the sofpironium bromide Investigator’s Brochure for more 
information on DB20 and IPM gel formulations and their use in nonclinical and clinical studies to date. The IPM 
gel formulation will be used for all future clinical studies and commercialization. Unless otherwise indicated, 
“sofpironium bromide gel” refers to the IPM formulation. The DB20 and IPM formulation designations are used 
for clarity as needed. 
In the current multicenter, randomized, open-label, Phase 3 long-term safety study, we are studying the long-term 
safety and tolerability of sofpironium bromide IPM gel, 5% and 15% when applied topically in subjects with 
axillary hyperhidrosis, over a 48-week period. Additionally, this study will evaluate the long-term effect of 
sofpironium bromide IPM gel, 5% and 15% on Investigator and patient-reported local tolerability assessments 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 17 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
and patient-reported subject satisfaction. 
Nonclinical Studies 
A comprehensive battery of pharmacology, safety pharmacology, ADME, acute to chronic toxicity, genotoxicity, 
carcinogenicity (ongoing) and reproductive toxicity evaluations has been conducted to evaluate the safety of 
sofpironium bromide administration by the intended clinical route of administration. 
Results of in vitro pharmacology evaluations have demonstrated high binding activity of sofpironium at all 
muscarinic receptors, and ex vivo anticholinergic activity was shown in a guinea pig model. Pharmacokinetic 
studies showed that sofpironium protein binding and distribution to blood cells was low, concentration-
independent, and similar across animal species and human. Sofpironium distribution to tissues was wide, and 
distribution and elimination were independent of administration route following single subcutaneous (SC) or 
topical dosing. Placental transfer of 14C-sofpironium or its metabolites was low and transfer into the milk of 
lactating rats was observed. Extensive toxicologic evaluations demonstrated that sofpironium bromide gel was 
well tolerated locally and was not systemically toxic following administration by any route. 
Sofpironium bromide was not mutagenic or clastogenic in a comprehensive battery of genotoxicity assays nor 
was it identified as a reproductive toxicant. Sofpironium bromide is currently under evaluation for 
carcinogenicity potential following dermal administration in mice and SC administration in rats. Sofpironium 
bromide gel was not identified as a dermal sensitizer. In vitro, sofpironium bromide gel, 20% demonstrated the 
potential to cause eye damage. Neither sofpironium bromide gel (DB20 and IPM) absorbed ultraviolet light 
between the 290 nm to 700 nm wavelengths and thus do not possess phototoxicity potential. Safety 
pharmacology studies did not identify any central nervous system, cardiovascular, or respiratory adverse effects.  
Overall, the results of the extensive nonclinical program encompassing pharmacologic, pharmacokinetic, and 
toxicological evaluations support the safe use of sofpironium bromide topical gel at the intended maximum 
dosage for the treatment of primary axillary hyperhidrosis. Please refer to the sofpironium bromide Investigator’s 
Brochure for additional information pertaining to the nonclinical studies. 
Prior Human Experience 
As of 31 December 2017, a total of 10 clinical studies, encompassing approximately 640 subject exposures, have 
been conducted with sofpironium bromide gel. Brief summaries are provided in the following paragraphs. Please 
refer to the sofpironium bromide Investigator’s Brochure for more detailed descriptions and results. 
Study BBI-4000-01 (ex-US)  
This was a Phase 1, randomized, within-group controlled, double-blinded study of sofpironium bromide DB20 
gel conducted in 28 healthy adult males. The study objective was to investigate skin irritability and safety of a 
single application of sofpironium bromide gel by patch test. Each subject received all of the following substances 
applied on the back, which were left on the subjects for 48 hours: 5%, 10%, and 15% sofpironium bromide DB20 
gel; 0% sofpironium bromide DB20 gel (placebo); 0.5% sodium lauryl sulfate solution (positive-control); 
deionized water (negative-control); and patch test unit only. 
Study BBI-4000-03 (ex-US)  
This was a Phase 1, randomized, repeat-dose study of sofpironium bromide IPM gel conducted in 24 adults with 
primary axillary hyperhidrosis. The objective of this study was to investigate the pharmacokinetics (PK), local 
tolerability, safety, and efficacy of sofpironium bromide gel, 5%, 10%, or 15% when applied to the axillae in 
primary axillary hyperhidrosis. Subjects were randomized to either sofpironium bromide gel, 5%, 10%, or 15%, 
or vehicle gel (N=6 subjects per group), and applied the assigned product to the axillae once daily before bed for 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 18 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
28 days. The primary endpoint was assessment of PK measurements (plasma concentrations, urinary 
concentrations) of sofpironium and its metabolite, BBI-4010. 
Study BBI-4000-04 (ex-US)  
This was a Phase 2, randomized, vehicle-controlled, double-blinded study of sofpironium bromide gel conducted 
in 207 adults with primary axillary hyperhidrosis. The objective of this study was to investigate the efficacy, 
safety, and dose-relationship of sofpironium bromide gel in primary axillary hyperhidrosis. Subjects were 
randomized to 1 of 4 cohorts, either sofpironium bromide gel, 5% (n=52), 10% (n=51), 15% (n=52), or vehicle 
gel (placebo; n=52), and applied the assigned product to the axillae once daily, at bedtime, for 42 days. The 
primary efficacy objective was to assess the effect of sofpironium bromide gel, 5%, 10%, or 15% on sweat 
production. Measures associated with sweat production included direct measurement of gravimetric sweat 
production (GSP) and subjective assessments by the subjects (Hyperhidrosis Disease Severity Scale [HDSS], 
HDSM-Ax, DLQI).  
Study BBI-4000-05 (ex-US)  
This was a Phase 1, randomized, double-blinded, parallel-group, 14-day, repeat-dose study of sofpironium 
bromide IPM gel conducted in 24 adults with primary axillary hyperhidrosis. The objective of this study was to 
investigate the PK, local tolerability, and safety of 15% sofpironium bromide IPM1 gel vs. IPM2 gel when 
applied to the axillae in primary axillary hyperhidrosis patients once daily before bed for 14 days. IPM1 and 
IPM2 gel formulations differ in the citric acid concentration; IPM has 5.9g sofpironium bromide with 0.001% 
citric acid in a single 45ml pump, whereas IPM2 gel has 5.9g sofpironium bromide with 0.05% citric acid in a 
single 45ml pump. The primary endpoint was plasma concentration of sofpironium and its metabolite, BBI-4010. 
Study BBI-4000-CL-101  
This was a Phase 1, randomized, double-blinded, single-center study conducted in 24 subjects with primary 
axillary hyperhidrosis. The objective of this study was to investigate the local tolerability, safety, and effect of 
sofpironium bromide DB20 gel on sweat production (using GSP and HDSS). The study consisted of 2 
consecutive cohorts, where Cohort 1 (N=6) established acceptable tolerability of sofpironium bromide DB20 gel, 
5% (applied to one axilla) and vehicle gel to the other axilla prior to enrolling a separate group of subjects into 
Cohort 2. Subjects in Cohort 2 (N=18; 6 in each group) were randomized to receive sofpironium bromide DB20 
gel, 5% or 10%, or vehicle gel (control) to both axillae once daily for 14 days. The primary efficacy endpoint was 
reduction in sweat production from baseline.  
Study BBI-4000-CL-201  
This was a Phase 2, multicenter, randomized, double-blinded, vehicle-controlled, parallel-group comparison 
study of 3 concentrations of sofpironium bromide DB20 gel (5%, 10%, and 15%) in 189 adults with primary 
axillary hyperhidrosis. The objectives of this study were to evaluate the safety and local tolerability of 
sofpironium bromide DB20 gel; the efficacy of sofpironium bromide DB20 gel as assessed by HDSS, HDSM-
Ax, and GSP; the PK of sofpironium; and the psychometric performance of the HDSM-Ax as a measure of 
hyperhidrosis severity. Subjects applied the assigned study product topically to the axillae once a day for 28 days. 
In Part 1 of the study, 24 subjects were enrolled (6 in each arm). These subjects underwent PK blood draws and 
additional ECG analysis. After an interim safety and tolerability analysis, an additional 165 subjects were 
enrolled in Part 2 of the study.  
Study BBI-4000-CL-202  
This was a Phase 2, multicenter, randomized, double-blinded, vehicle-controlled, parallel-group study of 
sofpironium bromide DB20 gel, 15% conducted in 50 subjects with primary palmar hyperhidrosis. The objectives 
of this study were to assess the safety, local tolerability, and effect of sofpironium bromide DB20 gel, 15% on 
sweat production. This study was not powered to show statistically significant differences in the efficacy 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 19 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
endpoints. Subjects were randomized to either sofpironium bromide DB20 gel, 15% (n=25) or vehicle gel 
(placebo; n=25), and applied the assigned product to the palms of both hands once daily for 28 days. Measures 
associated with sweat production included GSP and subjective assessments by the subjects (HDSS, 
Hyperhidrosis Disease Severity Measure-Palm [HDSM-Palm], Palmar Hyperhidrosis Impact Scale [PHIS], and 
modified Dermatology Life Quality Index-Palm [DLQI-Palm]).  
Study BBI-4000-CL-103  
This was a Phase 1, single-center, 3-cohort, open-label, repeat-dose, PK, safety and tolerability study of 
sofpironium bromide IPM gel, 5%, sofpironium bromide IPM gel, 15% and sofpironium bromide DB20 gel, 15% 
formulations in 30 healthy subjects. The primary objective of this study was to evaluate the PK profile of 
sofpironium bromide and its metabolite, BBI-4010, following topical dosing. The secondary objective was to 
assess the safety and tolerability of topical dosing of sofpironium bromide. Subjects were randomized to 1 of 
3 cohorts (n=10 each): 5% IPM gel, 15% IPM gel; and 15% DB20 gel; and applied the assigned drug to axillae 
once daily for 14 days.  
Study BBI-4000-CL-203  
This was a Phase 2, confirmatory, multicenter, randomized, double-blinded, vehicle-controlled, study comparing 
3 different concentrations of sofpironium bromide IPM gel, 5%, 10%, and 15% with vehicle (placebo) in 227 
adults with primary axillary hyperhidrosis. Subjects applied the assigned study product topically to the axillae 
once daily at bedtime for 42 consecutive days. The primary objectives of this study were to evaluate the effect of 
sofpironium bromide gel, 5%, 10%, and 15% on HDSM-Ax, and the safety and local tolerability of sofpironium 
bromide gel, 5%, 10%, and 15% when applied topically in subjects with axillary hyperhidrosis. Secondary 
objectives were to evaluate the effect of sofpironium bromide gel, 5%, 10%, and 15% on hyperhidrosis disease 
severity as it relates to GSP, HDSS, and DLQI. Subjects were randomized to 1 of 4 cohorts, either sofpironium 
bromide gel, 5% (n=57), 10% (n=57), 15% (n=56), or vehicle gel (placebo; n=57), and applied the assigned 
product to the axillae once daily, at bedtime, for 42 days.  
Study BBI-4000-CL-102 (MUPK)  
This was a Phase 1, open-label, non-randomized, repeat-dose study of sofpironium bromide gel, 15% under 
maximum-use conditions (3-fold higher clinical dose). The primary objective of this study was to evaluate the PK 
of sofpironium bromide gel, 15% and its major metabolite BBI-4010 following topical dosing. The secondary 
objectives of this study were to determine the safety, tolerability and efficacy of topical dosing of sofpironium 
bromide gel, 15% in subjects with axillary hyperhidrosis, as well as urine concentrations of sofpironium and its 
metabolite BBI-4010. 
Overall Safety Conclusions  
Sofpironium bromide was safe and well tolerated. All three, 5%, 10% and 15% dose groups have demonstrated 
comparable acceptability of safety and tolerability. TEAEs were dose-related with fewer subjects reporting AEs 
in the 5% dose group relative to 10% and 15% gel groups.  
Consistent with the soft drug design, sofpironium bromide gel exhibited low incidence of anticholinergic AEs.  
The most common anticholinergic AE was dry mouth.  All anticholinergic AEs were expected. Of note, the 
anticholinergic AEs were predominantly mild or moderate in severity and transient in duration. Of the application 
site AEs reported by Investigators (erythema, pain, dryness) and local tolerability signs reported by subjects 
(burning and itching), most were minimal in severity. All TEAEs resolved spontaneously with treatment 
discontinuation. 
Overall Efficacy Conclusions  
All three, 5%, 10% and 15% sofpironium bromide dose groups exhibited a larger absolute mean reduction in 
GSP from baseline to EOT compared to vehicle. Better improvement in GSP response was associated with higher 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 20 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
concentrations of sofpironium bromide. However, while there was a slight trend toward dose-response, all dose 
groups were essentially equivalent in patient-reported outcome measures based on HDSM-Ax, HDSS, and DLQI. 
This suggests that each of the concentrations are efficacious. The response was seen as early as Day 8 and 
remained consistent throughout the applicable treatment period. 
Overall Pharmacokinetics Conclusions  
There was systemic exposure to both sofpironium and BBI-4010 analytes in the majority of subjects. Systemic 
exposure to sofpironium bromide appeared to increase in an approximately dose proportional manner between the 
5% and 15% gel concentrations, indicating that applying a more concentrated gel increased exposure. However, 
inter-subject variability of PK parameters was extremely high. Absorption is thought to be affected by skin 
thickness, temperature, hydration, and degree of occlusion.  
Systemic exposure of sofpironium and BBI-4010 was typically minimal following the first dose (Day 1) and also 
after multiple doses (Day 21). The PK of sofpironium did not show accumulation. The plasma concentrations of 
BBI-4010 appear to be lower than those of sofpironium. Steady-state is reached by Day 14 and possibly Day 7. In 
general, preliminary PK analysis of the plasma concentrations of sofpironium and BBI-4010 showed most 
samples analyzed were below 1 ng/mL, with many below the lower limit of quantification of 0.050 ng/mL for 
sofpironium and BBI-4010, respectively.  
Risk to Subjects  
As an anticholinergic drug, topical administration of sofpironium bromide gel could be associated with signs or 
symptoms typical of a systemic anticholinergic effect such as dry mouth, blurred vision, dizziness, constipation, 
urinary retention, or tachycardia, among others. The previous sofpironium bromide exposure to humans has 
demonstrated a low incidence of these effects, which are generally mild in severity and transient. Of the  
approximately 640 total subjects exposed to sofpironium bromide, only ~2.0% subjects have discontinued from 
clinical studies due to anticholinergic effects.  
2 
STUDY DESIGN 
This is a multicenter, randomized, open-label, Phase 3 long-term safety study of topically applied sofpironium 
bromide gel, 5% and 15% in subjects with axillary hyperhidrosis. 
A maximum of 300 subjects, at approximately 30 clinical sites, will be enrolled to obtain approximately  
150 subjects that have completed 12 months of dosing and clinical assessments. 
Subjects will be randomized 1:2 to receive either sofpironium bromide gel, 5% or 15% (100 subjects dosed with 
5% gel and 200 subjects dosed with 15% gel). Subjects will apply the investigational product once daily at 
bedtime, to their axillae for 12 months. 
Vital signs and adverse events will be collected at each visit. Local tolerability assessments (including burning, 
itching, dryness, scaling, and erythema assessed using standardized scales) will be collected at each post-
Screening visit. Blood and urine samples will be collected and analyzed at Screening and then Weeks 4, 12, 24, 
36, and 48 for routine hematology, chemistry, and urinalysis parameters. Additionally, a urine pregnancy test 
(UPT) for females of child-bearing potential will be collected and analyzed at each visit except at Week 2 (Visit 
3), Week 6 (Visit 5), and Week 52 (Visit 17). Patient-reported outcomes HDSM-Ax, PGI-S, PGI-C, and DLQI 
will be recorded during the study at predefined time points. HidroQoL will be recorded at baseline, Week 2, and 
Week 6; only the first 100 subjects enrolled in the study will complete this assessment. 
A total of 17 scheduled visits will take place over approximately 52 weeks. See Section 7.1 for an events table of 
this study.   


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 21 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
3 
STUDY OBJECTIVES AND ASSESSMENTS 
The purpose of this Phase 3 study is to assess the long-term safety, local tolerability, and efficacy of sofpironium 
bromide gel, 5% and 15% when applied topically in subjects with axillary hyperhidrosis.  
3.1 
Study Objectives 
Primary: 
To evaluate the long-term safety and local tolerability of sofpironium bromide gel, 5% and 15% when applied 
topically in subjects with axillary hyperhidrosis. 
Secondary: 
• To evaluate the long-term effect of topically applied sofpironium bromide gel, 5% and 15% on HDSM-
Ax in subjects with axillary hyperhidrosis. 
• To evaluate the long-term effect of topically applied sofpironium bromide gel, 5% and 15% on DLQI in 
subjects with axillary hyperhidrosis. 
Other: 
To evaluate the effect of topically applied sofpironium bromide gel, 5% and 15% on HidroQoL in subjects with 
axillary hyperhidrosis. 
3.2 
Study Assessments 
Safety Measures: 
The following safety assessment measures will be conducted to evaluate the long-term safety and local 
tolerability of sofpironium bromide gel, 5% and 15%: 
• Adverse events  
• Local tolerability assessments including burning, itching, dryness, scaling and erythema 
• Vital signs (blood pressure, pulse rate, respiratory rate, and temperature) 
• Laboratory tests (hematology, chemistry, and urinalysis) and pregnancy testing in FOCBP 
Efficacy Assessments: 
The following assessment measures will be conducted to evaluate the long-term efficacy of sofpironium bromide 
gel, 5% and 15%: 
• HDSM-Ax as measured by the subject 
• DLQI as measured by the subject for subjects ≥17 years of age 
• Patient Global Impression Scales*; Severity (PGI-S)** and Change (PGI-C)†  
 
* these questions will be included in the HDSM-Ax questionnaires  
** administered with each administration of the HDSM-Ax  
† administered at Visit 10 (Week 24) and end of treatment Visit 16 (Week 48) only  
 
Additionally, HidroQoL assessment will be conducted as an exploratory analysis, as measured by the subject (for 
subjects ≥17 years of age). This assessment will be performed at baseline, Visit 3 (Week 2), and Visit 5 (Week 6) 
for only the first 100 subjects enrolled in the study.  
 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 22 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
 
 
4 
STUDY POPULATION 
4.1 
Number of Subjects  
A maximum of 300 subjects, at approximately 30 clinical sites, will be randomized to receive either 5% or 15% 
sofpironium bromide gel in a 1:2 ratio to obtain approximately 150 subjects (50 subjects dosed for 48 weeks with 
5% gel and 100 subjects dosed for 48 weeks with 15% gel) who have completed 12 months of dosing and clinical 
assessments. 
4.2 
Inclusion Criteria 
Subjects must fulfill all of the following criteria to be eligible for study admission: 
1. Male or female subject ≥12 years of age in good general health. 
2. Diagnosis of primary axillary hyperhidrosis in the opinion of the Investigator that meets all the following 
criteria: 
a. HDSM-Ax of 3-4 inclusive at both of the Screening visits (Visit 1) and Baseline Visit (Visit 2). 
b. Symptoms of axillary hyperhidrosis for 6 months’ duration prior to Baseline Visit (Visit 2) 
3. The ability to understand and sign a written informed consent form (ICF), which must be obtained prior to 
any study-related procedures (including medication wash-out, if required) and treatment. Subjects less 
than the age of consent must sign an Assent for the study and a parent or a legal guardian must sign the 
informed consent (if the subject reaches age of consent during the study they should be re-consented at 
the next study visit). 
4. The ability to understand and sign a Health Insurance Portability and Accountability Act (HIPAA) 
authorization form which shall permit the use and disclosure of the subject’s individually identifiable 
health information. 
5. The ability to understand and follow all study-related procedures including study drug administration.  
6. Sexually active females of childbearing potential (FOCBP)* must agree to periodic pregnancy testing and 
use a medically acceptable method of contraception while receiving protocol-assigned product. 
Acceptable contraceptive methods include the following:  
a. Abstinence for the duration of the study, or where partner is sterile (e.g., vasectomy), is an 
acceptable form of contraception; 
b. Hormonal contraception, including oral, injectable, or implantable methods started 2 months 
prior to screening; OR 
c. Two forms of non-hormonal contraception, including intrauterine devices (IUD; 1 week status 
post placement), or properly used barrier methods (e.g., male or female condoms, cervical 
cap/diaphragm, spermicidal agents). 
*  FOCBP for this study includes any premenopausal female capable of becoming pregnant who has 
not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation [6 months prior 
to baseline] or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea  
>12 consecutive months in women 55 years of age).  


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 23 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
4.3 
Exclusion Criteria 
Meeting any of the following criteria will exclude a subject from participating in this study: 
1. In the Investigators opinion, any skin or SC tissue conditions of the axilla(e), (i.e., the axillary area should 
be deemed otherwise “normal”, besides the hyperhidrosis diagnosis, and free of blisters, large boils or 
sinus tracts, significant scarring or open wounds). 
2. Prior use of any prohibited medication(s) or procedure(s) within the specified timeframe for the treatment 
of axillary hyperhidrosis: 
a. Botulinum toxin to the axillary area within 6 months of the Baseline Visit (Visit 2). 
b. Axillary thermolysis, sympathectomy or surgical procedures of the axillary area at any time in the 
past. 
c. Serotonergic agonist (or drugs that increase serotonin activity including Selective serotonin re-
uptake inhibitors [SSRIs]), beta-blocker, alpha-adrenergic agonist (clonidine), dopamine partial 
agonist or tricyclic antidepressant treatment within 28 days of the Baseline Visit (Visit 2). 
However, if a subject has been on a stable dose (in the opinion of the PI) of any of these 
medications and has not had a recent change in hyperhidrosis frequency or severity for 3 months 
prior to the Baseline Visit; they may be included.  Doses of these agents should not be altered 
during the course of the study. 
d. Any topical prescription treatment for hyperhidrosis within 15 days of Baseline Visit (Visit 2). 
3. Anticholinergic agents used to treat conditions such as, but not limited to, hyperhidrosis, asthma, 
incontinence, gastrointestinal cramps, and muscular spasms by any route of administration (e.g., 
intravenous [IV], oral, inhaled, topical, etc.) within 28 days of the Baseline Visit (Visit 2).   
4. Use of potent oral inhibitors of cytochrome P450 CYP3A & CYP2D6 and transporter inhibitors 
(OCT2/MATE1/MATE2) within 14 days prior to the Baseline Visit (Visit 2). The use of topical 
antifungal medications is permitted if not applied in the treatment area. See Appendices 6 and 7. 
5. Any oral or topical homeopathic or herbal treatment (i.e., alternative therapies such as sage tablets, 
chamomile, valerian root and St. John’s Wort) within 7 days of the Baseline Visit (Visit 2). 
6. Use of any cholinergic drug (e.g., bethanechol) within 15 days of the Baseline Visit (Visit 2). 
7. Use of any anti-anxiety and/or anti-depressant, amphetamine product or drugs with known anticholinergic 
side effects is prohibited with the following exceptions: 
a. If a subject has been on a stable dose of an anti-anxiety and/or anti-depressant drug and has not had a 
recent change in hyperhidrosis frequency or severity for 3 months; they may be included.   
b. An amphetamine product may be allowed if the dose has been stable for ≥ 6 months without change in 
hyperhidrosis frequency or severity. 
c. Drugs with known anticholinergic side effects (taken within the last 28 days) including dry mouth, 
blurred vision may be allowed based on the Investigator’s assessment. 
NOTE: If anticholinergic side effect(s) are experienced on these medications prior to starting study 
medication; document the side effect(s) and severities in the source document and the eCRF. The 
doses of these agents should not be altered during the course of the study. 
8. Known cause of hyperhidrosis or known history of a condition that may cause hyperhidrosis (i.e., 
hyperhidrosis secondary to any known cause such hyperthyroidism, diabetes mellitus, medications, etc.). 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 24 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
9. Subjects with hyperhidrosis symptoms initiated or exacerbated with menopause. 
10. Subjects with unstable type 1 or type 2 diabetes mellitus or thyroid disease, history of renal impairment, 
hepatic impairment, malignancy, glaucoma, intestinal obstructive or motility disease, obstructive 
uropathy, myasthenia gravis, benign prostatic hyperplasia (BPH), neurological conditions, psychiatric 
conditions, Sjögren’s syndrome, Sicca syndrome, or cardiac abnormalities that may alter normal sweat 
production or may be exacerbated by the use of anticholinergics in the Investigator’s opinion. 
11. Known hypersensitivity to glycopyrrolate, anticholinergics, or any of the components of the topical 
formulation. 
12. Subject is pregnant, lactating or is planning to become pregnant during the study.  
13. Participating in a study or used an investigational drug or device within 28 days prior to the Baseline Visit 
(Visit 2). 
14. Any major illness within 28 days before the Baseline Visit (Visit 2). 
15. Any other condition, including psychiatric illness (depression and/or anxiety) that would interfere with 
study participation and/or evaluation of study endpoints or laboratory abnormality that, in the opinion of 
the Investigator, would put the subject at unacceptable risk for participation in the study or may interfere 
with the assessments included in the study. 
16. History or presence of supraventricular tachycardia, ventricular arrhythmias, atrial fibrillation or atrial 
flutter. 
17. Employees of Brickell Biotech, Inc., the Investigator, or contract research organization (CRO) involved in 
the study, or an immediate family member (partner, offspring, parents, siblings, or sibling’s offspring) of 
an employee involved in the study. 
 
5 
INVESTIGATIONAL PRODUCT (IP) 
Sofpironium bromide gel is an anhydrous gel formulation containing the drug substance in a gel base comprising 
hydroxylpropyl cellulose National Formulary (NF), hexylene glycol NF, isopropyl myristate NF, citric acid 
anhydrous United States Pharmacopeia (USP), and alcohol dehydrated USP. Sofpironium bromide gel is a clear 
to slightly translucent colorless gel and is packaged in a white colored, metered pump container. One pump 
container is packaged in a carton with 2 applicators.  The total gel volume in each pump container is ~50 mL 
(~43 g). The gross weight of each full container at baseline is approximately 78 to 84 grams.  
Based on one full pump actuation delivering ~0.67 mL of the gel formulation, a total of approximately 38 mL of 
gel is required for 4 weeks (28 days) of daily dosing to the axillae. Therefore, each pump container is sufficient 
for 28 days of dosing per protocol instructions. A new container will be dispensed to each subject at Baseline 
and then Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44.  
5.1 
Storage of Investigational Product  
The investigational product must be stored in a secure area with access limited to the Investigator and authorized 
site staff and administered only to subjects entered into the clinical study, at no cost to the subject, in accordance 
with the conditions specified in this protocol. 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 25 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
Investigational product should be stored at controlled room temperature 68oF to 77oF (20oC to 25oC) with 
excursion permitted between 59°F to 86°F (15oC to 30oC). Maintenance of a temperature log (manual or 
automated) is required.   
5.2 
Instructions for Use and Administration of Investigational Product 
Investigational product kit cartons will be provided to each site and will include one individual plastic pump 
container per each carton. Each carton will also contain 2 applicators. An investigational plastic pump container 
will contain sufficient drug product for a 28-day treatment period.   
Each carton will have a unique identifier number printed on the label and the pump container label will display 
the same unique identifier number. 
Each subject will be randomized via an Interactive Response Technology (IRT) system to receive either 
sofpironium bromide gel, 5% or 15% to topically apply, once daily at bedtime, to each axilla using the supplied 
applicators for 48 consecutive weeks.  Instructions on the use of the IRT system will be provided in a separate 
manual.  
Subjects will be instructed to apply the investigational gel product to each axilla using all the gel expressed from 
ONE FULL ACTUATION of the pump per each axillary dose application. Each full actuation of the pump 
corresponds to approximately 0.551 grams for the 5% and 0.576 grams for the 15% investigational product.   
The subject will apply all doses of investigational product at night, prior to going to bed using the supplied 
applicators. Subjects will apply their first dose of gel prior to bedtime on the night of their Baseline Visit. The 
subject will be instructed to continue applying the investigational product each night with the last application to 
occur the night before attending the end of-treatment evaluation (i.e., Week 48, Visit 16). Subjects should wash 
the applicator each night after dosing. Two applicators are provided in each kit to compensate for loss or damage 
during handling; it is not necessary to use all the applicators over the specified dosing interval. 
To ensure accurate dosing, the study staff will be instructed to first prime and then weigh each pump container 
before dispensing to the subject. Priming is accomplished by fully pressing the pump for five (5) sequential 
actuations; the dispensed gel from these 5 priming actuations is considered waste and should be discarded.   
The weight of the pump container, with the cap on, will be recorded for the uniquely numbered container after 
priming and can then be dispensed to the subject. Over the course of the study, a container will be 
primed/weighed/dispensed at each of the Baseline Visit (Day1) and then Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 
40, and 44 (Visits 4-15) for a total of 12 containers. Each of the 12 containers previously dispensed will be 
returned by the subject at the next respective visit, weighed and weight recorded per the unique bottle number. At 
the End of Treatment visit (Week 48), the subject will bring the 12th container to his/her visit for the final weight 
determination, however, no additional investigational product will be dispensed. Study subjects may return the 
applicators, or they may discard them after dosing is completed. 
At each visit, gel application instructions and compliance will be discussed and documented.  
5.3 
Instructions for the Subjects 
Subjects will be instructed to apply the investigational product every day, at night prior to bedtime using a 
supplied applicator as follows (a written instruction sheet, and access to a study product application video and 
digital mobile application will be supplied to the Subject): 
1. Expose the underarm areas and ensure they are dry. Do not wash the underarm areas for at least 30 minutes 
prior to application. 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 26 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
2. Hold the plastic applicator between the index and middle fingers and the thumb of the left hand. Carefully, by 
applying consistent pressure to the actuator with an index finger, dispense the gel of ONE FULL actuation 
onto the dome of the white plastic applicator. 
3. Immediately apply study product to the right underarm area. 
4. Distribute all the gel expressed using the plastic applicator in a way that covers all the underarm area where 
the hair grows by gently applying a layer of the product. 
5. Repeat the procedure to apply the study product to the left underarm using the right hand. 
6. Wash both hands and the plastic applicator thoroughly for about 2 minutes. 
7. Allow the study product to dry for 5 minutes before putting any clothes on the upper body. 
Important information: 
• The subject should sleep in a T-shirt or similar pajama to avoid touching the underarm area while sleeping. 
• Subjects should maintain their underarm areas grooming habits but should not shower, shave, or wash the 
underarm area for at least 8 hours after study product application. If the subject takes a shower, shaves or 
washes the underarm area at night then it should be at least 30 mins before study product application. Ensure 
the underarm areas are dry prior to application of the study product. 
• Subjects should not apply any other product to the axillary area (including deodorant) for at least 8 hours after 
study product application.  
• The subject should use the applicator provided to avoid contact with skin of the hands. Special care should be 
taken to avoid contact of the gel with the eyes or mouth. Of note, hands should be washed after applying the 
gel to avoid possible skin and eye contact with the gel. 
• The study product contains alcohol and is flammable. The subject should avoid fire, flames or smoking 
during the application and until the gel has dried.  The subject should not expose the container to fire, flames 
or extreme heat. 
6 
CONCOMITANT MEDICATIONS/TREATMENTS 
Information on concomitant medications/treatments (e.g., aspirin, Tylenol, birth control pills, IUD, vitamins) 
taken during study participation, or which may require a washout for study participation will be recorded. Every 
effort should be made to keep dosing with any concomitant medications consistent/constant during the study.  
6.1 
Permissible Medications/Treatments 
Therapy considered necessary for the subject's welfare may be given at the discretion of the Investigator. If the 
permissibility of a specific medication/treatment is in question, the Medical Monitor should be contacted. 
Subjects will be instructed to not apply any contraindicated topical product to their axillary area (see list in 
Section 6.2). Deodorant should not be applied within 8 hours following the application of study product (suggest 
applying in the morning). 
6.2 
Prohibited Medications/Treatments 
The decision to administer a prohibited medication/treatment is made with the safety of the study participant as 
the primary consideration. When possible, Brickell Biotech’s Medical Monitor should be notified before a 
prohibited medication/treatment is administered.  


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 27 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
Prior to the inclusion of a subject in the study, as specified in Sections 4.2 and 4.3 (I/E criteria), and throughout 
the duration of the study, the use of the following medications/treatments is prohibited: 
• Anticholinergic agents used to treat conditions such as, but not limited to, hyperhidrosis, asthma, 
incontinence, gastrointestinal cramps, and muscular spasms by any route of administration (e.g., IV, oral, 
inhaled, topical including topical glycopyrrolate or derivatives ).   
 
• Any oral or topical homeopathic or herbal treatment (i.e., alternative therapies such as sage tablets, 
chamomile, valerian root and St. John’s Wort). 
• Any prescription topical products, including topical prescription antiperspirants or similar agents (e.g., 
Drysol, Xerac AC, Certain DRI) and hand sanitizers applied to the axillae for the duration of the study.     
• Any treatment or procedure for axillary hyperhidrosis including but not limited to: 
o botulinum toxin  
o thermolysis treatments including microwave (e.g., MiraDry), laser or other(s)  
o sympathectomy 
• Any surgical procedure involving the axillae (including laser hair removal), or any surgical procedures that 
will result in significant scarring of the axillae. 
• Any oral cholinergic (e.g. bethanechol) throughout the duration of the study. 
• Addition of, or change of dose for any medication that is allowed as specified in  
Sections 4.2 and 4.3 (I/E criteria) including serotonergic agonists (or drugs that increase serotonin activity 
including SSRIs), beta-blockers, alpha-adrenergic agonist (clonidine), dopamine partial agonists, tricyclic 
antidepressants, anti-anxiety and/or other anti-depressant drugs, amphetamine products and drugs with known 
anticholinergic side effects. 
Since no drug-drug interaction studies have been conducted to evaluate whether concomitant medications affect 
sofpironium bromide, potent inhibitors of CYP3A and, CYP2D6 and transporter inhibitors (OCT2/MATE1/ 
MATE2) should not be administered as specified in Sections 4.2 and 4.3 (I/E criteria): see Appendices 6 and 7. 
7 
PROCEDURES 
The timing of each assessment is listed in the Time and Events Table (Section 7.1).   
Each subject will report for 17 distinct visits (over 52 weeks).  
All Screening assessment results must be completed and reviewed prior to the Baseline Visit (within 31 days).  
Therefore, none of the Screening Visit days can occur on the same day as the Baseline Visit. 
Subjects may be consented for up to 31 days before the Baseline Visit. Subjects outside this screening window 
shall be re-consented and certain screening activities may need to be repeated. Prior to enrollment into the 
treatment phase of the study, the Investigator or designee will contact the Medical Monitor to address such 
subjects on a case-by-case basis. 
 
 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 28 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
7.1 
Time and Events Table 
VISIT 
1 
2 
3 – 61 
7 – 162 
173 
Time Point 
Screening 
(-31 to 0 Days) 
Baseline 
(Day 1) 
Weeks 
2, 4, 6, 8 ±3 days 
Q4 Weeks 
(Weeks 12 – 48) ±5 days 
End of Study  
Week 52 ±5 days 
PROCEDURE 
Informed Consent 
X 
 
 
 
 
Medical Hx, Demog 
X 
 
 
 
 
I/E Criteria 
X 
X 
 
 
 
Randomization 
 
X 
 
 
 
PE 
X 
 
 
 
X 
Vitals (BP, HR, RR, 
Temp) 
X 
X 
X 
X 
X 
HDSM-Ax 
X 
X 
X 
X 
X 
PGI-S4 
X 
X 
X 
X 
X 
PGI-C5 
 
 
X 
 
DLQI6 
 
X 
X 
X 
 
HidroQoL7 
 
X 
X 
 
 
Local Tolerability8 
 
X 
X 
X 
X 
Adverse Events8 
X 
X 
X 
X 
X 
UPT (FOCBP)9 
X 
X 
X 
X 
 
IP Dispensation/ Return/ 
Resupply10 
 
X 
X 
X 
 
IP Weight10 
 
X 
X 
X 
 
Compliance 
Training/Evaluation 
 
X 
X 
X 
X 
Safety Labs (heme., 
chem., urine)11 
X 
 
X 
X 
 
Conmeds 
X 
X 
X 
X 
X 
Abbreviations: BP = blood pressure; Chem. = chemistry; Conmeds = concomitant medications; DLQI = Dermatology Life Quality Index;  
FOCBP= females of child-bearing potential; HDSM-Ax = Hyperhidrosis Disease Severity Measure-Axillae; heme. = hematology; HR = heart rate;  
Hx = history; I/E = inclusion/exclusion; IP = investigational product; PE = physical examination; PGI-C = Patient Global Impression of Change;  
PGI-S = Patient Global Impression of Severity; RR = respiratory rate; UPT = urine pregnancy test, urine = urinalysis. 
1No more than 14±3 days may elapse between Visit 2 (Baseline) and Visit 3 (Week 2). 
2No more than 28±5 days may elapse between each of Visits 7-16 (Weeks 12-48). 
3The End of Study Visit may occur ±5 days of Week 52. 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 29 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
4Administered as Question #6 of HDSM-Ax at every assessment. 
5Administered as Question #7 of HDSM-Ax at Week 24 and Week 48 visits. 
6Administered at Baseline, Weeks 2, 6, 24, and 48.  
7Administered at Baseline, Week 2, and Week 6; only the first 100 subjects enrolled in the study will complete this assessment. 
8 Investigator local tolerability assessments to be performed after the Subject local tolerability assessments. 
9 Performed at Screening, Baseline, and then Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48.  
10 Performed at Baseline and then Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48.  
11 Performed at Screening and then Weeks 6, 24, and 48. 
7.2 
Visit-Specific Procedures 
7.2.1 
Visit 1 (Screening; Days -31 to 0) 
Written informed consent must be obtained prior to any study-related procedures. Potential subjects will be 
screened within 31 days prior to Visit 2 (Baseline) to assess their eligibility to enter the study. Only eligible 
subjects with axillary hyperhidrosis will be enrolled. 
After informed consent is obtained, the following procedures will be performed: 
• Collect and review subject medical history and demographics.  
• Assess inclusion/exclusion criteria.   
• Perform physical exam including collection of height and weight (see Section 8.1.1). 
• Collect vital signs (blood pressure, heart rate, respiratory rate, and temperature) after subject has been seated 
for 2 minutes (see Section 8.1.5). 
• Subject to complete the HDSM-Ax assessment.  
o Six multi-part questions and PGI-S question to be completed by the subject prior to other 
assessments.  
o Refer to Appendix 1 (HDSM-Ax).  
• Review the subject’s health (AEs).  
• Perform UPT if applicable (FOCBP only). If positive, the subject shall be screen failed.   
• Collect samples for laboratory assessments (hematology, chemistry and urinalysis) (see Section 8.1.6).  
• Review concomitant medications/treatments and assess for washouts.  
• Schedule the subject to return for Visit 2 (Day 1; Baseline) after any washout has been completed; must be 
within 31 days of Visit 1 (Screening).  
7.2.2 
Visit 2: Baseline (Day 1)  
Any washouts required for prohibited medications (See Section 4.3) must be completed prior to Visit 2 
(Baseline).  
The following activities will be conducted: 
• Provided the subject has passed all I/E criteria, randomize the subject according to separate instruction. 
Note the subject’s randomization number and the IP concentration the subject is assigned (5% or 15% 
sofpironium bromide gel). 
• Collect vital signs (blood pressure, heart rate, respiratory rate, and temperature) after subject has been 
seated for ≥2 minutes. 
• Subject to complete the Hyperhidrosis Disease Severity Measure-Axillary assessment.  


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 30 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
o Subject to complete Patient Global Impression of Severity (PGI-S) at the end of the HDSM-Ax 
questionnaire. 
• Subject to complete the DLQI questionnaire. 
o 10 questions to be completed by the subject. 
o Refer to Appendix 2. 
• Subject to complete the HidroQoL questionnaire. 
o Only the first 100 subjects enrolled in the study to complete the questionnaire.  
o 18 questions to be completed by the subject. 
o Refer to Appendix 3. 
• Perform local tolerability assessments (see Section 8.1.3).  
• Review changes to the subject’s health (AEs).  
• Perform Urine Pregnancy Testing (UPT) if applicable (FOCBP only). If positive, the subject shall be 
excluded from the study.   
• Pull from inventory, a pump container of correct IP concentration recalling the earlier randomization step. 
Record the unique IP gel pump container number on the source document and in the appropriate 
electronic data capture (EDC) (or IRT) data field. Dispense study product container 1 to the subject as 
follows: 
o Write patient number and initials on the study product container label.  
o Prime the pump (5 actuations) and discard expressed gel.   
o Weigh the primed pump and record in source prior to dispensing to the subject.  Dispense the 
pump to the subject in the kit carton with the included 2 applicators 
o Provide subject with patient study drug application brochure, access to a study product application 
video and digital mobile application. 
o Review with subject the study drug application procedure (Refer to Appendix 5). 
o Instruct subject to apply the first application of study medication at home the evening of Visit 2 
(Baseline). 
• Review concomitant medications/treatments. 
• Schedule the subject to return for the next study visit.  
7.2.3 
Visits 3-6 (Weeks 2, 4, 6, and 8) ±3 Days 
Visits 3, 4, 5 and 6 will occur as separate visits on Weeks 2, 4, 6, and 8 respectively, after the Baseline visit 
(Visit 2).   
No more than 14±3 days may elapse between Visit 2 (Baseline) and Visit 3 (Week 2).    
The following activities will be conducted: 
• Collect vital signs (blood pressure, heart rate, respiratory rate and temperature) after subject has been 
seated for 2 minutes.  
• Subject to complete HDSM-Ax assessment.   
o Subject to complete PGI-S at the end of the HDSM-Ax questionnaire. 
• Subject to complete the DLQI questionnaire at Visit 3 (Week 2) and Visit 5 (Week 6).  
• Subject (only the first 100 subjects enrolled in the study) to complete HidroQoL at Visit 3 (Week 2) and 
Visit 5 (Week 6). 
• Perform local tolerability assessments.  
• Review changes to the subject’s health (AEs). 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 31 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
• Perform UPT if applicable (FOCBP only) at Visit 4 (Week 4) and Visit 6 (Week 8). If positive, the 
subject shall be withdrawn from the study.   
• Collect subject’s previously dispensed study product container (1 of 12 at Visit 4 and 2 of 12 at Visit 6), 
weigh and record weight of container. 
• Dispense study product container (2 of 12 at Visit 4; 3 of 12 at Visit 6) to the subject 
o Pull from inventory, a pump container of correct IP concentration recalling the randomization step 
(and which should match with the subject’s returned product container). Record the unique IP gel 
pump container number on the source document and in the appropriate EDC (or IRT) data field. 
o Write patient number and initials on the study product container label.  
o Prime the pump (5 actuations) and discard expressed gel.   
o Weigh the primed pump and record in source prior to dispensing to the subject.  
• Evaluate subject compliance:  
o Ask subjects if they applied the study product to the right and left axilla each evening as directed 
and confirm reason for any missed doses.  
o Verbally confirm application process.   
• Collect samples for laboratory assessments (hematology, chemistry, and urinalysis) at Visit 5 (Week 6) 
only.  
• Review concomitant medications/treatments. 
• Remind subject to bring their study medication product container to next visit.  
• Schedule the subject to return for the next study visit.   
7.2.4 
Visits 7-16 (Weeks 12-48) ±5 Days  
Visits 7 through 16 will occur as separate visits, every 4 weeks, on Weeks 12, 16, 20, 24, 28, 32, 36, 40, 44, and 
48, after the Baseline Visit (Visit 2).   
No more than 28±5 days may elapse between each of these visits.    
The following activities will be conducted: 
• Collect vital signs (blood pressure, heart rate, respiratory rate and temperature) after subject has been 
seated for 2 minutes.  
• Subject to complete HDSM-Ax assessment.  
o Subject to complete PGI-S at the end of the HDSM-Ax questionnaire. 
o Subject to complete PGI-C at the end of the HDSM-Ax questionnaire only at Visit 10 (Week 24) 
and Visit 16 EOT (Week 48). 
• Subject to complete the DLQI questionnaire at Visit 10 (Week 24) and Visit 16 EOT (Week 48). 
• Perform local tolerability assessments.  
• Review changes to the subject’s health (AEs). 
• Perform UPT if applicable (FOCBP only). If positive, the subject shall be withdrawn from the study.   
• Collect subject’s previously dispensed study product container, weigh and record weight of container. 
• Dispense study product container (4 of 12 at Visit 7; 5 of 12 at Visit 8; 6 of 12 at Visit 9; 7 of 12 at Visit 
10; 8 of 12 at Visit 11; 9 of 12 at Visit 12; 10 of 12 at Visit 13; 11 of 12 at Visit 14; and 12 of 12 at Visit 
15; at Visit 16 only the subject’s returned product container 12 will be weighed and recorded.) 
o At each dispensing, pull from inventory, a pump container of correct IP concentration recalling the 
randomization step (and which should match with the subject’s returned product container). 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 32 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
Record the unique IP gel pump container number on the source document and in the appropriate 
EDC (or IRT) data field. 
o Write patient number and initials on the study product container label.  
o Prime the pump (5 actuations) and discard expressed gel.   
o Weigh the primed pump and record in source prior to dispensing to the subject.  
• Evaluate subject compliance:  
o Ask subjects if they applied the study product to the right and left axilla each evening as directed 
and confirm reason for any missed doses.  
o Verbally confirm application process.   
• Collect samples for laboratory assessments (hematology, chemistry and urinalysis) at Visit 10 (Week 24) 
and Visit 16 (Week 48).   
• Review concomitant medications/treatments. 
• Remind subject to bring their study medication to next visit.  
• Schedule the subject to return for the next study visit.   
7.2.5 
Visit 17 (End of Study) ±5 Days  
The following activities will be conducted: 
• Perform physical exam including collection of height and weight. 
• Collect vital signs (blood pressure, heart rate, respiratory rate and temperature) after subject has been 
seated for 2 minutes.  
• Subject to complete HDSM-Ax assessment.  
o Subject to complete PGI-S at the end of the HDSM-Ax questionnaire. 
• Perform local tolerability assessments.  
• Review changes to the subject’s health (AEs). 
• Only if the subject did not return the study product container 12 at Visit 16, then weigh and record weight 
of container. 
• Review concomitant medications/treatments. 
• Discharge subject from the study. 
7.3 
Unscheduled Visits 
If a subject is seen for an unscheduled visit, an assessment and record of AEs should be completed, as 
appropriate. Additional evaluations should be performed as necessary, and the appropriate CRF pages should be 
completed. 
7.4 
Early Discontinuation of Subjects  
It is the right and duty of the Investigator to discontinue a subject’s participation if the subject's health or 
wellbeing is threatened by continuation in the study. In the event of premature discontinuation, the Investigator 
should determine the primary reason for discontinuation. A subject may be discontinued from the study if any of 
the following circumstances occur: 
• The subject experiences a serious adverse event (SAE) rendering him or her unable to continue study 
participation. 
• The subject experiences an AE that in the opinion of the Investigator may pose a significant risk for continued 
participation of the subject in the study. 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 33 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
• The subject is unable to physically or mentally tolerate the use of the investigational product. 
• An exclusion criterion becomes apparent at any time during the study; the Medical Monitor must be contacted 
to discuss prior to discontinuing subject participation.  
• The subject is not compliant with the study procedures; the Medical Monitor must be contacted to discuss 
prior to discontinuing subject participation. 
• The subject voluntarily withdraws from the study. When possible, identify the reason the subject withdrew 
consent should be documented with particular attention paid to whether an underlying AE is at cause.  
• If for any reason per the Investigator’s or the Sponsor’s judgment, discontinuation is in the subject’s best 
interest. 
• If the subject becomes pregnant. 
Subjects who discontinue the study prior to the completion of all treatment visits will be asked to complete the 
evaluations corresponding to Visit 16 (Week 48, End of Treatment). The Sponsor will be notified of early 
discontinuation as soon as possible during the study.  
8 
RESPONSE MEASURES AND SUMMARY OF DATA COLLECTION METHODS 
8.1 
Safety Measures 
The following safety assessment measures will be conducted as indicated in Section 7.1, Time and Events Table. 
• Adverse events  
• Local tolerability assessments including burning, itching, dryness, scaling and erythema 
• Vital signs (blood pressure, pulse rate, respiratory rate, and temperature) 
• Laboratory tests (hematology, chemistry, and urinalysis) and pregnancy testing in FOCBP 
8.1.1 
Physical Exam 
Physical examination will include assessments of the head, eyes, ears, nose, throat, skin, thyroid, neurological, 
lungs, cardiovascular, abdomen (liver and spleen), lymph nodes and extremities.  Height and weight will also be 
measured and recorded. 
8.1.2 
Adverse Events  
Adverse events (AEs; See Section 9.2) will be collected for all untoward medical occurrences in a subject entered 
into this clinical study (e.g., signed consent), whether or not a pharmaceutical product has been administered. 
Any event, including local tolerability assessments (see Section 8.1.3), that requires specific treatment, results in 
interruption of treatment, or results in discontinuation of the subject from the study will also be reported as an 
AE.   
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-leading verbal 
questioning of the subject is the preferred method to inquire about AE occurrence.   
Appropriate questions include: 
• “How are you feeling?”  
• “Have you had any (other) medical problems since your last visit/contact?” 
• “Have you taken any new medicines, other than those provided in this study, since your last visit/contact?” 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 34 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
8.1.3 
Local Tolerability Assessments 
Local tolerability assessments (See Appendix 4) will be evaluated through assessment of selected local signs and 
symptoms at the drug-application site. Burning, itching, dryness, scaling and erythema will be assessed using 
standardized 5-point scales (0-Absent to 4-Severe). These assessments are to be performed for both axillae 
individually. Subject assessments (burning and itching) will be made prior to the Investigator assessments 
(dryness, scaling and erythema).  
Subject Local Tolerability Assessments: Burning and itching for each axilla will be reviewed with the subject 
and assessed for the previous 24 hours using the standardized scales.   
Investigator Local Tolerability Assessments: Dryness, scaling, and erythema for each axilla will be assessed 
by the Investigator using the standardized scales. 
Local tolerability signs and symptoms that result in the subject’s requiring a concomitant therapy, interruption of 
treatment, or discontinuation from the study, will be reported as an AE.  
8.1.4 
Recommendations for Dose Interruption   
To manage AEs, the Investigator may consider interruption of treatment, and/or the use of concomitant therapy. 
Recommended concomitant therapy includes topically applied corticosteroids. Recommendations for dose 
interruption are described in the table below: 
Recommended Dose Interruption  
                                                         Dose Interruption 
First Dose Interruption 
Hold treatment until the adverse event has resolved. Resume daily 
dosing.  
Second Dose Interruption Hold treatment until the adverse event has resolved. Decrease dosing 
to every other day. 
Subjects who do not respond to a dose interruption or concomitant therapy can have the study drug withdrawn 
and be discontinued from the study. 
8.1.5 
Vital Signs 
Subjects should be seated for 2 minutes prior to measurements. Pulse rate (bpm) will be counted over  
60 seconds. Blood pressure (mmHg) will be measured with a sphygmomanometer. 
Vital sign measurements will include systolic and diastolic blood pressure, pulse rate, respiratory rate, and 
temperature. 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 35 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
8.1.6 
Clinical Laboratory Assessments 
Hematology, clinical chemistry, urinalysis and additional parameters to be tested are listed below: 
Hematology 
Platelet Count  
RBC Indices: 
Automated WBC Differential: 
RBC Count 
MCV 
Neutrophils 
WBC Count (absolute)  
MCH 
Lymphocytes 
Reticulocyte Count 
MCHC 
Monocytes 
Hemoglobin 
 
Eosinophils 
Hematocrit 
 
Basophils 
 
Clinical Chemistry 
BUN 
Chloride 
Alkaline phosphatase 
Creatinine 
AST (SGOT) 
Total and direct bilirubin 
Sodium 
ALT (SGPT) 
 
Potassium 
GGT 
 
 
Routine Urinalysis 
Specific gravity 
pH, glucose, protein, blood and ketones by dipstick 
Microscopic examination (if blood or protein is abnormal) 
 
Other Screening Tests 
Urine Pregnancy Test (females of childbearing potential* only, using UPT tests provided by the 
Sponsor.) 
* Females of childbearing potential for this study includes any female capable of becoming pregnant 
who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation [6 
months prior to baseline] or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea 
>12 consecutive months in women 55 years of age). 
All results will be reported and must be reviewed by the Investigator or designee. Abnormal results shall be 
assessed for clinical significance. Repeat lab testing may be requested at the discretion of the Investigator.  If an 
AE should require laboratory testing, the results of the test should be obtained by the investigative site and filed 
in the subject’s documentation.  
8.1.7 
Subject Assessments 
Subjects must complete ALL self-assessments while at the clinic (e.g., HDSM-Ax, DLQI, PCI-S, PCI-C, 
HidroQoL) prior to assessments being made by the Investigator. Please see Appendix 1, Appendix 2, and 
Appendix 3 for a full description of these assessments. The HDSM-Ax, DLQI, PCI-S, PCI-C, and HidroQoL 
assessments will be collected electronically using a tablet device. Site personnel will be trained and a separate 
eCOA manual will be supplied. 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 36 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
8.2 
Summary of Methods of Data Collection 
This protocol will utilize validated 21 CFR Part 11 compliant EDC software and eCOA software to collect 
required study data. The Investigator must ensure that data are properly recorded on each subject’s eCRFs, 
eCOAs, and related documents. When changes or corrections are made in the eCRF, the eCOA systems will 
maintain an audit trail of the person making the changes, the date and time of the change and the reason for the 
change. Only individuals listed on the Delegation of Responsibilities Log with responsibility for eCRF 
completion may make entries in the eCRFs. 
The Investigator or physician sub-investigator must electronically sign and date each subject’s eCRF and eCOA 
for each timepoint completed. Individuals who will be providing electronic signatures must first submit 
documentation with a handwritten signature acknowledging that their electronic signature is a legally binding 
equivalent to their handwritten signature. 
8.3 
Efficacy Measures 
The following assessment measures will be conducted to evaluate the long-term efficacy of sofpironium bromide 
gel, 5% and 15%, as indicated in the Procedures Section 7.1: 
• HDSM-Ax as measured by the subject  
• DLQI as measured by the subject (for subjects ≥17 years of age) 
• Patient Global Impression Scales; Severity (PGI-S) and Change (PGI-C)  
8.4 
Additional Efficacy Measure 
The following efficacy assessment measure will be conducted as an exploratory analysis to evaluate sofpironium 
bromide gel, 5% and 15%, as indicated in the Procedures Section 7.1: 
• HidroQoL as measured by the subject (for subjects ≥17 years of age); only the first 100 subjects enrolled 
in the study will complete this assessment  
9 
ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE) 
9.1 
Safety Evaluations 
The Investigator is responsible for the appropriate medical care and the safety of subjects who have entered this 
study. The Investigator must document any AE experienced by subjects who have entered this study and report 
all SAEs to the Sponsor (see Section 9.3.1).  Contact information for the Sponsor’s medical monitor is provided 
on the protocol covering page.  
9.2 
Adverse Events 
9.2.1 
Definitions of Adverse Events  
According to the Code of Federal Regulations, 21 CFR Parts 312.32 and 320.32 (IND Safety Reporting, 
Applicability of requirements regarding an "Investigational New Drug Application"), FDA Guidance for Industry 
(Investigational New Drug Safety Reporting Requirements for Human Drug and Biological Products and Safety 
Reporting Requirements for Bioavailability and Bioequivalence Studies in Humans) (Federal Register/Vol. 75, 
No. 188/September 29, 2010) and ICH E2A (Clinical Safety and Data Management:  Definitions and Standards 
for Expedited Reporting): 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 37 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
An adverse event (AE) means any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. 
A suspected adverse reaction means any AE for which there is a reasonable possibility that the drug caused the 
AE. 
The following information should be considered when determining whether or not to classify a test result, 
medical condition, or other incident as an adverse event: 
Adverse events will be recorded from the time of informed consent. 
Abnormal laboratory values should not generally be recorded as an adverse event unless an intervention is 
required, the laboratory abnormality results in a serious adverse event, the lab abnormality results in study 
termination or interruption/discontinuation of study treatment, or the lab abnormality is associated with clinical 
signs or symptoms. When recording an adverse event resulting from a laboratory abnormality, the resulting 
medical condition rather than the abnormality itself should be recorded (e.g., record “anemia” rather than “low 
hemoglobin”). 
Complications that occur in association with a protocol-mandated intervention (e.g., invasive procedures such as 
biopsies) should be recorded as AEs. 
Whenever possible, the Investigator should group signs or symptoms that constitute a single diagnosis under a 
single event term. For example, cough, rhinitis, and sneezing might be grouped together as “upper respiratory 
tract infection”. If possible, abnormal laboratory results that meet the definition of an adverse event (see above) 
should be reported as a clinical diagnosis rather than the abnormal value itself (e.g., “anemia” rather than 
“decreased blood count”). 
9.2.1.1 
Documentation and Monitoring Adverse Events  
All AEs encountered during the clinical trial following subject consent through the last dose of study drug will be 
recorded on the appropriate Adverse Events case report form (eCRF). 
Special considerations: 
Elective procedures or routinely scheduled treatments are not considered AEs. However, an untoward medical 
event occurring in association with a prescheduled elective procedure should be recorded as an AE. 
A baseline condition is not considered an AE unless the condition worsens following study drug administration. 
Death itself is not considered an AE; it is, instead, the outcome of an AE. 
SAEs that are considered related (i.e., determined to be possibly, probably, or definitely related) to sofpironium 
bromide by the Investigator or Sponsor should be followed until the event resolves or stabilizes (see Section 
9.3.1). 
9.2.1.2 
Assessment of Adverse Events 
For each AE, the start and resolution dates, intensity, seriousness (i.e., whether the event meets the definition of 
an SAE (Section 9.3.1), relationship of the event to the study drug, action taken regarding study drug, and 
outcome of the event will be documented on the eCRF. 
Intensity 
The following definitions should be used to assess and grade AE intensity, including laboratory abnormalities 
judged to be clinically significant.  


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 38 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
Severity 
Grade Description 
Mild  
1 
Awareness of sign or symptom, but easily tolerated 
Moderate  
2 
Discomfort enough to cause interference with usual activity 
Severe 
3 
Incapacitating with inability to work or do usual activity 
Note: a severe adverse event is not necessarily serious. 
Relationship  
The relationship of an AE to study drug should be assessed using the guidelines presented in the table below. An 
AE for which there has been no causal relationship reported will require follow-up to determine causality. 
Adverse Event Relationships to Study Drug 
Degree of Certainty 
Description 
Definitely Related 
An event that follows a reasonable temporal sequence from administration of 
the test article; that follows a known or expected response pattern to the test 
article; and that is confirmed by improvement on stopping or reducing the 
dosage, and reappearance of the event on repeated exposure (re-challenge). 
Probably Related 
An event that follows a reasonable temporal sequence from administration of 
the test article; that follows a known or expected response pattern to the test 
article; and that is confirmed by improvement on stopping or reducing the 
dosage of the test article; and that is unlikely to have been caused by 
concurrent/underlying illness or other drugs, procedures, or other causes. 
Possibly Related 
An event that follows a reasonable temporal sequence from administration of 
the test article; that follows a known or expected response pattern to the test 
article; but may have been caused by concurrent/underlying illness, other drug, 
procedure, or other causes. 
Unlikely Related 
An event that does not follow a reasonable temporal sequence from 
administration of the test article; that does not follow a known or expected 
response pattern to the test article, or most likely was caused by 
concurrent/underlying illness, other drug, procedure, or other causes, because 
of their known effects. 
Not related 
An event almost certainly caused by concurrent/underlying illness, other drug, 
procedure, or other causes. 
 
Outcome 
Each AE will be characterized according to the outcomes described in the following table: 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 39 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
Outcome 
Description 
Recovered/Resolved 
The subject has fully recovered from the event with no 
observable residual effects. 
Recovering/Resolving 
The effects of the event are improving, or events have 
stabilized (are constant and not expected to improve or 
worsen) but have not returned to baseline. 
Not recovered/Not Resolved 
The effects of the event are still present and changing. The 
event is not considered stabilized or resolved. 
Recovered/Resolved with Sequelae 
The subject has fully recovered from the event with some 
observable residual effects. 
Fatal 
The event was the primary cause of death (may or may not 
be the immediate cause of death). 
Unknown 
The event outcome is unknown. 
Death is an outcome of an event and not an event per se. Sudden death or death due to unexplainable cause(s) is 
to be reported, but follow-up will be pursued until cause of death is determined. 
 
Action Taken with Study Drug 
Action taken with study drug in relation to each adverse event will be characterized as follows: 
None 
Drug withdrawn  
Drug interrupted  
Unknown 
Not applicable 
Other (specify on CRF) 
9.3 
Serious Adverse Events 
Any AE that is serious (see definition below) and occurs after administration of study drug must be reported to 
the Sponsor within 24 hours of discovery of the event. An event occurring after informed consent but before 
administration of study drug that is considered serious and possibly related to a protocol procedure must also be 
reported to the Sponsor within 24 hours of discovery of the event. 
9.3.1 
Definition and Reporting Procedures 
An AE should be classified as an SAE if it meets one of the following criteria: 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 40 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
Fatal: 
The adverse event resulted in death. 
Life Threatening: 
The adverse event placed the patient at immediate risk of death. This 
classification does not apply to an adverse event that hypothetically might 
cause death if it were more severe. 
Hospitalization: 
The AE required or prolonged an existing inpatient hospitalization. 
Hospitalizations for elective medical or surgical procedures or treatments 
planned before the signing of informed consent in the study or routine check-
ups are not serious adverse events by this criterion. Hospitalizations or 
prolonged hospitalizations for scheduled therapy need not be captured as 
SAEs. 
Disabling/Incapacitating: Resulted in a substantial and permanent disruption of the patient’s ability to 
carry out activities of daily living. 
Congenital Anomaly or 
Birth Defect: 
An adverse outcome in a child or fetus of a patient exposed to the study drug 
or study treatment regimen before conception or during pregnancy. 
Medically Significant: 
The adverse event did not meet any of the above criteria, but could have 
jeopardized the patient and might have required medical or surgical 
intervention to prevent one of the outcomes listed above. 
Every SAE (regardless of suspected causality) should be reported to the Sponsor within 24 hours of discovery of 
the event. The processes for reporting and documenting SAEs are provided in the study manual. Investigators are 
responsible for reporting these events to their Institutional Review Board/Institutional Ethics Committee 
(IRB/IEC) in accordance with federal and institutional laws and regulations. 
Additional updates from the Investigator may be necessary as more information becomes available on the SAE, 
and all treatment-related SAEs will be followed until the acute event has resolved or stabilized, even if the 
subject discontinues study participation prior to the SAE resolution. Any new information or follow-up 
information pertaining to previously reported SAEs will be reported to the Sponsor within 24 hours of becoming 
aware of the new or follow-up information. The new or follow-up information should be faxed to the Sponsor at 
1-866-666-7392 or emailed to safety@brickellbio.com. 
Any SAE that occurs after study completion, and is considered by the Investigator to be related to sofpironium 
bromide, should be reported to the Sponsor. 
Reporting Serious Adverse Events to Regulatory Agencies 
The Sponsor will determine which SAEs qualify for expedited reporting to regulatory agencies. SAEs that 
qualify for expedited reporting will be submitted to regulatory agencies in accordance with federal regulation 
(21CFR 312.32).  
9.4 
Follow-up of Adverse Events and Laboratory Test Abnormalities 
AE information will be collected during the clinical trial from the time the subject signs informed consent 
through the final study visit. SAEs that are considered related to study drug by the Investigator or Sponsor should 
be followed until the events resolve or stabilize. 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 41 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
9.5 
Pregnancy Reporting  
Sexually active females of childbearing potential (FOCBP)* must have a negative pregnancy test prior to study 
enrollment and must use an effective method of contraception during the course of the study, in a manner such 
that risk of failure is minimized. Prior to study enrollment, FOCBP must be advised of the importance of 
avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy. The 
subject must sign an informed consent form documenting this discussion. 
FOCBP must agree to periodic pregnancy testing and use a medically acceptable method of contraception while 
receiving protocol-assigned product. This includes perimenopausal women who are <12 months from their last 
menses. Acceptable contraceptive methods include the following:  
• Abstinence for the duration of the study or where partner is sterile (e.g., vasectomy) is acceptable form of 
contraception; 
• Hormonal contraception, including oral, injectable, or implantable methods started 2 months prior to 
screening; OR 
• Two forms of non-hormonal contraception, including IUD (1-week status post placement), or properly 
used barrier methods (e.g., male or female condoms, cervical cap/diaphragm, spermicidal agents). 
* FOCBP for this study includes any premenopausal female capable of becoming pregnant who has not 
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation [6 months prior to baseline] or 
bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea 12 consecutive months in women  
55 years of age).   
Subjects who become sexually active or begin to have relations with a partner who is not sterile during the trial 
must agree to use an effective form of birth control for the duration of the study. 
9.5.1 
Time period for collecting pregnancy information 
FOCBP should be instructed to contact the Investigator immediately if they suspect they might be pregnant (e.g., 
missed or late menstrual period). If a subject or Investigator suspects that a subject may be pregnant at any time 
during the study, the investigational product must be withheld until the results of laboratory pregnancy testing are 
available.  If pregnancy is confirmed, the subject must not receive or apply further investigational product and 
must be discontinued from the study. 
9.5.2 
Action to be taken if pregnancy occurs 
If following initiation of investigational product, it is subsequently discovered that a trial subject was pregnant or 
may have been pregnant at the time of investigational product exposure, the Investigator must immediately notify 
the Medical Monitor of this event, and record the pregnancy on the appropriate pregnancy surveillance form. The 
form will be sent to the Medical Monitor by fax to 1-866-666-7392 or email at safety@brickellbiotech.com. The 
Investigator must notify the IRB of any pregnancy associated with the study therapy and keep careful source 
documentation of the event. 
Protocol-required procedures for those subjects that are discontinued from the study must be performed on the 
subject unless contraindicated by pregnancy (e.g., x-ray studies). Other appropriate pregnancy follow-up 
procedures should be considered if indicated, including counseling of the subject by the Investigator and her 
managing physician or health care provider (e.g., obstetrician). In addition, the Investigator must report to the 
Medical Monitor, on the appropriate pregnancy surveillance form(s), any follow-up information regarding the 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 42 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
course of the pregnancy, including perinatal (period immediately before and after birth) and neonatal (infants up 
to 28 days after birth) outcome.   
Although pregnancy itself is not an AE, any complications during pregnancy should be recorded as AEs (or 
SAEs – if they fulfill the SAE criteria). Offspring will be followed for a minimum of eight weeks. Any 
congenital anomaly/birth defect in a child born to a subject exposed to the test article(s) will be recorded as a 
SAE and details documented in the pregnancy surveillance form. An abortion, whether accidental, therapeutic or 
spontaneous will be reported as a SAE. 
9.6 
Other Safety Measures 
Safety will also be assessed by physical examinations, laboratory tests, and measurement of vital signs assessed 
as indicated throughout the study schedule. Clinically significant changes in these parameters may be captured as 
adverse events. All analyses will be performed separately for the 5% and 15% IP concentrations. 
10 
STATISTICAL PROCEDURES 
A detailed statistical analysis plan will be generated prior to the final database lock. Database lock will follow 
completion of data entry, verification and validation, database audit, and data clarification resolution. 
10.1 
Analysis Populations 
Subjects will be classified into the Safety, Intent-to-Treat (ITT), and Per-Protocol (PP) patient sets according to the 
following definitions. 
Safety Patient Set 
The Safety Patient Set will include all subjects randomized in the study who received study drug at least once.  
Subjects will be included in the treatment group based on the majority of actual treatment they received (even if 
not the treatment group to which they were randomized).  
ITT Population 
The ITT Patient Set will include all subjects who were randomized and dispensed study drug. Subjects will be 
included in the treatment group to which they were randomized, regardless of the treatment received. 
PP Population 
The PP Patient Set will be a subset of the ITT Patient Set and will include subjects who meet the following criteria: 
• Meets the inclusion/exclusion criteria 
• Has not taken or applied any interfering concomitant medications. 
• Completed the following visits: 
o Visit 1 (Screening) and the required data collection 
o Visit 2 (Baseline) and the required data collection 
o Visit 4 (Week 4), and the required data collection 
o Visit 7 (Week 12), and the required data collection 
o Visit 10 (Week 24), and the required data collection 
o Visit 16 (Week 48), and the required data collection 
o Visit 17 (Week 52), and the required data collection 
• Required treatment received per randomization  


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 43 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
10.2 
Endpoints 
Primary endpoints include evaluation of the long-term safety and local tolerability of 5% and 15% sofpironium 
bromide gel when applied topically in subjects with axillary hyperhidrosis. Assessment will include: 
• Adverse events 
• Local tolerability assessments including burning, itching, dryness, scaling, and erythema 
• Vital signs (blood pressure, pulse rate, respiratory rate, and temperature) 
• Laboratory tests (hematology, chemistry, and urinalysis) and pregnancy testing in FOCBP 
Secondary endpoints - Efficacy: 
Definitions 
“Baseline” HDSM-Ax = Visit 2 (Week 2) assessment 
“End of treatment” HDSM-Ax = Visit 16 (Week 48) assessment  
Efficacy Endpoints 
1. The proportion of subjects achieving 1-point improvement in HDSM-Ax from baseline to end of treatment  
2. The proportion of subjects achieving 1.5-point improvement in HDSM-Ax from baseline to end of treatment 
3. The proportion of subjects achieving 2-point improvement in HDSM-Ax from baseline to end of treatment 
4. Change of HDSM-Ax from baseline to end of treatment as a continuous measure 
Other Efficacy Endpoints 
1. The proportion of subjects achieving 1-point improvement in the HDSM-Ax score from baseline to each of 
Visits 2-15 and 17 (Weeks 2-44 and Week 52) 
2. The proportion of subjects achieving 1.5-point improvement in the HDSM-Ax score from baseline to each 
of Visits 2-15 and 17 (Weeks 2-44 and Week 52) 
3. The proportion of subjects achieving 2-point improvement in the HDSM-Ax score from baseline to each of 
Visits 2-15 and 17 (Weeks 2-44 and Week 52) 
4. Change in HDSM-Ax from baseline to each of Visits 2-15 and 17 (Weeks 2-44 and 52) as a continuous 
measure 
5. DLQI from baseline to each of Visits 5, 10, and 16 (Weeks 2, 6, 24, and 48) 
6. PGI-S summarized as frequency counts and percentages for each category (none, mild, moderate, severe, very 
severe) at each assessment, change from baseline as a 5x5 table with frequency counts and percentages at 
each post-baseline assessment  
7. PGI-C summarized as frequency counts and percentages for each category (very much better, moderately 
better, a little better, no change, a little worse, moderately worse, very much worse) at Visits 10 and 16 
(Weeks 24 and 48)   
Exploratory Efficacy Endpoint 
1. HidroQoL from baseline to each of Visits 3 and 5 (Weeks 2 and 6); only the first 100 subjects enrolled in the 
study will complete this assessment, and an interim analysis will be performed 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 44 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
10.3 
Safety Analyses 
Safety variables are local tolerability assessments, AEs, laboratory evaluations, and vital signs. 
At each post-screening visit, local tolerability (burning, itching, scaling, dryness, and erythema at either axilla) 
will be tabulated by severity. At each post-baseline visit, local tolerability will also be summarized as cumulative 
shift tables vs. baseline.  Subject counts for each symptom will be cross tabulated by baseline severity and the 
maximum post baseline severity reported for either axilla up to the current visit. 
Adverse events will be coded from the verbatim text into preferred term (PT) and primary system organ class 
(SOC) using the most current version of Medical Dictionary for Regulatory Activities (MedDRA). At each post-
baseline visit, treatment-emergent adverse events (TEAEs, i.e., AEs occurring during or after treatment initiation) 
will be summarized in the following tables: all reported AEs, all treatment-related AEs, all SAEs, and AEs 
leading to investigational product discontinuation. Three sets of the above tables will be produced at each visit: 
(a) for TEAEs reported at the current visit by those making the visit, (b) for cumulative TEAEs up to the current 
visit reported by those making the visit, and (c) for cumulative TEAEs up to the current visit reported by all 
enrolled patients (including those absent from the current visit).  For each TEAE, a patient will appear at most 
once by the highest severity reported.   
Laboratory parameters will be descriptively summarized (mean, SD, median, minimum, maximum) for values at 
each visit and for changes from screening at each subsequent visit. In addition, at each post-screening visit, 
parameter status (low, normal, high) will also be summarized as shift tables vs. screening status. 
Vital signs will be descriptively summarized (mean, SD, median, minimum, maximum) for values at each visit 
and for changes from screening at each subsequent visit. 
10.4 
Efficacy Analyses  
Descriptive summaries will be provided for all efficacy endpoints listed in Section 8.3 for each of the two dose 
groups. Mean, standard deviation, median, minimum and maximum will be reported for continuous variables. 
Frequencies and proportions will be reported for categorical variables.    
For HDSM-Ax, the mean of the items in sections No. 1, 2, and 3 (11 sub-items in total) will be used for 
analysis. The mean will be derived by taking the total score and dividing it by the number of questions answered. 
Subjects must answer 6 of the 11 sub-items to be evaluable for HDSM-Ax total score.  
Missing data will not be imputed for any analyses.   
10.5 
Exploratory Analysis 
Change in the HidroQoL from baseline to Week 2 and Week 6 will be assessed. Only the first 100 subjects 
enrolled in the study will complete this assessment, and an interim analysis will be performed. 
10.6 
Sample Size 
A maximum of 300 subjects, at approximately 30 clinical sites, will be randomized to receive either sofpironium 
bromide gel, 5% or 15% in a 1:2 ratio to obtain approximately 150 subjects (50 subjects dosed with 5% gel and 
100 subjects dosed with 15% gel) who have completed 48 weeks of dosing and 52 weeks of clinical assessments. 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 45 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
11 
STUDY ADMINISTRATION PROCEDURES 
11.1 
Subject Entry Procedures 
11.1.1 
Overview of Entry Procedures 
Subjects with hyperhidrosis as defined by the criteria Sections 4.2 and 4.3 (inclusion/exclusion criteria) will be 
considered for entry into this study. 
11.1.2 
Informed Consent and Subject Privacy 
The study will be discussed with the subject, and a subject wishing to participate must give informed consent 
prior to any study-related procedures or change in treatment. The subject must also give Authorization for Use 
and Release of Health and Research Study Information and other written documentation in accordance with the 
relevant country and local privacy requirements (where applicable) prior to any study-related procedures or 
change in treatment.  
11.1.3 
Method for Assignment to Study Product Groups 
All subjects who have signed an ICF will receive a 7-digit subject screening number, this number will be 
composed of a 1-digit study number (3), a 3-digit site number followed by a 3-digit sequentially assigned number 
stating at 001, at each site. For instance, the first subject from site 01 will have 3001001 as their assigned subject 
screening number; the subsequent subject from this site will have 3001002 as their assigned subject screening 
number. The first subject from site 02 will have 3002001 as their assigned subject screening number; the 
subsequent subject from this site will have 3002002 as their assigned subject screening number. This number will 
be unique to each subject and will be used to identify the subject throughout the study. 
After subjects qualify for the study (as determined by the Investigator at the Screening Visit), they will be 
scheduled to return for a Baseline Visit where they will be randomized to one of the two investigational product 
concentrations (5% or 15%), notified of the IP gel concentration they are assigned to, and their screening number 
becomes their post-randomization subject number. Each kit carton will contain a treatment plastic pump, which 
will be labeled with the IP drug concentration contained within and have a unique bottle number displayed on the 
label. A kit of the proper drug concentration will be selected from inventory and dispensed to the subject after the 
proper prep/priming operation (see Section 5.2). 
The next eligible subject will be assigned the next available randomization slot from the randomization list 
queue. In this manner, eligible subjects will be randomized to the investigational product in accordance with the 
randomization schedule. The Investigator will document the randomization and kit numbers dispensed to the 
subject in the source, in the IRT system and on the CRF. The tear-off portion of the carton label from the outer 
carton will be removed along the label perforation and placed into the study subject source file. In the event a 
subject is randomized but is not dispensed study medication (e.g., deemed ineligible at Baseline, withdraws 
consent) the randomization number will not be reassigned; the subject will be considered an early termination and 
the kit shall be placed in quarantine in the site’s inventory.  
Up to 300 subjects will be randomized to receive either sofpironium bromide gel, 5% or 15% in a ratio of 1:2 
(100 subjects dosed with 5% gel and 200 subjects dosed with 15% gel). 
 
 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 46 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
11.2 
Compliance with Protocol 
At each post-baseline visit, the following activities will occur to ensure compliance with the protocol: 
• Subjects will be asked if they have used the investigational product as instructed. 
• Subjects will be reminded to perform ONE FULL pump actuation and use the gel expressed per 
application to each axilla and asked if they experienced any problems dispensing the investigational 
product. 
• Subjects will be asked if they used any other products on their axillae. 
• Site staff will review concomitant medication use since the previous visit and determine if any 
concomitant medication use qualifies as a protocol deviation  
• At each post baseline visit until EOT, site staff will collect the dispensing container from the subject, then 
weigh and record the weight of the used container. 
11.3 
Study Termination 
The study may be stopped at a study site at any time by the site Investigator, after first notifying the Sponsor and 
discussing the reason(s) for stopping the study. Brickell Biotech, Inc. may stop the study with appropriate 
notification.  
12 
ADMINISTRATIVE ISSUES 
12.1 
Posting of Information on Clinicaltrials.gov 
Study information from this protocol will be posted on clinicaltrials.gov before enrollment of subjects begins. 
12.2 
Protection of Human Subjects 
12.2.1 
Compliance with Informed Consent Regulations (US 21 CFR Part 50) and Relevant 
Country Regulations 
Written informed consent is to be obtained from each subject prior to enrollment into the study. Subjects may be 
consented at the Screening Visit and up to 31 days before the Baseline visit. 
12.2.2 
Compliance with IRB Regulations 
This study is to be conducted in accordance with IRB regulations (US 21 CFR Part 56.103). The Investigator 
must obtain approval from a properly constituted IRB prior to initiating the study and re-approval or review at 
least annually. Brickell Biotech, Inc. is to be notified immediately if the responsible IRB has been disqualified or 
if proceedings leading to disqualification have begun. Copies of all IRB correspondence with the Investigator 
must be provided to Brickell Biotech, Inc. 
12.2.3 
Compliance with Good Clinical Practice 
This protocol is to be conducted in accordance with the applicable Good Clinical Practice (GCP) regulations and 
guidelines, e.g., the International Conference on Harmonisation (ICH) Guideline on GCP. 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 47 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
12.3 
Changes to the Protocol 
The Investigator should not implement any deviation from or changes to the protocol without approval by 
Brickell Biotech, Inc. and prior review and documented approval/favorable opinion from the IRB of a protocol 
amendment, except where necessary to eliminate immediate hazards to study subjects, or when the changes 
involve only logistical or administrative aspects of the study (e.g., change in monitors, change of telephone 
numbers). 
12.4 
Subject Confidentiality 
A report of the results of this study may be published or sent to the appropriate health authorities in any country 
in which the investigational product may ultimately be marketed, but a subject’s name will not be disclosed in 
these documents. A subject's name may be disclosed to the Sponsor of the study, Brickell Biotech, Inc., the 
governing health authorities, or the FDA if they inspect the study records. Appropriate precautions will be taken 
to maintain confidentiality of medical records and personal information. 
12.4.1 
Subject Privacy 
Written Authorization and other documentation in accordance with the relevant country and local privacy 
requirements (where applicable) is to be obtained from each subject prior to enrollment into the study, in 
accordance with the applicable privacy requirements (e.g., the Health Insurance Portability and Accountability 
Act Standards for Privacy of Individually Identifiable Health Information; HIPAA). 
12.5 
Documentation 
12.5.1 
Source Documents 
Source documents may include a subject's medical records, hospital charts, clinic charts, the Investigator's subject 
study files, as well as the results of diagnostic tests. The Investigator's copy of the CRF serves as part of the 
Investigator's record of a subject's study-related data.  
12.5.2 
Electronic Case Report Form Completion 
The Investigator is responsible for ensuring that data are properly recorded on each subject's eCRFs and related 
documents. The eCRFs are to be completed in a timely manner as defined in the clinical study agreement, or as 
otherwise specified by Brickell Biotech. 
12.5.3 
Retention of Documentation 
All study related correspondence, subject records, consent forms, subject privacy documentation, records of the 
distribution and use of all investigational products, and copies of CRFs should be maintained on file. 
The Sponsor-specific essential documents should be retained until 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications in an ICH 
region or 2 years have elapsed since the formal discontinuation of clinical development of the investigational 
product. These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirement(s) or if needed by the Sponsor. 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 48 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
Brickell Biotech, Inc. requires that it be notified in writing if the Investigator wishes to relinquish ownership of 
the data so that mutually agreed-upon arrangements can be made for transfer of ownership to a suitably qualified, 
responsible person. 
12.6 
Labelling, Packaging, Storage, and Return or Disposal of Investigational Product 
12.6.1 
Labeling/Packaging 
The investigational product will be packaged, labeled, and supplied by Brickell Biotech, Inc. The product will be 
identified as an investigational compound, for external use. The study number and a unique bottle number will be 
identified on the unit label of the product.  
12.6.2 
Storage of Investigational Product  
The investigational product must be stored in a secure area with access limited to the Investigator and authorized 
site staff and administered only to subjects entered into the clinical study, at no cost to the subject, in accordance 
with the conditions specified in this protocol. 
Investigational product should be stored at controlled room temperature 68oF to 77oF (20oC to 25oC) with 
excursion permitted between 59°F to 86°F (15oC to 30oC). Maintenance of a temperature log (manual or 
automated) is required.   
12.6.3 
Clinical Supply Inventory 
The investigational product must be prepped and dispensed only by an appropriately qualified person to subjects 
in the study. The investigational product is to be used in accordance with the protocol by subjects who are under 
the direct supervision of the Principal Investigator. 
The Investigator or designated site staff are responsible for investigational product accountability, reconciliation, 
and record maintenance. The Investigator or designated site staff must maintain investigational product 
accountability records throughout the course of the study. Discrepancies are to be reconciled or resolved and 
documented.   
12.6.4 
Return or Disposal of Investigational Product 
All investigational product (used and unused) will be returned to Brickell Biotech, Inc. or its designee for 
destruction.  
12.7 
Monitoring by the Sponsor 
A representative of the Sponsor will monitor the study on a periodic basis. The determination of the extent and 
nature of monitoring will be based on considerations such as the objective, purpose, design, complexity, size, and 
endpoints of the study.  
Authorized representatives of Brickell Biotech, Inc. and/or regulatory authority representatives will conduct on-
site visits to review, audit, and copy study-related documents. These representatives will meet with the 
Investigator(s) and appropriate staff at mutually convenient times to discuss study-related data and questions. 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 49 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
12.8 
Publications 
Brickell Biotech, Inc. as the sponsor has proprietary interest in this study. Authorship and manuscript 
composition will reflect joint cooperation between the Investigator and Brickell Biotech, Inc. personnel. 
Authorship will be established prior to the writing of the manuscript. No manuscripts regarding this study will be 
submitted without written authorization from Brickell Biotech, Inc. 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 50 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
13 
REFERENCES 
1. Doolittle J, Walker P, Mills T, Thurston J. Hyperhidrosis: an update on prevalence and severity in the United 
States. Arch Dermatol Res. 2016; 308(10):743-749. 
 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 51 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
14 
APPENDICES 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 52 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
APPENDIX 1:  HYPERHIDROSIS DISEASE SEVERITY MEASURE-
AXILLARY (HDSM-AX)  
 
Hyperhidrosis Disease Severity Measure--Axillary, Version 1.3 
(HDSM-Ax)* 
 
INSTRUCTIONS:  We are interested in finding out about your current experience with excessive underarm 
sweating.   
• 
Please consider excessive sweating in your underarms only when selecting the answer to each 
question. 
• 
For each statement, please provide the response that best describes your experience since you woke 
up yesterday. 
• 
Please answer ALL questions even if some seem similar to others or seem irrelevant to you. 
_______________________________________________________________________________ 
1. Since you woke up yesterday, how often did you experience the following while you were awake?  
(Please select the number that best describes your experience.) 
 
None of 
the time  
A little of 
the time 
Some of 
the time 
Most of 
the time 
All of 
the time 
a) Damp or wet clothing caused by underarm 
sweating? 
0 
1 
2 
3 
4 
b) Underarm sweating for no apparent reason? 
0 
1 
2 
3 
4 
 
2. Since you woke up yesterday, how severe was your experience with the following? (Please select the 
number that best describes your experience.) 
 
I did not 
experience 
this  
Mild 
Moderate Severe 
Very 
severe 
a) Underarm sweating when you felt 
nervous, stressed or anxious? 
0 
1 
2 
3 
4 
b) Damp or wet clothing caused by 
underarm sweating? 
0 
1 
2 
3 
4 
c) 
Underarm sweating after little or no 
physical exercise? 
0 
1 
2 
3 
4 
d) Underarm wetness? 
0 
1 
2 
3 
4 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 53 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
e) Underarm sweating for no apparent 
reason? 
0 
1 
2 
3 
4 
f) 
Underarm sweating that was 
unmanageable? 
0 
1 
2 
3 
4 
g) Underarm sweating when you were 
cool? 
0 
1 
2 
3 
4 
 
3. Since you woke up yesterday, what was your experience with each of the following? (Please select the 
number that best describes your experience.) 
 
Not at all  
Slight  
Moderate Strong 
Very 
strong 
a) Feeling the need to change clothes because 
of underarm sweating? 
0 
1 
2 
3 
4 
b) Feeling the need to wipe sweat from your 
underarms? 
0 
1 
2 
3 
4 
 
 
SUMMARY QUESTIONS (ANCHORS): 
4. Since you woke up yesterday, how much of the time did you experience excessive underarm sweating 
while you were awake?  (Please select the number that best describes your experience.) 
0 
None of the time 
1 
A little of the time 
2 
Some of the time 
3 
Most of the time 
4 
All of the time 
 
5.  How severe was your underarm sweating AT ITS WORST since you woke up yesterday? (Please 
select the number that best describes your experience.) 
0 
I did not have underarm sweating (i.e., completely dry) 
1 
I had underarm sweating but it was mild (i.e., slightly damp) 
2 
I had underarm sweating and it was moderate (i.e., damp) 
3 
I had underarm sweating and it was severe (i.e., wet) 
4 
I had underarm sweating and it was very severe (i.e., soaking) 
 


Sofpironium Bromide (BBI-4000) Gel 
 
Protocol BBI-4000-CL-303/01 
Page 54 of 74  
CONFIDENTIAL                                                                                                                        15MAY2018 
 
6. Patient Global Impression of Severity (PGI-S) 
Please choose the response below that best describes the severity of your underarm sweating over 
the past week.** 
0 
None 
1 
Mild 
2 
Moderate 
3 
Severe 
4 
Very severe 
 
 
7. Patient Global Impression of Change (PGI-C) 
Please choose the response below that best describes the overall change in your underarm sweating 
since you started taking the study medication. † 
  Very much better 
  Moderately better 
  A little better 
  No change 
  A little worse 
  Moderately worse 
  Very much worse 
 
 
 
 
* These HDSM-Ax questions can appear slightly different when administered in an electronic format. 
**Administered with each administration of the HDSM-Ax 
† Administered at the 24 Week and 48 Week (EOT) visits only 
 
 


BBI-4000 Gel 
 
Protocol BBI-4000-CL-303/01 
Page 55 of 74 
CONFIDENTIAL                                                                                                                        15MAY2018 
APPENDIX 2: DERMATOLOGY LIFE QUALITY INDEX-AXILLA; 
FOR SUBJECTS 17 YEARS OF AGE 
DERMATOLOGY LIFE QUALITY INDEX-Axilla 
The aim of this questionnaire is to measure how much the SWEATING in your underarms has 
affected your life OVER THE LAST WEEK. 
Please tick one box for each question. 
_______________________________________________________________________________ 
1. 
Over the last week, how itchy, sore, painful or 
stinging has your underarm skin been? 
Very much 
 
A lot 
 
A little 
 
Not at all 
 
 
 
 
2. 
Over the last week, how embarrassed or self-
conscious have you been because of your 
underarm sweating? 
Very much 
 
A lot 
 
A little 
 
Not at all 
 
 
 
 
3. 
Over the last week, how much has your underarm 
sweating interfered with you going shopping or 
looking after your home or garden?  
Very much 
 
A lot 
 
A little 
 
Not at all 
 
Not relevant 
 
 
 
 
4. 
Over the last week, how much has your underarm 
sweating influenced the clothes you wear? 
Very much 
 
A lot 
 
A little 
 
Not at all 
 
Not relevant 
 
5. 
Over the last week, how much has your underarm 
sweating affected any social or leisure activities? 
Very much 
 
A lot 
 
A little 
 
Not at all 
 
Not relevant 
 
 
6. 
Over the last week, how much has your underarm 
sweating made it difficult for you to do any sport? 
Very much 
 
 
A lot 
A little 
Not at all 
Not relevant 
 
 
 
 


BBI-4000 Gel 
 
Protocol BBI-4000-CL-303/01 
Page 56 of 74 
CONFIDENTIAL                                                                                                                        15MAY2018 
DERMATOLOGY LIFE QUALITY INDEX-Axilla 
 
7. 
Over the last week, has your underarm sweating 
prevented you from working or studying? 
A little 
 
Not at all 
 
Not relevant 
 
 
 
 
 
 
If "No", over the last week how much has your 
underarm sweating been a problem at work or 
studying? 
A lot 
 
A little 
 
Not at all 
 
 
 
 
8. 
Over the last week, how much has your underarm 
sweating created problems with your partner or 
any of your close friends or relatives? 
Very much 
 
A lot 
 
A little 
 
Not at all 
 
Not relevant 
 
 
 
 
9 
Over the last week, how much has your underarm 
sweating caused any sexual difficulties? 
Very much 
 
A lot 
 
A little 
 
Not at all 
 
Not relevant 
 
 
 
 
10. Over the last week, how much of a problem has the 
treatment for your underarm sweating been, for 
example by making your home messy, or by taking 
up time? 
Very much 
 
A lot 
 
A little 
 
Not at all 
 
Not relevant 
 
 
Please check that you have answered EVERY question.  Thank you. 
AY Finlay, GK Khan, April 1992 www.dermatology.org.uk, this must not be copied without the permission of the authors. 
 
 
 
 
 


BBI-4000 Gel 
 
Protocol BBI-4000-CL-303/01 
Page 57 of 74 
CONFIDENTIAL                                                                                                                        15MAY2018 
APPENDIX 3:  HYPERHIDROSIS QUALITY OF LIFE INDEX 
(HIDROQOL©); FOR SUBJECTS 17 YEARS OF AGE 
 
Hyperhidrosis Quality of Life Index (HidroQoL) 
 
Domain 1: Daily life activities 
 
 
Very much 
A little 
No, not at all 
1. My choice of clothing is affected 
 
 
 
 
2. My physical activities are affected 
 
 
 
 
3. My hobbies are affected 
 
 
 
 
4. My work is affected 
 
 
 
 
5. I worry about the additional activities in dealing 
with my condition 
 
 
 
 
6. My holidays are affected (e.g., planning, 
activities) 
 
 
 
 
Domain 2: Psychosocial life 
 
 
Very much 
A little 
No, not at 
all 
7. 
I feel nervous 
 
 
 
 
8. 
I feel embarrassed 
 
 
 
 
9. 
I feel frustrated 
 
 
 
 
10. I feel uncomfortable physically expressing 
affection (e.g., hugging) 
 
 
 
 
11. I think about sweating 
 
 
 
The statements in this questionnaire relate to how your life has been affected by your excessive 
sweating condition (hyperhidrosis) in the last seven days including today. 
Please choose one box for each statement. If a statement does not apply to you please choose 
‘No, not at all’.  


BBI-4000 Gel 
 
Protocol BBI-4000-CL-303/01 
Page 58 of 74 
CONFIDENTIAL                                                                                                                        15MAY2018 
 
12. I worry about my future health 
 
 
 
 
13. I worry about people’s reactions 
 
 
 
 
14. I worry about leaving sweat marks on things 
 
 
 
 
15. I avoid meeting new people 
 
 
 
 
16. I avoid public speaking (e.g., presentations) 
 
 
 
 
17. My appearance is affected 
 
 
 
 
18. My sex life is affected 
 
 
 
Domain 1 Score: __________  Domain 2 Score: __________ Total score ____ (out of 36) 
 
Please check that you have answered all questions 
Thank you! 
© HidroQoL MS Salek P Kamudoni 2013 
 
 


BBI-4000 Gel 
 
Protocol BBI-4000-CL-303/01 
Page 59 of 74 
CONFIDENTIAL                                                                                                                        15MAY2018 
APPENDIX 4:  TOLERABILITY ASSESSMENTS 
 
These assessments are to be performed for each axilla individually. The designation of “Right Axilla” 
or “Left Axilla” in the source documents and e-CRFs refers to the subject’s right and left axilla 
respectively in all cases. Subject assessments are to be performed prior to Investigator assessments. 
Local Tolerability (Subject): The severity of burning and itching of the axilla as reported by the 
Subject to the Investigator: 
Score 
Burning 
Itching 
0 = Absent 
Normal, no discomfort 
Normal, no discomfort 
1 = Minimal 
An awareness, but no discomfort  
An awareness, but no discomfort  
2 = Mild 
Noticeable discomfort causing 
intermittent awareness 
Noticeable discomfort causing 
intermittent awareness 
3 = Moderate 
Noticeable discomfort causing 
continuous awareness 
Noticeable discomfort causing 
continuous awareness 
4 = Severe 
Definite discomfort causing 
continuous awareness, interfering 
occasionally with normal daily 
activities 
Definite discomfort causing 
continuous awareness, interfering 
occasionally with normal daily 
activities 
Local tolerability (Investigator): The Investigator will grade the severity of dryness, scaling, and 
erythema on each axilla as observed: 
Score 
Dryness 
Scaling 
Erythema 
0 = Absent 
None 
No scaling 
No redness 
1 = Minimal 
Barely perceptible dryness by palpation 
with no accentuation of skin markings, 
skin desquamation (flakes), or fissure 
formation 
Fine scaling, 
barely 
perceptible 
Faint red or pink 
coloration, barely 
perceptible 
2 = Mild 
Easily perceptible dryness by palpation 
with accentuation of skin markings but no 
skin desquamation (flakes) or fissure 
formation 
Slight scaling, 
noticeable only 
with light 
scratching 
Light red or pink 
coloration 
3 = Moderate 
Easily noted dryness with accentuation of 
skin markings and skin desquamation 
(small flakes) but no fissure formation 
Definitely 
noticeable 
scaling 
Medium red 
coloration 
4 = Severe 
Easily noted dryness with accentuation of 
skin markings, skin desquamation (large 
flakes), and/or fissure formation 
Extensive 
scaling 
Beet red 
coloration 


BBI-4000 Gel 
 
Protocol BBI-4000-CL-303/01 
Page 60 of 74 
CONFIDENTIAL                                                                                                                        15MAY2018 
APPENDIX 5:  STUDY DRUG APPLICATION & SUBJECT 
INSTRUCTIONS 
 
Apply the investigational product every day, at night prior to bedtime as follows: 
1. Expose the underarm areas and ensure they are dry. Do not wash the underarm areas for at least  
30 minutes prior to application. 
2. Hold the plastic applicator between the index and middle fingers and the thumb of the left hand. 
Carefully, by applying consistent pressure to the actuator with an index finger, dispense the gel of 
ONE FULL actuation onto the dome of the white plastic applicator. 
3. Immediately apply study product to the right underarm area. 
4. Distribute all the gel expressed using the plastic applicator in a way that covers all the underarm 
area where the hair grows by gently applying a layer of the product. 
5. Repeat the procedure to apply the study product to the left underarm using the right hand. 
6. Wash both hands and the plastic applicator thoroughly for about 2 minutes. 
7. Allow the study product to dry for 5 minutes before putting any clothes on the upper body. 
Important information: 
• 
The subject should sleep in a T-shirt or similar pajama to avoid touching the underarm area while sleeping. 
• 
Subjects should maintain their underarm areas grooming habits but should not shower, shave, or wash the 
underarm area for at least 8 hours after study product application. If the subject takes a shower, shaves or 
washes the underarm area at night then it should be at least 30 mins before study product application. 
Ensure the underarm areas are dry prior to application of the study product. 
• 
Subjects should not apply any other product to the axillary area (including deodorant) for at least 8 hours 
after study product application.  
• 
The subject should use the applicator provided to avoid contact with skin of the hands.  Special care should 
be taken to avoid contact of the gel with the eyes or mouth. Of note, hands should be washed after applying 
the gel to avoid possible skin and eye contact with the gel. 
• 
The study product contains alcohol and is flammable. The subject should avoid fire, flames or smoking 
during the application and until the gel has dried.  The subject should not expose the container to fire, 
flames or extreme heat. 


BBI-4000 Gel 
 
Protocol BBI-4000-CL-303/01 
Page 61 of 74 
CONFIDENTIAL                                                                                                                        15MAY2018 
SUBJECT INSTRUCTIONS 
Please follow these instructions carefully. If you do not understand anything in these instructions, ask 
the study doctor for help. To contact the study staff, call the telephone number noted below if you 
have any questions: 
Contact: 
 
 
 
 
 
 
At: 
 
 
 
 
If you participate in this study, you will be expected to: 
• 
Follow the instructions you are given and come to the study center for all visits with the study doctor or 
study staff. 
• 
Tell the study doctor or study staff about any changes in your health or the way you feel. 
• 
Tell the study doctor or study staff if you want to stop being in the study at any time. 
• 
Do not shower, shave, or wash the underarm area for at least 8 hours after study product application. 
• 
Be careful not to touch your eyes or mouth with the gel or with your hands while applying the gel. 
• 
Use or practice the required method of birth control throughout the entire study if you are able to become 
pregnant. 
• 
Not breastfeed while you are in the study (for applicable females). 
• 
Use a T-shirt to sleep or similar pajama and avoid touching the underarm area. 
• 
Do not apply any other product to the axillary area (including deodorant) for at least 8 hours after study 
product application. 
• 
Not start any new medications or change your medications without approval from the study doctor. 
• 
Not allow access to the study medication assigned to you to anyone beside the study staff. 
• 
Store the study medications according to the instructions on the label. 
 
IMPORTANT:  
• 
The investigational product contains alcohol and is flammable.  
• 
Avoid fire, flames or smoking during the application and until the gel has dried.  
• 
Do not expose the container to fire, flame or extreme heat. 
 
Bring your previously dispensed Study Drug container to the following clinic visits AFTER Visit 2 
(Baseline): Visits 4 (Week 4), Visit 6 (Week 8), Visit 7 (Week 12), Visit 8 (Week 16), Visit 9 (Week 20), 
Visit 10 (Week 24), Visit 11 (Week 28), Visit 12 (Week 32), Visit 13 (Week 36), Visit 14 (Week 40), Visit 
15 (Week 44) and Visit 16 (Week 48).  


BBI-4000 Gel 
 
Protocol BBI-4000-CL-303/01 
Page 62 of 74 
CONFIDENTIAL                                                                                                                        15MAY2018 
APPENDIX 6:  EXAMPLE POTENT INHIBITORS OF CYP3A AND 
CYP2D6 
 
Example Potent Inhibitors of CYP3A 
apigenin 
hydroxyzine 
protease inhibitors 
antipsychotics 
interferon 
ritonavir 
candesartan 
isoniazid 
St. John’s Wort  
(and other herbal 
supplements) 
chloramphenicol 
itraconazole 
chlorpheniramine 
ketoconazole 
clarithromycin 
methoxsalen 
sulphaphenazole 
cobicistat 
mibefradil 
telithromycin 
cilexetil 
(cyclohexylcarbonate ester 
prodrug of candesartan) 
miconazole 
tripelennamine 
mifepristone 
valproic acid 
mometasone furoate  
voriconazole 
diphenhydramine 
montelukast 
zafirlukast 
felodipine  
nefazodone 
 
gestodene  
promethazine  
 
 
Example Potent Inhibitors of CYP2D6 
bupropion 
fluoxetine 
paroxetine 
quinidine 
terbinafine 
 
Also refer to FDA reference link “Drug Development and Drug Interactions: Table of Substrates, 
Inhibitors and Inducers” 
[http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsL
abeling/ucm093664.htm#table2-2] 
Prohibited medications (see Section 6.2) 
Discontinue within 14 days of the Baseline Visit (Visit 2) for hyperhidrosis. 
 
 
 


BBI-4000 Gel 
 
Protocol BBI-4000-CL-303/01 
Page 63 of 74 
CONFIDENTIAL                                                                                                                        15MAY2018 
APPENDIX 7:  EXAMPLE POTENT INHIBITORS OF  
OCT-2/MATE1/MATE2 TRANSPORTERS 
 
Example Potent Inhibitors of OCT2 
Cimetidine 
 
 
 
Example Potent Inhibitors of MATE1/MATE2 
Cimetidine 
Dolutegravir 
Isavuconazole 
Ranolazine 
Trimethoprim 
Vandetanib 
 
Also refer to FDA reference link “Drug Development and Drug Interactions: Table of Substrates, 
Inhibitors and Inducers” 
[http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsL
abeling/ucm093664.htm#table2-2] 
Prohibited medications (see Section 6.2) 
Discontinue within 14 days of the Baseline Visit (Visit 2) for hyperhidrosis. 
 


BBI-4000 Gel 
 
Protocol BBI-4000-CL-303/01 
Page 64 of 74 
CONFIDENTIAL                                                                                                                        15MAY2018 
APPENDIX 8:  PROTOCOL AMENDMENTS 
 
AMENDMENT 01 SUMMARY OF CHANGES 
Change Number 
Section # / Name 
Details of Change 
1 
All pages of protocol 
Header: Added the version number to the protocol 
number /01 (Protocol BBI-4000-CL-303/01 on all 
pages 
 
Footer: Added the amendment date and 
“Confidential” to all pages 
 
Change Number 
Section # / Name 
Details of Change 
2 
Title Page 
Added the date of amendment  
 
Original Text 
VERSION: Original March 7, 2018 
 
Revised Text 
ORIGINAL PROTOCOL: March 7, 2018  
AMENDMENT 01: May 15, 2018 
 
Change Number 
Section # / Name 
Details of Change 
3 
SYNOPSIS,  
Study Objectives 
Removed HidroQoL from the secondary endpoints 
and added it as an “other” endpoint, which will be 
completed by only the first 100 subjects enrolled in 
the study 
 
Original Text 
Secondary: 
• To evaluate the long-term effect of topically 
applied sofpironium bromide gel, 5% and 15% 
on Hyperhidrosis Disease Severity Measure-
Axillary (HDSM-Ax©) in subjects with axillary 
hyperhidrosis. 
• To evaluate the long-term effect of topically 
applied sofpironium bromide gel, 5% and 15% 
on the Hyperhidrosis Quality of Life Index 
(HidroQoL©) in subjects with axillary 
hyperhidrosis. 
• To evaluate the long-term effect of topically 
applied sofpironium bromide gel, 5% and 15% 
on patient reported Dermatology Life Quality 


BBI-4000 Gel 
 
Protocol BBI-4000-CL-303/01 
Page 65 of 74 
CONFIDENTIAL                                                                                                                        15MAY2018 
Index (DLQI) in subjects with axillary 
hyperhidrosis. 
 
Revised Text 
Secondary: 
• To evaluate the long-term effect of topically 
applied sofpironium bromide gel, 5% and 15% 
on Hyperhidrosis Disease Severity Measure-
Axillary (HDSM-Ax©) in subjects with axillary 
hyperhidrosis. 
• To evaluate the long-term effect of topically 
applied sofpironium bromide gel, 5% and 15% 
on patient reported Dermatology Life Quality 
Index (DLQI) in subjects with axillary 
hyperhidrosis. 
Other: 
• To evaluate the effect of topically applied 
sofpironium bromide gel, 5% and 15% on the 
Hyperhidrosis Quality of Life Index 
(HidroQoL©) in subjects with axillary 
hyperhidrosis. Only the first 100 subjects 
enrolled will complete this assessment. 
 
Change Number 
Section # / Name 
Details of Change 
4 
SYNOPSIS, Study 
Design 
Reordered study design to present safety measures 
followed by efficacy assessments. Also removed 
HidroQoL assessment from key efficacy 
assessments 
 
Original Text 
Patient-reported outcomes: HDSM-Ax, HidroQoL, 
and DLQI will be recorded during the study at 
predefined time points. Patient Global Impression 
of Severity (PGI-S) will be administered with each 
administration of the HDSM-Ax and the Patient 
Global Impression of Change (PGI-C) will be 
administered at the 24 Week and 48 Week (EOT) 
visits. Vital signs, local tolerability assessments 
(including burning, itching, dryness, scaling and 
erythema assessed using standardized scales), and 
adverse events will be collected at each visit. Urine 
pregnancy tests (UPT) for FOCBP will be taken 
throughout the course of the study and blood and 
urine samples will be collected and analyzed at the 
Screening Visit and at Visit 5 (Week 6), Visit 10 


BBI-4000 Gel 
 
Protocol BBI-4000-CL-303/01 
Page 66 of 74 
CONFIDENTIAL                                                                                                                        15MAY2018 
(Week 24), and Visit 16 (Week 48) for routine 
hematology, chemistry, and urinalysis parameters. 
 
Revised Text 
Vital signs, local tolerability assessments 
(including burning, itching, dryness, scaling and 
erythema assessed using standardized scales), and 
adverse events will be collected at each visit. Urine 
pregnancy tests (UPT) for FOCBP will be taken 
throughout the course of the study and blood and 
urine samples will be collected and analyzed at the 
Screening Visit and at Visit 5 (Week 6), Visit 10 
(Week 24), and Visit 16 (Week 48) for routine 
hematology, chemistry, and urinalysis parameters. 
Patient-reported outcomes: HDSM-Ax and DLQI 
will be recorded during the study at predefined time 
points. Patient Global Impression of Severity (PGI-
S) will be administered with each administration of 
the HDSM-Ax and the Patient Global Impression 
of Change (PGI-C) will be administered at the 24 
Week and 48 Week (EOT) visits. HidroQoL will be 
recording during the study at baseline, Visit 3 
(Week 2), and Visit 5 (Week 6); only the first 100 
subjects enrolled will complete this asessment. 
 
Change Number 
Section # / Name 
Details of Change 
5 
SYNOPSIS, Safety 
Measures and 
Efficacy Assessments 
Inverted order of Efficacy Assessments section 
and Safety Measures section to align with order 
presented elsewhere in the protocol 
 
Change Number 
Section # / Name 
Details of Change 
6 
SYNOPSIS, Efficacy 
Assessments 
Removed HidroQoL assessment from key efficacy 
assessments 
 
Original Text 
Efficacy Assessments 
The following assessment measures will be 
conducted to evaluate the long-term efficacy of 
sofpironium bromide gel, 5% and 15%: 
• HDSM-Ax as measured by the subject  
• HidroQoL as measured by the subject (for 
subjects ≥17 years of age) 
• DLQI as measured by the subject (for 
subjects ≥17 years of age) 


BBI-4000 Gel 
 
Protocol BBI-4000-CL-303/01 
Page 67 of 74 
CONFIDENTIAL                                                                                                                        15MAY2018 
• Patient Global Impression Scales; Severity 
(PGI-S) and Change (PGI-C) 
 
Revised Text 
Efficacy Assessments 
The following assessment measures will be 
conducted to evaluate the long-term efficacy of 
sofpironium bromide gel, 5% and 15%: 
• HDSM-Ax as measured by the subject  
• DLQI as measured by the subject (for 
subjects ≥17 years of age) 
• Patient Global Impression Scales; Severity 
(PGI-S) and Change (PGI-C) 
The HidroQoL assessment will be conducted as an 
exploratory analysis, as measured by the subject 
(for subjects ≥17 years of age). This assessment 
will be completed by only the first 100 subjects 
enrolled in the study. 
 
Change Number 
Section # / Name 
Details of Change 
7 
SYNOPSIS, 
Statistical Methods 
Changed the sub-header “Safety Analysis” to 
“Safety Analyses”, and sub-header “Efficacy 
Analysis” to “Efficacy Analyses” 
 
Change Number 
Section # / Name 
Details of Change 
8 
SYNOPSIS, 
Statistical Methods 
Amended statistical methods to move the 
HidroQoL assessment from the Efficacy Analyses 
section to a new Exploratory Analysis section; to 
update the schedule of HidroQoL; and to note only 
the first 100 subjects will complete this assessment  
 
Original Text 
Change in the HidroQoL and DLQI from baseline 
to Week 2, Week 6, Week 24, and Week 48 (EOT). 
 
Revised Text 
Change in the DLQI from baseline to Week 2, 
Week 6, Week 24, and Week 48 (EOT). 
Exploratory Analysis 
Change in the HidroQoL from baseline to Week 2 
and Week 6 will be assessed. Only the first 100 
subjects enrolled in the study will complete this 
assessment, and an interim analysis including 
descriptive statistics will be performed. 
 


BBI-4000 Gel 
 
Protocol BBI-4000-CL-303/01 
Page 68 of 74 
CONFIDENTIAL                                                                                                                        15MAY2018 
Change Number 
Section # / Name 
Details of Change 
9 
Section 2, Study 
Design 
Reordered study design to present safety measures 
followed by efficacy assessments. Also updated to 
amend HidroQoL assessment schedule 
 
Original Text 
Patient-reported outcomes HDSM-Ax, HidroQoL, 
DLQI, PGI-S, and PGI-C will be recorded during 
the study at predefined time points. Vital signs and 
adverse events will be collected at each visit. Local 
tolerability assessments (including burning, itching, 
dryness, scaling, and erythema assessed using 
standardized scales) will be collected at each post-
Screening visit. Blood and urine samples will be 
collected and analyzed at Screening and then 
Weeks 4, 12, 24, 36, and 48 for routine 
hematology, chemistry, and urinalysis parameters. 
Additionally, a urine pregnancy test (UPT) for 
females of child-bearing potential will be collected 
and analyzed at each visit except at Week 2 (Visit 
3), Week 6 (Visit 5), and Week 52 (Visit 17).  
 
Revised Text 
Vital signs and adverse events will be collected at 
each visit. Local tolerability assessments (including 
burning, itching, dryness, scaling, and erythema 
assessed using standardized scales) will be 
collected at each post-Screening visit. Blood and 
urine samples will be collected and analyzed at 
Screening and then Weeks 4, 12, 24, 36, and 48 for 
routine hematology, chemistry, and urinalysis 
parameters. Additionally, a urine pregnancy test 
(UPT) for females of child-bearing potential will be 
collected and analyzed at each visit except at Week 
2 (Visit 3), Week 6 (Visit 5), and Week 52 (Visit 
17). Patient-reported outcomes HDSM-Ax, DLQI, 
PGI-S, and PGI-C will be recorded during the study 
at predefined time points. HidroQoL will be 
recorded at baseline, Week 2, and Week 6; only the 
first 100 subjects enrolled in the study will 
complete this assessment. 
 
 
 


BBI-4000 Gel 
 
Protocol BBI-4000-CL-303/01 
Page 69 of 74 
CONFIDENTIAL                                                                                                                        15MAY2018 
Change Number 
Section # / Name 
Details of Change 
10 
Section 3.1, Study 
Objectives 
Removed the HidroQoL assessment from the 
secondary objectives and added it as an “other” 
objective 
 
Original Text 
Secondary: 
• To evaluate the long-term effect of topically 
applied sofpironium bromide gel, 5% and 15% 
on Hyperhidrosis Disease Severity Measure-
Axillary (HDSM-Ax©) in subjects with axillary 
hyperhidrosis. 
• To evaluate the long-term effect of topically 
applied sofpironium bromide gel, 5% and 15% 
on the Hyperhidrosis Quality of Life Index 
(HidroQoL©) in subjects with axillary 
hyperhidrosis. 
• To evaluate the long-term effect of topically 
applied sofpironium bromide gel, 5% and 15% 
on patient reported Dermatology Life Quality 
Index (DLQI) in subjects with axillary 
hyperhidrosis. 
 
Revised Text 
Secondary: 
• To evaluate the long-term effect of topically 
applied sofpironium bromide gel, 5% and 15% 
on Hyperhidrosis Disease Severity Measure-
Axillary (HDSM-Ax©) in subjects with axillary 
hyperhidrosis. 
• To evaluate the long-term effect of topically 
applied sofpironium bromide gel, 5% and 15% 
on patient reported Dermatology Life Quality 
Index (DLQI) in subjects with axillary 
hyperhidrosis. 
Other: 
• To evaluate the effect of topically applied 
sofpironium bromide gel, 5% and 15% on the 
Hyperhidrosis Quality of Life Index 
(HidroQoL©) in subjects with axillary 
hyperhidrosis.  
 
 
 


BBI-4000 Gel 
 
Protocol BBI-4000-CL-303/01 
Page 70 of 74 
CONFIDENTIAL                                                                                                                        15MAY2018 
Change Number 
Section # / Name 
Details of Change 
11 
Section 3.2, Study 
Assessments 
Removed HidroQoL from the efficacy assessment, 
and added additional assessments section with 
HidroQoL 
 
Original Text 
The following assessment measures will be 
conducted to evaluate the long-term efficacy of 
sofpironium bromide gel, 5% and 15%: 
• HDSM-Ax as measured by the subject 
• HidroQoL as measured by the subject for 
subjects ≥17 years of age 
• DLQI as measured by the subject for subjects 
≥17 years of age 
• Patient Global Impression Scales*; Severity 
(PGI-S**) and Change (PGI-C)†  
 
* these questions will be included in the HDSM-Ax 
questionnaires  
** administered with each administration of the HDSM-Ax  
† administered at Visit 10 (Week 24) and end of treatment Visit 
16 (Week 48) only  
 
Revised Text 
Efficacy Assessments: 
The following assessment measures will be 
conducted to evaluate the long-term efficacy of 
sofpironium bromide gel, 5% and 15%: 
• HDSM-Ax as measured by the subject 
• DLQI as measured by the subject for subjects 
≥17 years of age 
• Patient Global Impression Scales*; Severity 
(PGI-S**) and Change (PGI-C)†  
 
* these questions will be included in the HDSM-Ax 
questionnaires  
** administered with each administration of the HDSM-Ax  
† administered at Visit 10 (Week 24) and end of treatment Visit 
16 (Week 48) only 
 
Additionally, HidroQoL assessment will be 
conducted as an exploratory analysis, as measured 
by the subject (for subjects ≥17 years of age). This 
assessment will be performed at baseline, Visit 3 
(Week 2), and Visit 5 (Week 6) for only the first 
100 subjects enrolled in the study. 
 
 
 


BBI-4000 Gel 
 
Protocol BBI-4000-CL-303/01 
Page 71 of 74 
CONFIDENTIAL                                                                                                                        15MAY2018 
Change Number 
Section # / Name 
Details of Change 
12 
Section 7.1, Time 
and Events Table 
Updated table/footnotes to present HidroQoL 
assessment after DLQI, and to reflect amended 
schedule of the HidroQoL assessment 
 
Original Text 
6Administered at Baseline, Weeks 2, 6, 24, and 48.  
7 Investigator local tolerability assessments to be performed after the 
Subject local tolerability assessments. 
8 Performed at Screening, Baseline, and then Weeks 4, 8, 12, 16, 20, 
24, 28, 32, 36, 40, 44, and 48.  
9 Performed at Baseline and then Weeks 4, 8, 12, 16, 20, 24, 28, 32, 
36, 40, 44, and 48.  
10 Performed at Screening and then Weeks 6, 24, and 48. 
 
Revised Text 
6Administered at Baseline, Weeks 2, 6, 24, and 48.  
7Administered at Baseline, Week 2, and Week 6; only the first 100 
subjects enrolled in the study will complete this assessment. 
8 Investigator local tolerability assessments to be performed after the 
Subject local tolerability assessments. 
9 Performed at Screening, Baseline, and then Weeks 4, 8, 12, 16, 20, 
24, 28, 32, 36, 40, 44, and 48.  
10 Performed at Baseline and then Weeks 4, 8, 12, 16, 20, 24, 28, 32, 
36, 40, 44, and 48.  
11 Performed at Screening and then Weeks 6, 24, and 48. 
 
Change Number 
Section # / Name 
Details of Change 
13 
Section 7.2.2, Visit 2 
Baseline (Day 1) 
Amended section to move HidroQoL after DLQI, 
to reflect reordered appendices, and to note 
HidroQoL will be completed only by the first 100 
subjects enrolled in the study  
 
Original Text 
• Subject to complete the HidroQoL 
questionnaire. 
o 18 questions to be completed by the 
subject. 
o Refer to Appendix 2. 
• Subject to complete the DLQI questionnaire. 
o 10 questions to be completed by the subject. 
o Refer to Appendix 3. 
 
Revised Text 
• Subject to complete the DLQI questionnaire. 
o 10 questions to be completed by the subject. 
o Refer to Appendix 2. 
• Subject to complete the HidroQoL 
questionnaire. 
o Only the first 100 subjects enrolled in the 
study to complete the questionnaire.  
o 18 questions to be completed by the 
subject. 
o Refer to Appendix 3. 


BBI-4000 Gel 
 
Protocol BBI-4000-CL-303/01 
Page 72 of 74 
CONFIDENTIAL                                                                                                                        15MAY2018 
 
Change Number 
Section # / Name 
Details of Change 
14 
Section 7.2.3, Visits 
3-6 (Weeks 2, 4, 6, 
and 8) ±3 Days 
Amended section to move HidroQoL after DLQI, 
to refect updated schedule of HidroQoL, and to 
note HidroQoL will be completed only by the first 
100 subjects enrolled in the study 
 
Original Text 
• Subject to complete HidroQoL at Visit 3 (Week 
2) and Visit 5 (Week 6). 
• Subject to complete the DLQI questionnaire at 
Visit 3 (Week 2) and Visit 5 (Week 6).  
 
Revised Text 
• Subject to complete the DLQI questionnaire at 
Visit 3 (Week 2) and Visit 5 (Week 6).  
• Subject (only the first 100 subjects enrolled in 
the study) to complete HidroQoL at Visit 3 
(Week 2) and Visit 5 (Week 6). 
 
Change Number 
Section # / Name 
Details of Change 
15 
Section 7.2.4, Visits 
7-16 (Weeks 12-48) 
±5 Days 
Deleted:  
• Subject to complete HidroQoL at Visit 10 (Week 
24) and Visit 16 EOT (Week 48). 
 
Change Number 
Section # / Name 
Details of Change 
16 
Section 8.1.7, 
Subject Assessments 
Amended section to list HidroQoL after other 
efficacy assessments, and to update links to 
inverted Appendices 2 and 3 
 
Original Text 
HDSM-Ax, HidroQoL, DLQI, PCI-S, and PCI-C 
 
Revised Text 
HDSM-Ax, DLQI, PCI-S, PCI-C, and HidroQoL 
 
Change Number 
Section # / Name 
Details of Change 
17 
Section 8.3, Efficacy 
Measures 
Amended section to list HidroQoL after other 
efficacy assessments, and to update links to 
inverted Appendices 2 and 3 
 
Original Text 
The following assessment measures will be 
conducted to evaluate the long-term efficacy of 
sofpironium bromide gel, 5% and 15%, as indicated 
in the Procedures Section 7.1: 
• HDSM-Ax as measured by the subject  
• HidroQoL as measured by the subject (for 


BBI-4000 Gel 
 
Protocol BBI-4000-CL-303/01 
Page 73 of 74 
CONFIDENTIAL                                                                                                                        15MAY2018 
subjects ≥17 years of age)  
• DLQI as measured by the subject (for 
subjects ≥17 years of age) 
• Patient Global Impression Scales; Severity 
(PGI-S) and Change (PGI-C)  
 
Revised Text 
The following assessment measures will be 
conducted to evaluate the long-term efficacy of 
sofpironium bromide gel, 5% and 15%, as indicated 
in the Procedures Section 7.1: 
• HDSM-Ax as measured by the subject  
• DLQI as measured by the subject (for 
subjects ≥17 years of age) 
• Patient Global Impression Scales; Severity 
(PGI-S) and Change (PGI-C)  
 
Change Number 
Section # / Name 
Details of Change 
18 
8.4, Additional 
Efficacy Measure 
Added new section 8.4 to include HidroQoL as an 
additional efficacy measure, as follows: 
The following efficacy assessment measure will be 
conducted as an exploratory analysis to evaluate 
sofpironium bromide gel, 5% and 15%, as indicated 
in the Procedures Section 7.1: 
• HidroQoL as measured by the subject (for 
subjects ≥17 years of age); only the first 100 
subjects enrolled in the study will complete this 
assessment  
 
Change Number 
Section # / Name 
Details of Change 
19 
10.2, Endpoints 
Moved HidroQoL from “Other Efficacy Endpoints” 
to “Exploratory Efficacy Endpoint” and amended 
HidroQoL assessment schedule, as follows: 
 
Exploratory Efficacy Endpoint 
1. HidroQoL from baseline to each of Visits 3 and 
5 (Weeks 2 and 6); only the first 100 subjects 
enrolled in the study will complete this assessment, 
and an interim analysis will be performed 
 


BBI-4000 Gel 
 
Protocol BBI-4000-CL-303/01 
Page 74 of 74 
CONFIDENTIAL                                                                                                                        15MAY2018 
Change Number 
Section # / Name 
Details of Change 
20 
10.5, Exploratory 
Analysis 
Added section 10.5 to include HidroQoL as an 
exploratory analysis, as follows: 
Exploratory Analysis 
Change in the HidroQoL from baseline to Week 2 
and Week 6 will be assessed. Only the first 100 
subjects enrolled in the study will complete this 
assessment, and an interim analysis will be 
performed. 
 
Change Number 
Section # / Name 
Details of Change 
21 
10.6, Sample Size 
Updated Sample Size section from 10.5 to 10.6 to 
reflect new section 10.5 added above 
 
Change Number 
Section # / Name 
Details of Change 
22 
Appendix 1 
Updated HDSM-Ax assessment form to reflect 
latest version (Version 1.3), with minimal changes 
in formatting and scale 
 
Change Number 
Section # / Name 
Details of Change 
23 
Appendices 2 and 3 
Inverted Appendices 2 and 3 to present DLQI 
questionnaire before HidroQoL questionnaire 
 
Change Number 
Section # / Name 
Details of Change 
24 
Appendix 8 
Added new Appendix 8 to detail changes made in 
AMENDMENT 01 
 

SAP_001.pdf: 
Version:  0.3 
STATISTICAL ANALYSIS PLAN 
24 February 2020 DRAFT 
 
 
CONFIDENTIAL 
 
A Multicenter, Randomized, Open-label, Phase 3 Long-term 
Safety Study of Topically Applied Sofpironium Bromide (BBI-
4000) Gel, 5% and 15% in Subjects with Axillary 
Hyperhidrosis 
 
 
 
PROTOCOL NUMBER: BBI-4000-CL-303 
 
 
 
SPONSOR: 
 
Brickell Biotech, Inc. 
5777 Central Ave., Suite 102 
Boulder, CO 80301 
 
 
 
 
PREPARED BY 
 
Rho, Inc. 
2635 E NC Hwy 54 
Durham, NC 27713 
Telephone:  (919) 408-8000 
Fax:  (919) 408-0999 
 
 
 
This document is confidential and proprietary to Brickell Biotech, Inc.  Acceptance of this document 
constitutes agreement by the recipient that no unpublished information contained herein will be reproduced, 
published, or otherwise disclosed without the prior written approval of Brickell Biotech, Inc., except that this 
document may be disclosed to appropriate Institutional Review Boards under the condition that they keep 
the information confidential. 
NCT03627468


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 2 of 51 
 
 
 
 
DOCUMENT VERSION CONTROL 
 
Version Number 
Date 
Comments/Changes 
0.1 
08 August 2019 
First Draft 
0.2 
17 September 2019 
Draft 2 
0.3 
09 October 2019 
Draft 3 
1.0 
24 February 2020 
Version 1.0 
 
 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 3 of 51 
 
 
 
 
APPROVALS 
 
 
Approved: 
 
Date: 
 
 
Julian Garro 
Senior Biostatistician III, Rho, Inc. 
 
 
 
 
Date: 
 
 
Ping-Yu Liu 
Biostatistician Consultant for Brickell Biotech, 
Inc. 
 
 
 
 
Date: 
 
 
Deepak Chadha 
Chief Research and Development Officer, 
Brickell Biotech, Inc. 
 
 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 4 of 51 
 
 
 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ............................................................................................ 6 
LIST OF IN-TEXT TABLES ............................................................................................. 8 
1. 
PURPOSE OF THE ANALYSES .............................................................................. 9 
2. 
PROTOCOL SUMMARY ........................................................................................ 10 
2.1 
Study Objectives ......................................................................................... 10 
2.2 
Study Endpoints .......................................................................................... 10 
 
Primary Endpoints ............................................................................. 10 
 
Secondary Endpoints ......................................................................... 10 
 
Other Endpoints ................................................................................. 11 
2.3 
Overall Study Design and Plan ................................................................... 12 
2.4 
Study Population ......................................................................................... 12 
2.5 
Treatment Regimens................................................................................... 12 
2.6 
Sample Size Determination ......................................................................... 12 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS.................................. 14 
3.1 
Reporting Conventions ................................................................................ 14 
3.2 
Standard Calculations ................................................................................. 15 
4. 
ANALYSIS POPULATIONS ................................................................................... 17 
5. 
STUDY SUBJECTS ............................................................................................... 18 
5.1 
Disposition of Subjects ................................................................................ 18 
5.2 
Protocol Deviations ..................................................................................... 18 
6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ......................... 19 
7. 
MEASUREMENTS OF TREATMENT COMPLIANCE ............................................ 20 
8. 
EFFICACY EVALUATION ..................................................................................... 21 
8.1 
Overview of Efficacy Analysis Issues .......................................................... 21 
 
Handling of Dropouts or Missing Data ................................................ 21 
 
Multicenter Studies ............................................................................ 21 
 
Assessment Time Windows ............................................................... 21 
 
Definitions .......................................................................................... 21 
8.2 
Secondary Efficacy Endpoints ..................................................................... 23 
 
Other Efficacy Endpoints ................................................................... 23 
 
Exploratory Efficacy Endpoints .......................................................... 24 
8.3 
Analysis Methods ........................................................................................ 24 
9. 
SAFETY EVALUATION ......................................................................................... 25 
9.1 
Overview of Safety Analysis Methods ......................................................... 25 
 
Handling of Dropouts or Missing Data ................................................ 25 
 
Multicenter Studies ............................................................................ 25 
 
Assessment Time Windows ............................................................... 25 
9.2 
Safety Variables .......................................................................................... 26 
9.3 
Extent of Exposure ...................................................................................... 26 
9.4 
Adverse Events ........................................................................................... 26 
9.5 
Local Tolerability Assessments ................................................................... 27 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 5 of 51 
 
 
 
 
9.6 
Clinical Laboratory Evaluation ..................................................................... 27 
9.7 
Vital Signs, Physical Findings, and Other Observations Related to Safety .. 28 
 
Vital Signs .......................................................................................... 28 
 
Physical Examinations (PE) ............................................................... 28 
 
Other Safety Measures ...................................................................... 28 
9.7.3.1 
Prior and Concomitant Medications ....................................... 28 
10. PHARMACOKINETIC/PHARMACODYNAMIC EVALUATION .............................. 30 
11. OTHER ANALYSES .............................................................................................. 31 
11.1 
Psychometric Analysis of the HDSM-Ax ...................................................... 31 
12. INTERIM ANALYSES AND DATA MONITORING ................................................. 32 
13. CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL ........................ 33 
14. REFERENCES ....................................................................................................... 34 
15. LIST OF PLANNED TABLES ................................................................................ 35 
16. LIST OF PLANNED FIGURES ............................................................................... 47 
17. LIST OF PLANNED DATA LISTINGS ................................................................... 48 
18. APPENDICES ........................................................................................................ 49 
18.1 
Schedule of Events ..................................................................................... 49 
19. ATTACHMENTS .................................................................................................... 51 
 
 
 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 6 of 51 
 
 
 
 
LIST OF ABBREVIATIONS 
AE 
Adverse event 
ATC 
Anatomic Therapeutic Chemical 
BBI-4000 
Sofpironium bromide 
BMI 
Body mass index 
BP 
Blood pressure 
CRF 
Case report form 
CSR 
Clinical study report 
DLQI 
Dermatology Life Quality Index 
EOT 
End of Treatment 
FOCBP 
Female of childbearing potential 
HDSM-Ax 
Hyperhidrosis Disease Severity Measure-Axillary 
HDSM-Ax-11 
Hyperhidrosis Disease Severity Measure-Axillary 11 item total 
HDSM-Ax-7 
Hyperhidrosis Disease Severity Measure-Axillary 7 item total 
HidroQoL 
Hyperhidrosis Quality of Life Index 
HR 
Heart rate 
ICH 
International Council on Harmonisation 
IP 
Investigational Product 
ITT 
Intent-to-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
PE 
Physical exam 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
PP 
Per-Protocol 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SE 
Standard error 
SI 
Systeme International 
TEAE 
Treatment-emergent adverse event 
TESAE 
Treatment-emergent serious adverse event 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 7 of 51 
 
 
 
 
UPT 
Urine pregnancy test 
WHO 
World Health Organization 
 
 
 
 
 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 8 of 51 
 
 
 
 
LIST OF IN-TEXT TABLES 
Table 1. Prescribed Frequencies, compliance dosing multiplier, and reasoning …. 21 
 
 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 9 of 51 
 
 
 
 
1. PURPOSE OF THE ANALYSES 
This statistical analysis plan (SAP) contains detailed information to aid in the 
implementation of the statistical analyses and reporting of the study data for use in the 
clinical study report (CSR) for study BBI-4000-CL-303.  This SAP is being written with 
due consideration of the recommendations outlined in the most recent International 
Conference on Harmonisation (ICH) E9 Guideline, entitled Guidance for Industry: 
Statistical Principles for Clinical Trials, and the most recent ICH E3 Guideline, entitled 
Guidance for Industry: Structure and Content of Clinical Study Reports. 
This SAP describes the data sets that will be used for analysis, as well as subject 
characteristics, safety, and clinician-reported and patient-reported perception of disease 
severity and improvement parameters.  The details of the specific statistical methods 
stated in the protocol will be provided and any changes from the protocol-specified 
analyses will be documented in the SAP prior to database lock.   If additional analyses 
are required to supplement the planned analyses described in this SAP after the database 
lock, they may be completed and will be described in the CSR.  Table, figure, and listing 
specifications are provided as an attachment in a separate document. This SAP is based 
on the latest version of the BBI-4000-CL-303 protocol (Amendment 4) dated 6 May 
2019. 
 
 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 10 of 51 
 
 
 
 
2. PROTOCOL SUMMARY 
The purpose of this Phase 3 study is to assess the long-term safety, local tolerability, and 
efficacy of sofpironium bromide gel, 5% and 15% when applied topically in subjects with 
axillary hyperhidrosis.  
 
2.1 Study Objectives 
Primary: 
To evaluate the long-term safety and local tolerability of sofpironium bromide gel, 5% 
and 15% when applied topically in subjects with axillary hyperhidrosis. 
 
Secondary: 
• To evaluate the long-term effect of topically applied sofpironium bromide gel, 5% 
and 15% on Hyperhidrosis Disease Severity Measure-Axillary (HDSM-Ax©) in 
subjects with axillary hyperhidrosis. 
• To evaluate the long-term effect of topically applied sofpironium bromide gel, 5% 
and 15% on patient reported Dermatology Life Quality Index (DLQI) in subjects 
with axillary hyperhidrosis. 
 
Other: 
To evaluate the effect of topically applied sofpironium bromide gel, 5% and 15% on the 
Hyperhidrosis Quality of Life Index (HidroQoL©) in subjects with axillary hyperhidrosis. 
Only the first 100 subjects enrolled will complete this assessment. 
 
2.2 Study Endpoints 
 Primary Endpoints 
Primary endpoints include evaluation of the long-term safety and local tolerability of 5% 
and 15% sofpironium bromide gel when applied topically in subjects with axillary 
hyperhidrosis. Assessments will include: 
• Adverse events  
• Local tolerability assessments  
• Vital signs (blood pressure, pulse rate, respiratory rate, and temperature) 
• Laboratory tests (hematology, chemistry, and urinalysis) and pregnancy testing in 
Females of child-bearing potential (FOCBP) 
 Secondary Endpoints 
The following secondary, efficacy endpoints will be analyzed: 
• The proportion of subjects achieving ≥1-point improvement in HDSM-Ax-11 (11-
item total) from baseline to end of treatment  


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 11 of 51 
 
 
 
 
• The proportion of subjects achieving ≥1.5-point improvement in HDSM-Ax-11 
from baseline to end of treatment 
• The proportion of subjects achieving ≥2-point improvement in HDSM-Ax-11 
from baseline to end of treatment 
• Change of HDSM-Ax-11 from baseline to end of treatment as a continuous 
measure 
 Other Endpoints 
• The proportion of subjects achieving ≥1-point improvement in HDSM-Ax-7 (7-
item total) from baseline to end of treatment  
• The proportion of subjects achieving ≥1.5-point improvement in HDSM-Ax-7 
from baseline to end of treatment 
• The proportion of subjects achieving ≥2-point improvement in HDSM-Ax-7 from 
baseline to end of treatment 
• Change of HDSM-Ax-7 from baseline to end of treatment as a continuous 
measure 
• The proportion of subjects achieving ≥1-point improvement in the HDSM-Ax-11 
score from baseline to each of Visits 2-15 and 17 (Weeks 2-44 and Week 52) 
• The proportion of subjects achieving ≥1.5-point improvement in the HDSM-Ax-
11 score from baseline to each of Visits 2-15 and 17 (Weeks 2-44 and Week 52) 
• The proportion of subjects achieving ≥2-point improvement in the HDSM-Ax-11 
score from baseline to each of Visits 2-15 and 17 (Weeks 2-44 and Week 52) 
• Change in HDSM-Ax-11 from baseline to each of Visits 2-15 and 17 (Weeks 2-
44 and 52) as a continuous measure 
• The proportion of subjects achieving ≥1-point improvement in the HDSM-Ax-7 
score from baseline to each of Visits 2-15 and 17 (Weeks 2-44 and Week 52) 
• The proportion of subjects achieving ≥1.5-point improvement in the HDSM-Ax-7 
score from baseline to each of Visits 2-15 and 17 (Weeks 2-44 and Week 52) 
• The proportion of subjects achieving ≥2-point improvement in the HDSM-Ax-7 
score from baseline to each of Visits 2-15 and 17 (Weeks 2-44 and Week 52) 
• Change in HDSM-Ax-7 from baseline to each of Visits 2-15 and 17 (Weeks 2-44 
and 52) as a continuous measure 
• DLQI from baseline to each of Visits 5, 10, and 16 (Weeks 2, 6, 24, and 48) 
• Patient Global Impression of Severity (PGI-S) summarized as frequency counts 
and percentages for each category (none, mild, moderate, severe, very severe) at 
each assessment, change from baseline as a 5x5 table with frequency counts and 
percentages at each post-baseline assessment  
• Patient Global Impression of Change (PGI-C) summarized as frequency counts 
and percentages for each category (very much better, moderately better, a little 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 12 of 51 
 
 
 
 
better, no change, a little worse, moderately worse, very much worse) at Visits 10 
and 16 (Weeks 24 and 48)   
Exploratory Efficacy Endpoint 
HidroQoL from baseline to each of Visits 3 and 5 (Weeks 2 and 6); only the first 100 
subjects enrolled in the study were to be eligible complete this assessment. 
2.3 Overall Study Design and Plan 
This is a multicenter, randomized, open-label, Phase 3 long-term safety study of topically 
applied sofpironium bromide gel, 5% and 15% in subjects with axillary hyperhidrosis. 
A maximum of 300 subjects, at approximately 30 clinical sites, will be enrolled to obtain 
approximately 150 subjects that have completed 12 months of dosing and clinical 
assessments. 
Subjects will be randomized 1:2 to receive either sofpironium bromide gel, 5% or 15% 
(100 subjects dosed with 5% gel and 200 subjects dosed with 15% gel). Subjects will 
apply the investigational product once daily at bedtime, to their axillae for 48 weeks. 
Vital signs and adverse events will be collected at each visit.  Local tolerability 
assessments will be collected at each post-Screening visit.  Blood and urine samples will 
be collected and analyzed at Screening and then Week 6 (Visit 5), Week 24 (Visit 10), 
and Week 48 (Visit 16) for routine hematology, chemistry, and urinalysis parameters. 
Additionally, a urine pregnancy test for females of child-bearing potential will be 
collected and analyzed at each visit except at Week 2 (Visit 3), Week 6 (Visit 5), and 
Week 52 (Visit 17).  Patient-reported outcomes HDSM-Ax, PGI-S, PGI-C, and DLQI 
will be recorded during the study at predefined time points.  HidroQoL will be recorded 
at baseline, Week 2, and Week 6; only the first 100 subjects eligible and enrolled in the 
study will complete this assessment. 
A total of 17 scheduled visits will take place over approximately 52 weeks.  
 
2.4 Study Population 
Subjects aged ≥9 years with a diagnosis of axillary hyperhidrosis. 
2.5 Treatment Regimens 
Either sofpironium bromide gel, 5% or 15%, will be topically applied to both axillae once 
daily at bedtime for 48 weeks. 
2.6 Sample Size Determination 
A maximum of 300 subjects, at approximately 30 clinical sites, will be randomized to 
receive either 5% or 15% sofpironium bromide gel in a 1:2 ratio to obtain approximately 
150 subjects (50 subjects dosed for 48 weeks with 5% gel and 100 subjects dosed for 48 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 13 of 51 
 
 
 
 
weeks with 15% gel) who have completed 12 months of dosing and clinical assessments. 
No formal sample size calculations were performed. 
 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 14 of 51 
 
 
 
 
3. GENERAL ANALYSIS AND REPORTING CONVENTIONS 
3.1 Reporting Conventions 
The following is a list of general analysis and reporting conventions to be applied to this 
study, unless otherwise specified. 
All data displays (tables, listings, and figures) will have a header showing the sponsor 
company name, protocol number, page number, and display status (i.e. “DRAFT” or 
“FINAL”), as well as a footer indicating path, file name, and run date/time.  Summary 
tables and data listings will be summarized by treatment. All data collected per-protocol 
and all derived variables will be listed.   
Categorical variables will be summarized using counts (n) and percentages (%) and will 
be presented in the form “n (xx.x).” If a count is 0, 0% will be shown for the percentage. 
If a percentage is 100%, 100% will be shown with no decimal place. To ensure 
completeness, summaries for categorical variables will include all categories, even if no 
subjects had a response in a particular category.  Unless otherwise specified, the 
denominator for each percentage will be based on the number of subjects with available 
data in the population being summarized.  If missing values are present, counts will be 
shown but will not be included in percentage calculations. 
Continuous variables will be summarized using mean, standard deviation (SD), 
minimum, maximum, median, and number of subjects.  The mean and median will be 
reported to an additional level of precision than the original observation in its rawest form 
(i.e. on the Case report form (CRF)), and the SD and other measures of variability (e.g. 
standard error (SE)) will be reported to two additional levels of precision than the original 
observations.  The minimum and maximum will be the same precision as the original 
data.  In general, any calculated values, such as those due to unit conversion, will be 
rounded to the same number of decimal places as the original data. 
No tests of hypothesis of treatment group differences are planned; however, should they 
be performed as part of exploratory and ad hoc analyses, the associated p-value will be 
reported. All p-values will be rounded to 4 decimal places.  P-values less than 0.0001 will 
be presented as “<0.0001” ; p-values greater than 0.9999 will be displayed as “>0.9999”.  
Any p-values generated will be considered descriptive in nature; there will be no 
adjustments for multiple comparisons. 
Summary tables and data listings:  
• No preliminary rounding will be performed; rounding will only occur after 
analysis.  


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 15 of 51 
 
 
 
 
• Data from subjects excluded from an analysis population will be presented in the 
data listings but will not be included in the calculation of summary statistics, 
where applicable. 
• Data from each subject will be separated by a blank line. Within a data listing, if a 
descriptive item appears line after line (e.g., repetition of a subject number, date, 
visit, etc.), only the first occurrence will be displayed (e.g., in Listing of Vital 
Signs, subject number, date and visit will only be displayed on first row when 
presenting all parameters collected at same visit). Repetition of actual results or 
outcomes (e.g., Adverse Events (AEs), lab results, vital sign values, etc.) will not 
be collapsed.  
• Data listings will be sorted by site, subject, treatment, and week and/or time of 
assessment, unless otherwise noted. 
• When change from baseline is calculated, baseline is the last observation obtained 
prior to dosing of the study drug. 
Mock tables and data listings will be provided as attachments to this analysis plan. Minor 
changes to the mocks after formal SAP approval will not necessitate re-approval unless 
changes to the text of the SAP are required. 
All statistical deliverables will be produced, validated, and reviewed for 
accuracy/consistency in accordance with Rho, Inc. standard operating procedures and the 
processes described in the statistical validation plan. 
SAS® (SAS Institute, Cary, North Carolina) statistical software, version 9.4 or later, will 
be used for all analyses. Adverse Events and Medical History will be coded using the 
most recent version of the Medical Dictionary for Regulatory Activities (MedDRA). 
Concomitant medications will be coded using the latest version of the World Health 
Organization (WHO) Drug and Anatomic Therapeutic Chemical (ATC) classification and 
preferred term. 
3.2 Standard Calculations 
Unless otherwise noted, baseline is defined as the last observed data value prior to the 
receiving the first application of treatment for treated subjects, and the last observed data 
value prior to the randomization date for randomized subjects who were not treated. The 
baseline derivation can include unscheduled visits. 
Study day will be determined as: 
• The assessment/event date minus the date of first dose of gel, if the 
assessment/event date is prior to the date of first dose of gel; and 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 16 of 51 
 
 
 
 
• The assessment/event date minus the date of first dose of gel + 1, if the 
assessment/event date is on or after the date of first dose of gel. 
Note that if the subject is randomized but not treated then the randomization date will be 
substituted for first dose date of gel. 
Change from baseline will be calculated as the post-baseline data value minus the 
baseline value.  Percent change from baseline will be calculated as the change from 
baseline divided by the baseline value, multiplied by 100. 
At any particular time point, for ranked transformation of any data item of interest, all 
observed data will be ranked together without regard to treatment assignment, from 
smallest to highest value. The smallest observation will be assigned the rank of 1, the 
second smallest the rank of 2, and so on. Average ranks will be used for tied 
observations.  
Unless otherwise noted, values reported as greater than or less than some quantifiable 
limit (e.g., “< 2.0”) will be summarized with the symbol suppressed in summary tables 
and figures, which will use the numeric equivalent. 
Partial or missing dates used in calculations of duration may be imputed with logic 
similar to that of Adverse Events (Section 9.1.1). 
 
 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 17 of 51 
 
 
 
 
4. ANALYSIS POPULATIONS 
Identification of the subjects to be included in each analysis population will be determined 
and finalized prior to database lock.  Subjects will be classified into the Safety, Intent-to-
Treat (ITT), Per Protocol (PP), and HidroQoL (HQL) populations according to the 
following definitions: 
 
Safety Population 
The Safety Population will include all subjects randomized in the study who received study 
drug at least once.  Subjects will be included in the treatment group based on the majority 
of actual treatment they received (even if not the treatment group to which they were 
randomized).  
 
ITT Population 
The ITT Population will include all subjects who were randomized. Subjects will be 
included in the treatment group to which they were randomized, regardless of the treatment 
received. 
 
PP Population 
The PP Population will be a subset of the ITT Population and will include subjects who 
meet the following criteria: 
• Meets the inclusion/exclusion criteria 
• Has not taken or applied any interfering concomitant medications. 
• Completed the following visits: 
o Visit 1 (Screening) and the required HDSM-Ax data collection 
o Visit 2 (Baseline) and the required HDSM-Ax data collection 
o Visit 4 (Week 4), and the required HDSM-Ax data collection 
o Visit 7 (Week 12), and the required HDSM-Ax data collection 
o Visit 10 (Week 24), and the required HDSM-Ax data collection 
o Visit 16 (Week 48), and the required HDSM-Ax data collection 
o Visit 17 (Week 52), and the required HDSM-Ax data collection 
• Treatment received per randomization assignment  
 
HQL Population 
The HQL Population will be used for HidroQol analyses.  Subjects with “Yes” noted for 
the question “Subject flagged for the Baseline-Visit 5 HidroQol Protocol” on the Subject 
CRF page are included. The first 100 subjects ≥ 17 years of age enrolled were eligible for 
this population.  
 
 
 
 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 18 of 51 
 
 
 
 
5. STUDY SUBJECTS 
5.1 Disposition of Subjects 
Subject disposition will be summarized for all randomized subjects by treatment group.  
Summaries will include the number and percentage of subjects in each analysis 
population, reason for exclusion from the PP population, completing treatment, 
completing the study, and discontinuing the study early by the primary reason for 
discontinuation.  Analysis populations are defined in Section 4.  Treatment completers 
are subjects with “Yes” noted for the question “Did the subject complete treatment?” on 
the Study Disposition CRF page. Study completers are subjects with “Normal Study 
Completion” noted for the question “Subject’s Status or Primary Reason for Early 
Termination” on the Study Disposition CRF page.  Study discontinuers are subjects with 
any response to “Subject’s Status or Primary Reason for Early Termination” other than 
“Normal Study Completion” on the Study Disposition CRF page. 
All subject disposition data will be listed for all randomized subjects. 
5.2 Protocol Deviations 
Major protocol violations will be summarized by treatment group for the Safety 
Population.  Major protocol violations may include, but will not be limited to the 
following: 
  
• Violation of eligibility criteria;  
• Randomization error;  
• Non-compliance with study drug dosing;  
• On-study administration of a prohibited medication;  
• Unauthorized changes to protocol procedure that could potentially affect subject 
safety or are a flagrant deviation of protocol defined procedures.  
All major protocol violations will be determined and appropriately categorized by the 
sponsor prior to database lock.  The number and percentage of subjects with any major 
protocol violations as well as the number and percentage of subjects with violations 
within each category will be presented.  A by-subject listing will be provided for all 
protocol violations, major or minor, for the Safety Population.  
 
 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 19 of 51 
 
 
 
 
6. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic variables including age, sex, ethnicity, race, and predominant race, will be 
summarized by treatment group for the Safety, ITT, and PP Populations. 
Age in years will be summarized using descriptive statistics.  Age will also be 
categorized into 9-12, 13-16, and ≥ 17 years of age.  Age groups, sex, ethnicity, race, and 
predominant race will be summarized with the number and percentage of subjects in each 
parameter category.  If more than one race is reported, subjects will be counted in each 
relevant category. 
Baseline characteristics include medical history, height, weight, time since onset of 
axillary hyperhidrosis symptoms, and body mass index (BMI).  Medical history will be 
summarized for the Safety Population.  Other baseline characteristics will be summarized 
for the Safety, ITT, and PP Populations by treatment group.   
Height, weight, BMI, and time since onset of axillary hyperhidrosis symptoms at baseline 
will be summarized using descriptive statistics.  BMI will be calculated as: weight (kg) / 
(height (cm) / 100)2.  If height is entered in inches, height is converted to cm by Height 
(cm) = 2.54 *Height (inches).  If weight is entered in lbs, weight is converted to kg by 
Weight (kg) = 1/(2.2046)*Weight (lbs).  Time since onset of axillary hyperhidrosis 
symptoms will be reported in months and calculated by dividing the duration in days by 
(365.25 / 12).  Duration in days will be calculated as (date of informed consent – start 
date of axillary hyperhidrosis symptoms + 1).  
Medical history events will be coded to system organ class using the most current version 
of MedDRA.  Frequency counts and percentages will be used to summarize subjects 
reporting abnormal medical history by system organ class.  Subjects reporting more than 
one event for a given system organ class will be counted only once for that system organ 
class. 
All demography, baseline characteristics, and medical history data collected will be 
presented in listings. 
 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 20 of 51 
 
 
 
 
7. MEASUREMENTS OF TREATMENT COMPLIANCE 
Study drug compliance will be calculated as the percentage of study drug taken for each 
subject. Percentage of study drug taken will be calculated by taking into account whether 
a subject took all doses of study drug as instructed, including protocol indicated dosing 
modifications collected on the Dosing CRF page.  For each dosing entry, percentage of 
study drug taken will be determined as the total number of doses received divided by the 
number of expected doses, multiplied by 100.   
Expected doses for the study will be calculated as the sum of the expected dose per 
dosing period (i.e. a 28-day treatment period).  The expected dose per dosing period will 
be calculated as the end date of the period minus the start date of the period, plus one, 
times a multiplier as shown in the table below. The prescribed frequency for dosing and 
the multiplier are based on dose reductions allowed per protocol Section 8.1.4. 
Table 1. Prescribed Frequencies, compliance dosing multiplier, and reasoning 
Prescribed Frequency for 
Dosing Period 
Dosing 
Multiplier Reasoning 
Daily 
2 Drug applied once daily per axilla (2) 
PI Withheld 
0 No dose administered 
Every Other Day 
1 Drug applied every other day (0.5), once per axilla (2) 
Divided Daily 
1 Half (0.5) of drug applied, once daily per axilla (2) 
Divided Every Other Day 
0.5 Half (0.5) of drug applied, once every other day (0.5), per axilla (2) 
 
The total number of doses received will be calculated as the sum of the number of doses 
received during the dosing period.  The number of doses received during the dosing 
period will be calculated as the expected dose for the period minus the number of missed 
doses recorded on the Dosing CRF page for that period.   
Percentage of study drug taken over the course of the study will be calculated at the 
subject-level (i.e. across all dosing entries) and will be summarized by treatment arm 
using descriptive statistics based on the Safety Population. 
 
 
 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 21 of 51 
 
 
 
 
8. EFFICACY EVALUATION 
8.1 Overview of Efficacy Analysis Issues 
The primary objective of this study is to evaluate long-term safety and tolerability of 5% 
and 15% sofpironium bromide gel.  Primary endpoints are safety parameters and are 
described in Section 9. 
Efficacy is of secondary importance for the study; all efficacy endpoints are described 
below. 
 Handling of Dropouts or Missing Data 
Missing data will not be imputed for any of the efficacy endpoints. 
 
 Multicenter Studies 
This is a multicenter study, with approximately 30 sites expected to participate. Data 
collected from all sites will be pooled for data analysis.  
 Assessment Time Windows 
Allowable windows for each study visit are laid out in the Schedule of Events in Section 
18.1. Assessments that occur outside of the allowable window for each study visit will be 
flagged as protocol deviations, but will be used in all analyses. In general, all data will be 
associated with the nominal study visit for which it was intended. Repeat assessments and 
unscheduled visits will be included in study listings, but will not be used in place of 
nominal timepoint data. It is not expected that there will be multiple measurements that 
occur within the same assessment time window. Should that occur, the closest 
measurement will be used in the analysis; an earlier measure will be used in case of a tie. 
 Definitions 
For the purposes of analysis, Baseline and End of Treatment (EOT) definitions for 
HDSM-Ax as well as the other efficacy parameters of interest are defined below. 
 
HDSM-Ax   
 
The HDSM-Ax 11-Item scale (HDSM-Ax-11) will be defined as mean of the items in 
sections No. 1, 2, and 3 of the HDSM-Ax (11 sub-items in total). This will be applied to 
both the ≥ 12 years of age scale and the child scale. The mean will be derived by taking 
the total score and dividing by the number of questions answered. Subjects must answer 
at least 6 of the 11 sub-items to be evaluable for HDSM-Ax-11 total score. 
 
The HDSM-Ax 7-Item scale (HDSM-Ax-7) will be defined as the mean of the items in 
section No. 1 and questions 2a. through 2e. of the HDSM-Ax (7 sub-items in total). This 
will be applied to both the ≥ 12 years of age scale and the child scale. The mean will be 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 22 of 51 
 
 
 
 
derived by taking the total score and dividing by the number of questions answered. 
Subjects must answer all of the 7 sub-items to be evaluable for HDSM-Ax-7 total score. 
 
Baseline and EOT values are defined as follows: 
• Baseline = Visit 2 (Day 1) assessment 
• EOT = Visit 16 (Week 48) assessment 
 
HidroQoL 
 
The HidroQoL is split up into two domains. The Daily Life Activities domain is derived 
as the sum of questions 1 through 6, and the Psychosocial Life domain is derived as the 
sum of questions 7 through 18, where the answers are coded as such: 
 
“Very Much” = 2 
“A little” = 1 
“No, not at all” = 0 
 
The HidroQoL total score is derived as the sum of the 2 domain scores (range 0 to 36). 
 
DLQI 
 
The DLQI total score is calculated by summing answers to questions 1 through 10, 
including both parts of Question 7.  All questions must be answered at the first DLQI 
assessment.  Subsequent DLQI assessments with a single missing answer will be scored 0 
for that question and totaled.  Subjects with more than one missing question will have the 
instrument dropped for that visit. The DLQI answers are coded as such: 
 
“Very much” = 3 
“A lot” = 2 
“A little” = 1 
“Not at all” = 0 
“Not relevant” = 0 
Question 7, ‘prevented work or studying’ = 3 
 
The DLQI is calculated by summing the score of each question resulting in a maximum 
of 30 and a minimum of 0. The higher the score, the more quality of life is impaired. 
 
PGI-S and PGI-C 
 
PGI-S will be defined as Question #6 of the HDSM-Ax at each assessment.  PGI-C will 
be defined as Question #7 of the HDSM-Ax at the Day 43 visit only. 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 23 of 51 
 
 
 
 
8.2 Secondary Efficacy Endpoints 
The following secondary efficacy endpoints will be analyzed: 
• The proportion of subjects achieving ≥1-point improvement in HDSM-Ax-11 (11-
item total) from baseline to end of treatment  
• The proportion of subjects achieving ≥1.5-point improvement in HDSM-Ax-11 from 
baseline to end of treatment 
• The proportion of subjects achieving ≥2-point improvement in HDSM-Ax-11 from 
baseline to end of treatment 
• Change of HDSM-Ax-11 from baseline to end of treatment as a continuous measure 
 Other Efficacy Endpoints 
The following other efficacy endpoints will be analyzed: 
• The proportion of subjects achieving ≥1-point improvement in HDSM-Ax-7 (7-item 
total) from baseline to end of treatment  
• The proportion of subjects achieving ≥1.5-point improvement in HDSM-Ax-7 from 
baseline to end of treatment 
• The proportion of subjects achieving ≥2-point improvement in HDSM-Ax-7 from 
baseline to end of treatment 
• Change of HDSM-Ax-7 from baseline to end of treatment as a continuous measure 
• The proportion of subjects achieving ≥1-point improvement in the HDSM-Ax-11 
score from baseline to each of Visits 2-15 and 17 (Weeks 2-44 and Week 52) 
• The proportion of subjects achieving ≥1.5-point improvement in the HDSM-Ax-11 
score from baseline to each of Visits 2-15 and 17 (Weeks 2-44 and Week 52) 
• The proportion of subjects achieving ≥2-point improvement in the HDSM-Ax-11 
score from baseline to each of Visits 2-15 and 17 (Weeks 2-44 and Week 52) 
• Change in HDSM-Ax-11 from baseline to each of Visits 2-15 and 17 (Weeks 2-44 
and 52) as a continuous measure 
• The proportion of subjects achieving ≥1-point improvement in the HDSM-Ax-7 score 
from baseline to each of Visits 2-15 and 17 (Weeks 2-44 and Week 52) 
• The proportion of subjects achieving ≥1.5-point improvement in the HDSM-Ax-7 
score from baseline to each of Visits 2-15 and 17 (Weeks 2-44 and Week 52) 
• The proportion of subjects achieving ≥2-point improvement in the HDSM-Ax-7 score 
from baseline to each of Visits 2-15 and 17 (Weeks 2-44 and Week 52) 
• Change in HDSM-Ax-7 from baseline to each of Visits 2-15 and 17 (Weeks 2-44 and 
52) as a continuous measure 
• DLQI from baseline to each of Visits 5, 10, and 16 (Weeks 2, 6, 24, and 48) 
• PGI-S summarized as frequency counts and percentages for each category (none, 
mild, moderate, severe, very severe) at each assessment, change from baseline as a 
5x5 table with frequency counts and percentages at each post-baseline assessment  


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 24 of 51 
 
 
 
 
• PGI-C summarized as frequency counts and percentages for each category (very 
much better, moderately better, a little better, no change, a little worse, moderately 
worse, very much worse) at Visits 10 and 16 (Weeks 24 and 48)   
 Exploratory Efficacy Endpoints 
Exploratory efficacy endpoints to be analyzed include the following: 
• HidroQoL from baseline to each of Visits 3 and 5 (Weeks 2 and 6); only the first 
100 subjects ≥ 17 years of age enrolled in the study were to complete this 
assessment, and an exploratory analysis was performed. 
 
8.3 Analysis Methods 
All secondary and other efficacy endpoints will be summarized using descriptive 
statistics by treatment group for the ITT and PP populations.  For continuous measures, 
mean, standard deviation, median, minimum and maximum will be reported for results at 
time point and for change from baseline by visit as indicated in Section 8.2.1.  For 
categorical measures, frequency and percentage of subjects will be reported by the visits 
indicated in Sections 8.2 and 8.2.1.  The exploratory HidroQoL endpoint will be 
summarized by treatment group as a continuous measure using descriptive statistics. At 
each visit, both domain scores and the total score will be summarized for the HQL 
population.  No formal hypothesis testing or modeling of efficacy endpoints will be 
performed. Figures for proportion of subjects achieving ≥1-point, ≥1.5-point, and ≥2-
point imprpovment in HDSM-Ax (for both 7-Item and 11-Item) by visit will be provided. 
Additionally, figures of mean change from baseline over time for HDSM-Ax (for both 7-
Item and 11-Item) will be provided. 
 
 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 25 of 51 
 
 
 
 
9. SAFETY EVALUATION 
9.1 Overview of Safety Analysis Methods 
All safety data will be analyzed and presented by treatment received for the Safety 
Population. 
 Handling of Dropouts or Missing Data 
All available information will be used for descriptive statistics.  No imputation for 
missing data will be applied with the exception of the handling of partial dates. 
Partial AE and concomitant medication start and end dates will be imputed as follows:  
1. If the year and month are known: 
a. If the year and month are the same as the year and month of the treatment 
start date, impute to treatment start date and will therefore be recorded as 
TEAEs. 
b. Otherwise, use the 1st of the month. 
2. If only the year is known: 
a. If the year is the same as the year of treatment start date, impute to 
treatment start date and will therefore be recorded as TEAEs. 
b. Otherwise, impute to January 1st of that year. 
3. If the date is completely missing, impute to treatment start date. 
Listings will show the actual dates collected and not the imputed dates.  
 Multicenter Studies 
The study will be conducted at approximately 30 clinical sites.  Data from the sites will 
be pooled. 
 Assessment Time Windows 
Safety parameters will be collected according to the schedule of assessments in the Time 
and Events Table in Section 7 of the protocol (Appendix 18.1).  No more/less than 14 ± 3 
days may elapse between Visit 2 (Baseline) and Visits 3-6 (Weeks 2-8).  No more/less 
than 28 ± 5 days may elapse between each of Visits 7-16 (Weeks 12-48).  The End of 
Treatment visit may occur within ± 5 days of Week 52 (364 days).  Summaries will be 
presented by planned visits where applicable. 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 26 of 51 
 
 
 
 
9.2 Safety Variables 
Primary endpoints include evaluation of the long-term safety and local tolerability of 5% 
and 15% sofpironium bromide gel when applied topically in subjects with axillary 
hyperhidrosis. Assessment will include: 
• Adverse events 
• Local tolerability assessments  
• Vital signs (blood pressure, pulse rate, respiratory rate, and temperature) 
• Laboratory tests (hematology, chemistry, and urinalysis) and pregnancy testing in 
FOCBP 
9.3 Extent of Exposure 
Extent of exposure to study treatment will be summarized for the Safety Population by 
treatment group. The duration of exposure will be presented in days and summarized 
using descriptive statistics. Drug (pump) dispensation will be provided in a listing, to 
include total drug delivered per subject.  Each pump will be primed, then weighed, prior 
to dispensing pumps to subjects.  Each pump will be weighed upon return.  Total drug 
delivered will be calculated as the total weight of all pumps dispensed minus the total 
weight of all returned pumps.  
 
9.4 Adverse Events 
Treatment-emergent adverse events (TEAEs) are defined as those adverse events (AEs) 
with onset after the first dose of study drug or existing events that worsened after the first 
dose during the study.  Treatment-emergent AEs will be summarized by treatment group. 
Partial or missing start or end dates will be imputed per Section 9.1.1. 
 
Verbatim terms on case report forms will be mapped to preferred terms and system organ 
classes using the latest version of MedDRA. 
 
At Weeks 2, 4, 6, 12, 24, 48 and 52, treatment-emergent adverse events (TEAEs, i.e., 
AEs occurring during or after treatment initiation) will be summarized in the following 
tables: all reported TEAEs, all treatment-related TEAEs, severe TEAEs, TEAEs leading 
to dose interruption, TEAEs leading to dose modification, TEAEs leading to study 
discontinuation, TEAEs of special interest, and anticholinergic TEAEs. Two sets of the 
above tables will be produced: (a) for cumulative TEAEs up to the current visit reported 
by those making the visit, and (b) for cumulative TEAEs up to the current visit reported 
by all Safety Population subjects (including those absent from the current visit). At each 
of the 7 indicated weeks, each of the above tables will summarize the subject incidence 
(frequency count and %) for the specified TEAE, mapped to MedDRA System Organ 
Class and Preferred Term, according to the highest severity reported.  Subjects with only 
unknown severity for a TEAE will be counted under the severity unknown category. 
Additionally, serious TEAEs and treatment-related serious TEAEs will be summarized in 
the same manner for all data through Week 52. 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 27 of 51 
 
 
 
 
 
Summaries that are displayed by system organ class and preferred terms will be ordered 
by descending incidence of system organ class in the combined BBI-4000 group and 
preferred term within each system organ class.  The combined BBI-4000 group will not 
be displayed and will only be used for sorting. TEAEs of special interest include the 
following: 
 
• Vision blurred 
• Mydriasis 
• Urinary hesitation 
• Pupils unequal 
 
Adverse event data will be presented in data listings by subject, treatment group, and 
event. Serious TEAEs and TEAEs leading to discontinuation of the study will be 
presented in separate data listings.  Death is not expected.  However, should death 
occur on study, the event will be reported with detailed narratives. 
 
9.5 Local Tolerability Assessments 
Local tolerability assessments are performed for both axillae individually at all visits after 
screening (Visits 2-17). Visit 2 data are the baseline.  Should Visit 2 data be missing, 
baseline will be derived as the last value prior to first dose and as such unscheduled visits 
may be included. Subjects rate the severity of any symptoms of burning, stinging,  and  
itching at the application-site on a scale of 0 = absent, 1 = minimal, 2 = mild, 3 = 
moderate, and 4 = severe. Investigators assess the drug application site for the existence 
of significant local symptoms of scaling and erythema on a scale of 0 = absent, 1 = 
minimal, 2 = mild, 3 = moderate, and 4 = severe.   
 
Subject and Investigator assessments will be included in tables and listings. At each visit, 
local tolerability assessments will be descriptively summarized by severity for each 
treatment group. At each post-baseline visit, local tolerability will be summarized as 
cumulative shift tables vs. baseline. Subject counts and percentages for each symptom 
will be cross-tabulated with baseline severity according to the maximum post-baseline 
severity reported for either axilla up to the current visit.  
 
 
9.6 Clinical Laboratory Evaluation 
Laboratory parameter results will be collected at the Screening Visit and Visits 3-16. 
Baseline will be derived as the last value prior to first dose and as such unscheduled visits 
may be included.   
Laboratory parameters will be presented in Systeme International (SI) units and 
descriptively summarized for values at each visit and for changes from baseline at each 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 28 of 51 
 
 
 
 
subsequent visit.  In addition, at each post-baseline visit, parameter status (low, normal, 
high or normal, abnormal, as applicable) will also be summarized as shift tables vs. 
baseline status. Summary results will include the count and percentage of subjects within 
each shift category and treatment group. Unscheduled visits and early termination visits 
will be included in the shift tables.  
Laboratory parameters to be summarized and listed include hematology, clinical 
chemistry, and routine urinalysis. Urine pregnancy test results will be a by-subject listing 
only. Laboratory measurements identified as abnormal (i.e., outside the normal range) 
will also be listed separately by subject, laboratory test, and unit. 
 
9.7 Vital Signs, Physical Findings, and Other Observations Related to 
Safety 
 Vital Signs 
Vital sign results will be collected at each visit.  Visit 2 data are the Baseline.  Should 
Visit 2 data be missing, baseline will be derived as the last value prior to first dose and as 
such unscheduled visits may be included. Vital sign measurements will include systolic 
and diastolic blood pressure, pulse rate, respiratory rate, and temperature. Vital sign 
parameters will be summarized with descriptive statistics for values at each visit and for 
changes from baseline at each subsequent visit.  Vital signs will also be listed by subject.  
 Physical Examinations (PE) 
Physical examination results will be collected at the Screening Visit and End of Study 
Visit.  Physical examination will include assessments of the head, eyes, ears, nose, throat, 
skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph 
nodes, and extremities. Height and weight will also be measured and recorded. Results of 
the physical examination will be presented in subject data listings by subject, study visit, 
and body system. 
 Other Safety Measures 
9.7.3.1 Prior and Concomitant Medications 
Medications will be coded using the latest version of the WHO drug dictionary.  
Medications entered on the CRF will be mapped to ATC drug class (level 4) and drug 
name. 
 
Prior and concomitant medications will be summarized separately and the study phase of 
each medication will be determined programmatically based on medication start and end 
dates.  Partial or missing start and end dates will be imputed according to Section 9.1.1.  
 
A prior medication is defined as any medication administered prior to the date of the first 
dose of study drug. A concomitant medication is defined as any medication administered 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 29 of 51 
 
 
 
 
on or after the date of the first dose of study drug. A medication may be defined as both 
prior and concomitant.  
 
For the summary of both prior medications and concomitant medications, the number and 
percentage of subjects receiving any medication will be summarized by treatment group, 
as will the number and percentage receiving any medication by ATC drug class and 
generic drug name. Subjects reporting use of more than one medication at each level of 
summarization (any medication received, ATC class, and generic drug name) will be 
counted only once.  ATC class terms will be displayed by descending order of incidence, 
as will generic drug names within each ATC class.  The study phase during which each 
medication was received (e.g., prior, concomitant, or both) will be presented on the 
listing of prior and concomitant medications. 
 
Prior or concomitant therapies and procedures will be listed only. 
 
 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 30 of 51 
 
 
 
 
10. PHARMACOKINETIC/PHARMACODYNAMIC EVALUATION 
Pharmacokinetic and pharmacodynamic analyses are not part of this study protocol. 
 
 
 
 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 31 of 51 
 
 
 
 
11. OTHER ANALYSES 
11.1 Psychometric Analysis of the HDSM-Ax 
In parallel to the traditional statistical analysis, psychometric evaluation of the HDSM-Ax 
will be carried out to confirm the most appropriate HDSM-Ax scoring algorithm and to 
examine internal validity, construct validity (i.e., examination of the magnitude of 
correlation between the HDSM-Ax total score and key variable such as items 4 and 5 of 
the HDSM-Ax, PGI-S, and PGI-C), stability, reliability, ability to detect change, and 
interpretability of clinical trial results. 
The details regarding psychometric analyses will be described in a separate analysis plan. 
 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 32 of 51 
 
 
 
 
12. INTERIM ANALYSES AND DATA MONITORING 
There is no plan to establish a data monitoring committee for this study. 
There are no formal interim analyses planned, however the HidroQoL assessment was 
evaluated upon enrollment of 100 eligible subjects.  The treatment groups were not 
blinded. The mean, standard deviation, median, minimum, maximum and the same 
summary statistics for change from baseline for the HidroQoL total score, Daily Life 
Activities Domain score, and Psychosocial Life Domain score were reported using the 
HQL Population.  The results of this analysis are intended to be used to inform protocol 
development for subsequent studies.  
 
 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 33 of 51 
 
 
 
 
13. CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
Analyses specified in the protocol dated 6 May 2019 that have changed in this SAP 
include the following: 
• Protocol Synopsis 
o The synopsis describes the baseline of HDSM-Ax as the average of 
Screening and Day 0. The baseline definition has been updated to be the 
Day 1 visit. 
• Protocol Section 10.1 Analysis Populations 
o The definition of ITT population has been updated to include all subjects 
who were randomized.  
• Protocol Section 10.2 Endpoints  
o For the exploratory efficacy endpoint, the protocol describes an interim 
analysis. It has been clarified in this SAP that the interim analysis was not 
formal and that the treatment groups were not blinded. 
o Endpoints have been added to the ‘Other Efficacy Endpoint’ section to 
capture the 11-item total of HDSM-Ax and the 7-item total of HDSM-Ax. 
• Protocol Section 10.3 Safety Analysis 
o The protocol describes three sets of AE tables to be produced at each 
visit. The first set “(a) TEAEs reported at the current visit by those 
making the visit” will not be generated, as it will not provide any 
substantial information to the safety profile”. 
o The protocol states that all SAEs will be summarized by the three sets of 
AE tables. Due to an expected low incidence, one SAEs table and one 
treatment-related SAEs table will be generated for all data through Week 
52. 
 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 34 of 51 
 
 
 
 
14. REFERENCES 
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use. Statistical principles for clinical trials (E9). 
International Conference on Harmonization; 1998. 
 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 35 of 51 
 
 
 
 
15. LIST OF PLANNED TABLES 
Number 
Title 
Population 
14.1.1.1  
Summary of Subject Disposition  
All Randomized 
Subjects 
14.1.1.2  
Summary of Major Protocol Deviations 
Safety 
14.1.2.1  
Summary of Demographic Characteristics 
Safety 
14.1.2.2 
Summary of Demographic Characteristics 
ITT 
14.1.2.3 
Summary of Demographic Characteristics 
Per Protocol 
14.1.3.1 
Summary of Baseline Characteristics 
Safety 
14.1.3.2 
Summary of Baseline Characteristics 
ITT 
14.1.3.3 
Summary of Baseline Characteristics 
Per Protocol 
14.1.4 
Summary of Medical History 
Safety 
14.1.5 
Summary of Prior Medications by Drug Class and Generic 
Drug Name 
Safety 
14.2.1.1.1 
Proportion of Subjects Achieving ≥1-point Improvement in 
HDSM-Ax-11 from Baseline to End of Treatment 
ITT 
14.2.1.1.2 
Proportion of Subjects Achieving ≥1-point Improvement in 
HDSM-Ax-11 from Baseline to End of Treatment 
Per Protocol 
14.2.1.2.1 
Proportion of Subjects Achieving ≥1.5-point Improvement in 
HDSM-Ax-11 from Baseline to End of Treatment 
ITT 
14.2.1.2.2 
Proportion of Subjects Achieving ≥1.5-point Improvement in 
HDSM-Ax-11 from Baseline to End of Treatment 
Per Protocol 
14.2.1.3.1 
Proportion of Subjects Achieving ≥2-point Improvement in 
HDSM-Ax-11 from Baseline to End of Treatment 
ITT 
14.2.1.3.2 
Proportion of Subjects Achieving ≥2-point Improvement in 
HDSM-Ax-11 from Baseline to End of Treatment 
Per Protocol 
14.2.1.4.1 
Change from Baseline in HDSM-Ax-11 to End of Treatment 
ITT 
14.2.1.4.2 
Change from Baseline in HDSM-Ax-11 to End of Treatment 
Per Protocol 
14.2.2.1.1 
Proportion of Subjects Achieving ≥1-point Improvement in 
HDSM-Ax-7 from Baseline to End of Treatment 
ITT 
14.2.2.1.2 
Proportion of Subjects Achieving ≥1-point Improvement in 
HDSM-Ax-7 from Baseline to End of Treatment 
Per Protocol 
14.2.2.2.1 
Proportion of Subjects Achieving ≥1.5-point Improvement in 
HDSM-Ax-7 from Baseline to End of Treatment 
ITT 
14.2.2.2.2 
Proportion of Subjects Achieving ≥1.5-point Improvement in 
HDSM-Ax-7 from Baseline to End of Treatment 
Per Protocol 
14.2.2.3.1 
Proportion of Subjects Achieving ≥2-point Improvement in 
HDSM-Ax-7 from Baseline to End of Treatment 
ITT 
14.2.2.3.2 
Proportion of Subjects Achieving ≥2-point Improvement in 
HDSM-Ax-7 from Baseline to End of Treatment 
Per Protocol 
14.2.2.4.1 
Change from Baseline in HDSM-Ax-7 to End of Treatment 
ITT 
14.2.2.4.2 
Change from Baseline in HDSM-Ax-7 to End of Treatment 
Per Protocol 
14.2.2.5.1 
Proportion of Subjects Achieving ≥1-point Improvement in 
HDSM-Ax-11 from Baseline by Visit 
ITT 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 36 of 51 
 
 
 
 
14.2.2.5.2 
Proportion of Subjects Achieving ≥1-point Improvement in 
HDSM-Ax-11 from Baseline by Visit 
Per Protocol 
14.2.2.6.1 
Proportion of Subjects Achieving ≥1.5-point Improvement in 
HDSM-Ax-11 from Baseline by Visit 
ITT 
14.2.2.6.2 
Proportion of Subjects Achieving ≥1.5-point Improvement in 
HDSM-Ax-11 from Baseline by Visit 
Per Protocol 
14.2.2.7.1 
Proportion of Subjects Achieving ≥2-point Improvement in 
HDSM-Ax-11 from Baseline by Visit 
ITT 
14.2.2.7.2 
Proportion of Subjects Achieving ≥2-point Improvement in 
HDSM-Ax-11 from Baseline by Visit 
Per Protocol 
14.2.2.8.1 
Proportion of Subjects Achieving ≥1-point Improvement in 
HDSM-Ax-7 from Baseline by Visit 
ITT 
14.2.2.8.2 
Proportion of Subjects Achieving ≥1-point Improvement in 
HDSM-Ax-7 from Baseline by Visit 
Per Protocol 
14.2.2.9.1 
Proportion of Subjects Achieving ≥1.5-point Improvement in 
HDSM-Ax-7 from Baseline by Visit 
ITT 
14.2.2.9.2 
Proportion of Subjects Achieving ≥1.5-point Improvement in 
HDSM-Ax-7 from Baseline by Visit 
Per Protocol 
14.2.2.10.1 
Proportion of Subjects Achieving ≥2-point Improvement in 
HDSM-Ax-7 from Baseline by Visit 
ITT 
14.2.2.10.2 
Proportion of Subjects Achieving ≥2-point Improvement in 
HDSM-Ax-7 from Baseline by Visit 
Per Protocol 
14.2.2.11.1 
Change from Baseline in HDSM-Ax-11 by Visit 
ITT 
14.2.2.11.2 
Change from Baseline in HDSM-Ax-11 by Visit 
Per Protocol 
14.2.2.12.1 
Change from Baseline in HDSM-Ax-7 by Visit 
ITT 
14.2.2.12.2 
Change from Baseline in HDSM-Ax-7 by Visit 
Per Protocol 
14.2.2.13.1 
Change from Baseline in DLQI by Visit 
ITT 
14.2.2.13.2 
Change from Baseline in DLQI by Visit 
Per Protocol 
14.2.2.14.1 
Patient Global Impression - Severity (PGI-S) by Visit 
ITT 
14.2.2.14.2 
Patient Global Impression - Severity (PGI-S) by Visit 
Per Protocol 
14.2.2.15.1 
Patient Global Impression - Severity (PGI-S) Shift from 
Baseline to Each Visit 
ITT 
14.2.2.15.2 
Patient Global Impression - Severity (PGI-S) Shift from 
Baseline to Each Visit 
Per Protocol 
14.2.2.16.1 
Patient Global Impression of Change (PGI-C) by Visit 
ITT 
14.2.2.16.2 
Patient Global Impression - Change (PGI-C) by Visit 
Per Protocol 
14.2.3 
Change from Baseline in HidroQoL by Visit 
HQL 
14.3.1.1 
Overall Summary of Treatment Emergent Adverse Events 
Safety 
14.3.1.2 
Number and Percentage of Subjects with Serious Treatment-
Emergent Adverse Events by System Organ Class, Preferred 
Term, and Maximum Severity 
Safety 
14.3.1.3 
Number and Percentage of Subjects with Serious Treatment-
Related Treatment-Emergent Adverse Events by System 
Organ Class, Preferred Term, and Maximum Severity 
Safety 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 37 of 51 
 
 
 
 
14.3.1.4.1 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Cumulative to Week 2 by System Organ 
Class, Preferred Term, and Maximum Severity  
Safety (Subjects 
Reaching Week 2) 
14.3.1.4.2 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Cumulative to Week 2 by System Organ 
Class, Preferred Term, and Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 2 
or Not) 
14.3.1.4.3 
Number and Percentage of Subjects with Treatment-Related 
Treatment-Emergent Adverse Events Cumulative to Week 2 
by System Organ Class, Preferred Term, and Maximum 
Severity 
Safety (Subjects 
Reaching Week 2) 
14.3.1.4.4 
Number and Percentage of Subjects with Treatment-Related 
Treatment-Emergent Adverse Events Cumulative to Week 2 
by System Organ Class, Preferred Term, and Maximum 
Severity 
Safety (All Safety 
Subjects, 
Reaching Week 2 
or Not) 
14.3.1.4.5 
Number and Percentage of Subjects with Severe Treatment-
Emergent Adverse Events Cumulative to Week 2 by System 
Organ Class, Preferred Term, and Maximum Severity  
Safety (Subjects 
Reaching Week 2) 
14.3.1.4.6 
Number and Percentage of Subjects with Severe Treatment-
Emergent Adverse Events Cumulative to Week 2 by System 
Organ Class, Preferred Term, and Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 2 
or Not) 
14.3.1.4.7 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Dose Interruption Cumulative to 
Week 2 by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety (Subjects 
Reaching Week 2) 
14.3.1.4.8 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Dose Interruption Cumulative to 
Week 2 by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 2 
or Not) 
14.3.1.4.9 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Dose Modification Cumulative to 
Week 2 by System Organ Class, Preferred Term, and 
Maximum Severity  
Safety (Subjects 
Reaching Week 2) 
14.3.1.4.10 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Dose Modification Cumulative to 
Week 2 by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 2 
or Not) 
14.3.1.4.11 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Study Discontinuation Cumulative 
to Week 2 by System Organ Class, Preferred Term, and 
Maximum Severity  
Safety (Subjects 
Reaching Week 2) 
14.3.1.4.12 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Study Discontinuation Cumulative 
to Week 2 by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 2 
or Not) 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 38 of 51 
 
 
 
 
14.3.1.4.13 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events of Special Interest Cumulative to Week 2 by 
System Organ Class, Preferred Term, and Maximum Severity 
Safety (Subjects 
Reaching Week 2) 
14.3.1.4.14 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events of Special Interest Cumulative to Week 2 by 
System Organ Class, Preferred Term, and Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 2 
or Not) 
14.3.1.4.15 
Number and Percentage of Subjects with Anticholinergic 
Treatment-Emergent Adverse Events Cumulative to Week 2 
by System Organ Class, Preferred Term, and Maximum 
Severity  
Safety (Subjects 
Reaching Week 2) 
14.3.1.4.16 
Number and Percentage of Subjects with Anticholinergic 
Treatment-Emergent Adverse Events Cumulative to Week 2 
by System Organ Class, Preferred Term, and Maximum 
Severity 
Safety (All Safety 
Subjects, 
Reaching Week 2 
or Not) 
14.3.1.5.1 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Cumulative to Week 4 by System Organ 
Class, Preferred Term, and Maximum Severity  
Safety (Subjects 
Reaching Week 4) 
14.3.1.5.2 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Cumulative to Week 4 by System Organ 
Class, Preferred Term, and Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 4 
or Not) 
14.3.1.5.3 
Number and Percentage of Subjects with Treatment-Related 
Treatment-Emergent Adverse Events Cumulative to Week 4 
by System Organ Class, Preferred Term, and Maximum 
Severity  
Safety (Subjects 
Reaching Week 4) 
14.3.1.5.4 
Number and Percentage of Subjects with Treatment-Related 
Treatment-Emergent Adverse Events Cumulative to Week 4 
by System Organ Class, Preferred Term, and Maximum 
Severity 
Safety (All Safety 
Subjects, 
Reaching Week 4 
or Not) 
14.3.1.5.5 
Number and Percentage of Subjects with Severe Treatment-
Emergent Adverse Events Cumulative to Week 4 by System 
Organ Class, Preferred Term, and Maximum Severity  
Safety (Subjects 
Reaching Week 4) 
14.3.1.5.6 
Number and Percentage of Subjects with Severe Treatment-
Emergent Adverse Events Cumulative to Week 4 by System 
Organ Class, Preferred Term, and Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 4 
or Not) 
14.3.1.5.7 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Dose Interruption Cumulative to 
Week 4 by System Organ Class, Preferred Term, and 
Maximum Severity  
Safety (Subjects 
Reaching Week 4) 
14.3.1.5.8 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Dose Interruption Cumulative to 
Week 4 by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 4 
or Not) 
14.3.1.5.9 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Dose Modification Cumulative to 
Safety (Subjects 
Reaching Week 4) 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 39 of 51 
 
 
 
 
Week 4 by System Organ Class, Preferred Term, and 
Maximum Severity  
14.3.1.5.10 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Dose Modification Cumulative to 
Week 4 by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 4 
or Not) 
14.3.1.5.11 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Study Discontinuation Cumulative 
to Week 4 by System Organ Class, Preferred Term, and 
Maximum Severity  
Safety (Subjects 
Reaching Week 4) 
14.3.1.5.12 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Study Discontinuation Cumulative 
to Week 4 by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 4 
or Not) 
14.3.1.5.13 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events of Special Interest Cumulative to Week 4 by 
System Organ Class, Preferred Term, and Maximum Severity  
Safety (Subjects 
Reaching Week 4) 
14.3.1.5.14 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events of Special Interest Cumulative to Week 4 by 
System Organ Class, Preferred Term, and Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 4 
or Not) 
14.3.1.5.15 
Number and Percentage of Subjects with Anticholinergic 
Treatment-Emergent Adverse Events Cumulative to Week 4 
by System Organ Class, Preferred Term, and Maximum 
Severity  
Safety (Subjects 
Reaching Week 4) 
14.3.1.5.16 
Number and Percentage of Subjects with Anticholinergic 
Treatment-Emergent Adverse Events Cumulative to Week 4 
by System Organ Class, Preferred Term, and Maximum 
Severity 
Safety (All Safety 
Subjects, 
Reaching Week 4 
or Not) 
14.3.1.6.1 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Cumulative to Week 6 by System Organ 
Class, Preferred Term, and Maximum Severity  
Safety (Subjects 
Reaching Week 6) 
14.3.1.6.2 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Cumulative to Week 6 by System Organ 
Class, Preferred Term, and Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 6 
or Not) 
14.3.1.6.3 
Number and Percentage of Subjects with Treatment-Related 
Treatment-Emergent Adverse Events Cumulative to Week 6 
by System Organ Class, Preferred Term, and Maximum 
Severity 
Safety  (Subjects 
Reaching Week 6) 
14.3.1.6.4 
Number and Percentage of Subjects with Treatment-Related 
Treatment-Emergent Adverse Events Cumulative to Week 6 
by System Organ Class, Preferred Term, and Maximum 
Severity 
Safety (All Safety 
Subjects, 
Reaching Week 6 
or Not) 
14.3.1.6.5 
Number and Percentage of Subjects with Severe Treatment-
Emergent Adverse Events Cumulative to Week 6 by System 
Organ Class, Preferred Term, and Maximum Severity  
Safety  (Subjects 
Reaching Week 6) 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 40 of 51 
 
 
 
 
14.3.1.6.6 
Number and Percentage of Subjects with Severe Treatment-
Emergent Adverse Events Cumulative to Week 6 by System 
Organ Class, Preferred Term, and Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 6 
or Not) 
14.3.1.6.7 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Dose Interruption Cumulative to 
Week 6 by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety  (Subjects 
Reaching Week 6) 
14.3.1.6.8 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Dose Interruption Cumulative to 
Week 6 by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 6 
or Not) 
14.3.1.6.9 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Dose Modification Cumulative to 
Week 6 by System Organ Class, Preferred Term, and 
Maximum Severity  
Safety  (Subjects 
Reaching Week 6) 
14.3.1.6.10 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Dose Modification Cumulative to 
Week 6 by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 6 
or Not) 
14.3.1.6.11 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Study Discontinuation Cumulative 
to Week 6 by System Organ Class, Preferred Term, and 
Maximum Severity  
Safety  (Subjects 
Reaching Week 6) 
14.3.1.6.12 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Study Discontinuation Cumulative 
to Week 6 by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 6 
or Not) 
14.3.1.6.13 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events of Special Interest Cumulative to Week 6 by 
System Organ Class, Preferred Term, and Maximum Severity  
Safety  (Subjects 
Reaching Week 6) 
14.3.1.6.14 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events of Special Interest Cumulative to Week 6 by 
System Organ Class, Preferred Term, and Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 6 
or Not) 
14.3.1.6.15 
Number and Percentage of Subjects with Anticholinergic 
Treatment-Emergent Adverse Events Cumulative to Week 6 
by System Organ Class, Preferred Term, and Maximum 
Severity  
Safety  (Subjects 
Reaching Week 6) 
14.3.1.6.16 
Number and Percentage of Subjects with Anticholinergic 
Treatment-Emergent Adverse Events Cumulative to Week 6 
by System Organ Class, Preferred Term, and Maximum 
Severity 
Safety (All Safety 
Subjects, 
Reaching Week 6 
or Not) 
14.3.1.7.1 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Cumulative to Week 12 by System Organ 
Class, Preferred Term, and Maximum Severity 
Safety (Subjects 
Reaching Week 
12) 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 41 of 51 
 
 
 
 
14.3.1.7.2 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Cumulative to Week 12 by System Organ 
Class, Preferred Term, and Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 12 
or Not) 
14.3.1.7.3 
Number and Percentage of Subjects with Treatment-Related 
Treatment-Emergent Adverse Events Cumulative to Week 12 
by System Organ Class, Preferred Term, and Maximum 
Severity  
Safety (Subjects 
Reaching Week 
12) 
14.3.1.7.4 
Number and Percentage of Subjects with Treatment-Related 
Treatment-Emergent Adverse Events Cumulative to Week 12 
by System Organ Class, Preferred Term, and Maximum 
Severity 
Safety (All Safety 
Subjects, 
Reaching Week 12 
or Not) 
14.3.1.7.5 
Number and Percentage of Subjects with Severe Treatment-
Emergent Adverse Events Cumulative to Week 12 by System 
Organ Class, Preferred Term, and Maximum Severity  
Safety  (Subjects 
Reaching Week 
12) 
14.3.1.7.6 
Number and Percentage of Subjects with Severe Treatment-
Emergent Adverse Events Cumulative to Week 12 by System 
Organ Class, Preferred Term, and Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 12 
or Not) 
14.3.1.7.7 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Dose Interruption Cumulative to 
Week 12 by System Organ Class, Preferred Term, and 
Maximum Severity  
Safety (Subjects 
Reaching Week 
12) 
14.3.1.7.8 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Dose Interruption Cumulative to 
Week 12 by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 12 
or Not) 
14.3.1.7.9 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Dose Modification Cumulative to 
Week 12 by System Organ Class, Preferred Term, and 
Maximum Severity  
Safety (Subjects 
Reaching Week 
12) 
14.3.1.7.10 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Dose Modification Cumulative to 
Week 12 by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 12 
or Not) 
14.3.1.7.11 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Study Discontinuation Cumulative 
to Week 12 by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety (Subjects 
Reaching Week 
12) 
14.3.1.7.12 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Study Discontinuation Cumulative 
to Week 12 by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 12 
or Not) 
14.3.1.7.13 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events of Special Interest Cumulative to Week 12 by 
System Organ Class, Preferred Term, and Maximum Severity 
Safety (Subjects 
Reaching Week 
12) 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 42 of 51 
 
 
 
 
14.3.1.7.14 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events of Special Interest Cumulative to Week 12 by 
System Organ Class, Preferred Term, and Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 12 
or Not) 
14.3.1.7.15 
Number and Percentage of Subjects with Anticholinergic 
Treatment-Emergent Adverse Events Cumulative to Week 12 
by System Organ Class, Preferred Term, and Maximum 
Severity 
Safety  (Subjects 
Reaching Week 
12) 
14.3.1.7.16 
Number and Percentage of Subjects with Anticholinergic 
Treatment-Emergent Adverse Events Cumulative to Week 12 
by System Organ Class, Preferred Term, and Maximum 
Severity 
Safety (All Safety 
Subjects, 
Reaching Week 12 
or Not) 
14.3.1.8.1 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Cumulative to Week 24 by System Organ 
Class, Preferred Term, and Maximum Severity 
Safety (Subjects 
Reaching Week 
24) 
14.3.1.8.2 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Cumulative to Week 24 by System Organ 
Class, Preferred Term, and Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 24 
or Not) 
14.3.1.8.3 
Number and Percentage of Subjects with Treatment-Related 
Treatment-Emergent Adverse Events Cumulative to Week 24 
by System Organ Class, Preferred Term, and Maximum 
Severity  
Safety (Subjects 
Reaching Week 
24) 
14.3.1.8.4 
Number and Percentage of Subjects with Treatment-Related 
Treatment-Emergent Adverse Events Cumulative to Week 24 
by System Organ Class, Preferred Term, and Maximum 
Severity 
Safety (All Safety 
Subjects, 
Reaching Week 24 
or Not) 
14.3.1.8.5 
Number and Percentage of Subjects with Severe Treatment-
Emergent Adverse Events Cumulative to Week 24 by System 
Organ Class, Preferred Term, and Maximum Severity 
Safety  (Subjects 
Reaching Week 
24) 
14.3.1.8.6 
Number and Percentage of Subjects with Severe Treatment-
Emergent Adverse Events Cumulative to Week 24 by System 
Organ Class, Preferred Term, and Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 24 
or Not) 
14.3.1.8.7 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Dose Interruption Cumulative to 
Week 24 by System Organ Class, Preferred Term, and 
Maximum Severity  
Safety (Subjects 
Reaching Week 
24) 
14.3.1.8.8 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Dose Interruption Cumulative to 
Week 24 by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 24 
or Not) 
14.3.1.8.9 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Dose Modification Cumulative to 
Week 24 by System Organ Class, Preferred Term, and 
Maximum Severity  
Safety (Subjects 
Reaching Week 
24) 
14.3.1.8.10 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Dose Modification Cumulative to 
Safety (All Safety 
Subjects, 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 43 of 51 
 
 
 
 
Week 24 by System Organ Class, Preferred Term, and 
Maximum Severity 
Reaching Week 24 
or Not) 
14.3.1.8.11 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Study Discontinuation Cumulative 
to Week 24 by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety (Subjects 
Reaching Week 
24) 
14.3.1.8.12 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Study Discontinuation Cumulative 
to Week 24 by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 24 
or Not) 
14.3.1.8.13 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events of Special Interest Cumulative to Week 24 by 
System Organ Class, Preferred Term, and Maximum Severity 
Safety (Subjects 
Reaching Week 
24) 
14.3.1.8.14 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events of Special Interest Cumulative to Week 24 by 
System Organ Class, Preferred Term, and Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 24 
or Not) 
14.3.1.8.15 
Number and Percentage of Subjects with Anticholinergic 
Treatment-Emergent Adverse Events Cumulative to Week 24 
by System Organ Class, Preferred Term, and Maximum 
Severity  
Safety  (Subjects 
Reaching Week 
24) 
14.3.1.8.16 
Number and Percentage of Subjects with Anticholinergic 
Treatment-Emergent Adverse Events Cumulative to Week 24 
by System Organ Class, Preferred Term, and Maximum 
Severity 
Safety (All Safety 
Subjects, 
Reaching Week 24 
or Not) 
14.3.1.9.1 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Cumulative to Week 48 by System Organ 
Class, Preferred Term, and Maximum Severity 
Safety (Subjects 
Reaching Week 
48) 
14.3.1.9.2 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Cumulative to Week 48 by System Organ 
Class, Preferred Term, and Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 48 
or Not) 
14.3.1.9.3 
Number and Percentage of Subjects with Treatment-Related 
Treatment-Emergent Adverse Events Cumulative to Week 48 
by System Organ Class, Preferred Term, and Maximum 
Severity  
Safety (Subjects 
Reaching Week 
48) 
14.3.1.9.4 
Number and Percentage of Subjects with Treatment-Related 
Treatment-Emergent Adverse Events Cumulative to Week 48 
by System Organ Class, Preferred Term, and Maximum 
Severity 
Safety (All Safety 
Subjects, 
Reaching Week 48 
or Not) 
14.3.1.9.5 
Number and Percentage of Subjects with Severe Treatment-
Emergent Adverse Events Cumulative to Week 48 by System 
Organ Class, Preferred Term, and Maximum Severity 
Safety  (Subjects 
Reaching Week 
48) 
14.3.1.9.6 
Number and Percentage of Subjects with Severe Treatment-
Emergent Adverse Events Cumulative to Week 48 by System 
Organ Class, Preferred Term, and Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 48 
or Not) 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 44 of 51 
 
 
 
 
14.3.1.9.7 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Dose Interruption Cumulative to 
Week 48 by System Organ Class, Preferred Term, and 
Maximum Severity  
Safety (Subjects 
Reaching Week 
48) 
14.3.1.9.8 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Dose Interruption Cumulative to 
Week 48 by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 48 
or Not) 
14.3.1.9.9 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Dose Modification Cumulative to 
Week 48 by System Organ Class, Preferred Term, and 
Maximum Severity  
Safety (Subjects 
Reaching Week 
48) 
14.3.1.9.10 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Dose Modification Cumulative to 
Week 48 by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 48 
or Not) 
14.3.1.9.11 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Study Discontinuation Cumulative 
to Week 48 by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety (Subjects 
Reaching Week 
48) 
14.3.1.9.12 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Study Discontinuation Cumulative 
to Week 48 by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 48 
or Not) 
14.3.1.9.13 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events of Special Interest Cumulative to Week 48 by 
System Organ Class, Preferred Term, and Maximum Severity  
Safety (Subjects 
Reaching Week 
48) 
14.3.1.9.14 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events of Special Interest Cumulative to Week 48 by 
System Organ Class, Preferred Term, and Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 48 
or Not) 
14.3.1.9.15 
Number and Percentage of Subjects with Anticholinergic 
Treatment-Emergent Adverse Events Cumulative to Week 48 
by System Organ Class, Preferred Term, and Maximum 
Severity  
Safety  (Subjects 
Reaching Week 
48) 
14.3.1.9.16 
Number and Percentage of Subjects with Anticholinergic 
Treatment-Emergent Adverse Events Cumulative to Week 48 
by System Organ Class, Preferred Term, and Maximum 
Severity 
Safety (All Safety 
Subjects, 
Reaching Week 48 
or Not) 
14.3.1.10.1 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Cumulative to Week 52 by System Organ 
Class, Preferred Term, and Maximum Severity  
Safety (Subjects 
Reaching Week 
52) 
14.3.1.10.2 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Cumulative to Week 52 by System Organ 
Class, Preferred Term, and Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 52 
or Not) 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 45 of 51 
 
 
 
 
14.3.1.10.3 
Number and Percentage of Subjects with Treatment-Related 
Treatment-Emergent Adverse Events Cumulative to Week 52 
by System Organ Class, Preferred Term, and Maximum 
Severity  
Safety (Subjects 
Reaching Week 
52) 
14.3.1.10.4 
Number and Percentage of Subjects with Treatment-Related 
Treatment-Emergent Adverse Events Cumulative to Week 52 
by System Organ Class, Preferred Term, and Maximum 
Severity 
Safety (All Safety 
Subjects, 
Reaching Week 52 
or Not) 
14.3.1.10.5 
Number and Percentage of Subjects with Severe Treatment-
Emergent Adverse Events Cumulative to Week 52 by System 
Organ Class, Preferred Term, and Maximum Severity  
Safety  (Subjects 
Reaching Week 
52) 
14.3.1.10.6 
Number and Percentage of Subjects with Severe Treatment-
Emergent Adverse Events Cumulative to Week 52 by System 
Organ Class, Preferred Term, and Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 52 
or Not) 
14.3.1.10.7 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Dose Interruption Cumulative to 
Week 52 by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety (Subjects 
Reaching Week 
52) 
14.3.1.10.8 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Dose Interruption Cumulative to 
Week 52 by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 52 
or Not) 
14.3.1.10.9 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Dose Modification Cumulative to 
Week 52 by System Organ Class, Preferred Term, and 
Maximum Severity  
Safety (Subjects 
Reaching Week 
52) 
14.3.1.10.10 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Dose Modification Cumulative to 
Week 52 by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 52 
or Not) 
14.3.1.10.11 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Study Discontinuation Cumulative 
to Week 52 by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety (Subjects 
Reaching Week 
52) 
14.3.1.10.12 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events Leading to Study Discontinuation Cumulative 
to Week 52 by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 52 
or Not) 
14.3.1.10.13 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events of Special Interest Cumulative to Week 52 by 
System Organ Class, Preferred Term, and Maximum Severity 
Safety (Subjects 
Reaching Week 
52) 
14.3.1.10.14 
Number and Percentage of Subjects with Treatment-Emergent 
Adverse Events of Special Interest Cumulative to Week 52 by 
System Organ Class, Preferred Term, and Maximum Severity 
Safety (All Safety 
Subjects, 
Reaching Week 52 
or Not) 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 46 of 51 
 
 
 
 
14.3.1.10.15 
Number and Percentage of Subjects with Anticholinergic 
Treatment-Emergent Adverse Events Cumulative to Week 52 
by System Organ Class, Preferred Term, and Maximum 
Severity  
Safety  (Subjects 
Reaching Week 
52) 
14.3.1.10.16 
Number and Percentage of Subjects with Anticholinergic 
Treatment-Emergent Adverse Events Cumulative to Week 52 
by System Organ Class, Preferred Term, and Maximum 
Severity 
Safety (All Safety 
Subjects, 
Reaching Week 52 
or Not) 
14.3.6.1 
Worst Post-baseline Severity for Local Tolerability 
Assessments by Treatment Group 
Safety 
14.3.6.2 
Worst Severity for Local Tolerability Assessments by 
Treatment Group and Visit 
Safety 
14.3.6.3 
Summary of Vital Signs 
Safety 
14.3.4.1 
Mean and Mean Change from Baseline in Serum 
Biochemistry Values by Visit 
Safety 
14.3.4.2 
Mean and Mean Change from Baseline in Hematology Values 
by Visit 
Safety 
14.3.4.3 
Mean and Mean Change from Baseline in Continuous 
Urinalysis Values by Visit 
Safety 
14.3.4.4 
Categorical Urinalysis Values by Visit 
Safety 
14.3.4.5 
Shift in Serum Biochemistry Results from Baseline to Each 
Visit 
Safety 
14.3.4.6 
Shift in Hematology Results from Baseline to Each Visit 
Safety 
14.3.4.7 
Shift in Continuous Urinalysis Results from Baseline to Each 
Visit 
Safety 
14.3.4.8 
Shift in Categorical Urinalysis Results from Baseline to Each 
Visit 
Safety 
14.3.5 
Study Drug Administration Exposure and Compliance 
Safety 
14.3.6.4 
Summary of Concomitant Medications by Drug Class and 
Generic Drug Name 
Safety 
 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 47 of 51 
 
 
 
 
16. LIST OF PLANNED FIGURES 
Number 
Description 
Analysis Set 
14.2.1.1.1 
Proportion of Subjects Achieving ≥1-point 
Improvement in HDSM-Ax-11 by Visit 
ITT 
14.2.1.1.2 
Proportion of Subjects Achieving ≥1-point 
Improvement in HDSM-Ax-11 by Visit 
Per Protocol 
14.2.1.2.1 
Proportion of Subjects Achieving ≥1.5-point 
Improvement in HDSM-Ax-11 by Visit 
ITT 
14.2.1.2.2 
Proportion of Subjects Achieving ≥1.5-point 
Improvement in HDSM-Ax-11 by Visit 
Per Protocol 
14.2.1.3.1 
Proportion of Subjects Achieving ≥2-point 
Improvement in HDSM-Ax-11 by Visit 
ITT 
14.2.1.3.2 
Proportion of Subjects Achieving ≥2-point 
Improvement in HDSM-Ax-11 by Visit 
Per Protocol 
14.2.1.4.1 
Mean Change from Baseline in HDSM-Ax-11 by 
Visit 
ITT 
14.2.1.4.2 
Mean Change from Baseline in HDSM-Ax-11 by 
Visit 
Per Protocol 
14.2.2.1.1 
Proportion of Subjects Achieving ≥1-point 
Improvement in HDSM-Ax-7 by Visit 
ITT 
14.2.2.1.2 
Proportion of Subjects Achieving ≥1-point 
Improvement in HDSM-Ax-7 by Visit 
Per Protocol 
14.2.2.2.1 
Proportion of Subjects Achieving ≥1.5-point 
Improvement in HDSM-Ax-7 by Visit 
ITT 
14.2.2.2.2 
Proportion of Subjects Achieving ≥1.5-point 
Improvement in HDSM-Ax-7 by Visit 
Per Protocol 
14.2.2.3.1 
Proportion of Subjects Achieving ≥2-point 
Improvement in HDSM-Ax-7 by Visit 
ITT 
14.2.2.3.2 
Proportion of Subjects Achieving ≥2-point 
Improvement in HDSM-Ax-7 by Visit 
Per Protocol 
14.2.2.4.1 
Mean Change from Baseline in HDSM-Ax-7 by 
Visit 
ITT 
14.2.2.4.2 
Mean Change from Baseline in HDSM-Ax-7 by 
Visit 
Per Protocol 
 
 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 48 of 51 
 
 
 
 
17. LIST OF PLANNED DATA LISTINGS 
Number 
Description 
Analysis Set 
16.2.1 
Subject Disposition 
All Randomized Subjects 
16.2.2 
Protocol Deviations 
Safety 
16.2.3 
Analysis Populations 
All Randomized Subjects 
16.2.4.1 
Demographic and Baseline Characteristics 
Safety 
16.2.4.2 
Medical History 
Safety 
16.2.4.3 
Prior and Concomitant Medications 
Safety 
16.2.6.1 
Hyperhidrosis Disease Severity Measure-
Axillary Results 
ITT 
16.2.6.2 
Dermatology Quality of Life Index Results 
ITT 
16.2.6.3 
Hyperhidrosis Quality of Life Index Results 
HQL 
16.2.7.1 
All Adverse Events 
Safety 
14.3.2.1 
Serious Adverse Events 
Safety 
14.3.2.2 
Adverse Events Resulting in Study 
Discontinuation 
Safety 
14.3.2.3 
Adverse Events Resulting in Death 
Safety 
16.2.7.2 
Adverse Events of Special Interest 
Safety 
16.2.9.1 
Local Tolerability Results 
ITT 
16.2.9.2 
Vital Signs Results 
Safety 
16.2.9.3 
Physical Examination Results 
Safety 
16.2.8.5 
Pregnancy Results 
Safety 
16.2.8.1 
Serum Biochemistry Results 
Safety 
16.2.8.2 
Hematology Results 
Safety 
16.2.8.3 
Urinalysis Results 
Safety 
16.2.8.4 
Clinically Significant Laboratory Values 
Safety 
16.2.5.1 
Study Medication Dosing 
Safety 
16.2.5.2 
Study Drug Accountability 
Safety 
16.2.5.3 
Exposure Parameters 
Safety 
16.2.9.4 
Prior or Concomitant Therapies or Procedures 
Safety 
16.2.10 
Subject Study Visits 
All Randomized Subjects 
 
 
 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 49 of 51 
 
 
 
 
18. APPENDICES 
18.1 Schedule of Events 
VISIT 
1 
2 
3 – 61 
7 – 162 
173 
Time Point 
Screening 
(-31 to 0 Days) 
Baseline 
(Day 1) 
Weeks 
2, 4, 6, 8 ±3 days 
Q4 Weeks 
(Weeks 12 – 48) ±5 days 
End of Study  
Week 52 ±5 days 
PROCEDURE 
Informed Consent 
X 
 
 
 
 
Medical Hx, Demog 
X 
 
 
 
 
I/E Criteria 
X 
X 
 
 
 
Randomization 
 
X 
 
 
 
PE 
X 
 
 
 
X 
Vitals (BP, HR, RR, 
Temp) 
X 
X 
X 
X 
X 
HDSM-Ax 
X 
X 
X 
X 
X 
PGI-S4 
X 
X 
X 
X 
X 
PGI-C5 
 
 
 
X 
 
DLQI6 
 
X 
X 
X 
 
HidroQoL7 
 
X 
X 
 
 
Optional End of Study 
Survey8 
 
 
 
X 
Local Tolerability9 
 
X 
X 
X 
X 
Adverse Events9 
X 
X 
X 
X 
X 
UPT (FOCBP)10 
X 
X 
X 
X 
 
IP Dispensation/ Return/ 
Resupply11 
 
X 
X 
X 
 
IP Weight11 
 
X 
X 
X 
 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 50 of 51 
 
 
 
 
Compliance 
Training/Evaluation 
 
X 
X 
X 
X 
Safety Labs (heme., 
chem., urine)12 
X 
 
X 
X 
 
Conmeds 
X 
X 
X 
X 
X 
Abbreviations: BP = blood pressure; Chem. = chemistry; Conmeds = concomitant medications; DLQI = Dermatology 
Life Quality Index; FOCBP= females of child-bearing potential; HDSM-Ax = Hyperhidrosis Disease Severity 
Measure-Axillae; heme. = hematology; HR = heart rate; Hx = history; I/E = inclusion/exclusion; IP = investigational 
product; PE = physical examination; PGI-C = Patient Global Impression of Change; PGI-S = Patient Global Impression 
of Severity; RR = respiratory rate; UPT = urine pregnancy test, urine = urinalysis. 
1No more than 14±3 days may elapse between Visit 2 (Baseline) and Visit 3 (Week 2). 
2No more than 28±5 days may elapse between each of Visits 7-16 (Weeks 12-48). 
3The End of Study Visit may occur ±5 days of Week 52. 
4Administered as Question #6 of HDSM-Ax at every assessment. 
5Administered as Question #7 of HDSM-Ax at Week 24 and Week 48 visits. 
6Administered at Baseline, Weeks 2, 6, 24, and 48.  
7Administered at Baseline, Week 2, and Week 6; only the first 100 subjects enrolled in the study will complete this 
assessment. 
8 Administered at Week 52 visit; the End of Study Survey is optional. 
9 Investigator local tolerability assessments to be performed after the Subject local tolerability assessments. 
10 Performed at Screening, Baseline, and then Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48.  
11 Performed at Baseline and then Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48.  
12 Performed at Screening and then Weeks 6, 24, and 48. 
 
 
 
 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-303 
 
24 February 2020 
Version:  1.0 
 
Page 51 of 51 
 
 
 
 
19. ATTACHMENTS 
None.