Clinical trial NCT03836287
Conditions: Axillary Hyperhidrosis
Sponsor: Botanix Pharmaceuticals
Start date: 2020-10-09; Completion date: 2021-06-25
Enrollment: 350 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 safety and efficacy of sofpironium bromide, 15% gel versus vehicle (2 treatment arms), applied for the treatment of axillary hyperhidrosis.

Detailed description:
This is a multicenter, randomized, double-blind, vehicle-controlled study to evaluate the safety and efficacy of topically applied sofpironium bromide, 15% gel in subjects with axillary hyperhidrosis.

Safety will be assessed through collection of vital signs, adverse events, local skin responses, hematology, serum chemistry laboratory testing and urinalysis.

A maximum of 350 subjects will be randomized to receive either sofpironium bromide gel, 15% or vehicle.

Adverse events, vital signs, and local tolerability assessments will be collected at visits across the study. 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 13 scheduled visits to take place over approximately 11 to 15 weeks.

Arms: arm 1: Sofpironium bromide, 15% gel, once per day arm 2: Vehicle gel, once per day
Interventions: intervention 1: Sofpironium Bromide Gel, 15% intervention 2: Vehicle
Intervention descriptions: intervention 1: Active intervention 2: Vehicle gel

Protocol documents:
Prot_000.pdf: 
Sofpironium Bromide Gel 
 
Protocol BBI-4000-CL-301/03 
Page 1 of 102 
CONFIDENTIAL  
06 AUG 2020 
 
CONFIDENTIAL 
A Multicenter, Randomized, Double-Blinded, Vehicle-Controlled Study to 
Evaluate the Safety and Efficacy of Topically Applied Sofpironium Bromide 
Gel, 15% in Subjects with Axillary Hyperhidrosis (the “Cardigan I Study”) 
PROTOCOL NUMBER:  
BBI-4000-CL-301 
NAME OF INVESTIGATIONAL PRODUCT: 
Sofpironium Bromide (BBI-4000)  
ORIGINAL PROTOCOL 
September 20, 2019 
AMENDMENT 03 
August 6, 2020 
SPONSOR: 
 
Brickell Biotech, Inc. 
5777 Central Ave., Suite 102 
Boulder, CO 80301 
PHASE: 
3 (Pivotal) 
IND NUMBER: 
121,256 
MEDICAL MONITOR: 
IQVIA Medical Monitor 
Fax: 919.313.1412 (US Toll-free: 1-866-761-
1274) 
Email: safety-inbox.biotech@iqvia.com  
 
Copyright 2019 Brickell Biotech, Inc.  All rights reserved.  Unauthorized copying or use of this information is 
prohibited. 
NCT03836287


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SPONSOR SIGNATORY: 
 
 
 
 
 
Deepak Chadha, MS, MBA, RAC 
Chief Research and Development Officer 
 
Date 
 
SIGN


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INVESTIGATOR SIGNATURE PAGE 
I agree to: 
 
• Implement and conduct this study diligently and in strict compliance with the protocol, Good Clinical 
Practice (GCP), 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 
 
 


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TABLE OF CONTENTS 
SPONSOR SIGNATORY: ......................................................................................................................... 2 
INVESTIGATOR SIGNATURE PAGE................................................................................................... 3 
TABLE OF CONTENTS ........................................................................................................................... 4 
SYNOPSIS ................................................................................................................................................... 8 
ABBREVIATIONS ................................................................................................................................... 16 
1 BACKGROUND AND CLINICAL RATIONALE ......................................................................... 18 
2 STUDY DESIGN ................................................................................................................................. 19 
3 STUDY OBJECTIVES AND ASSESSMENTS ............................................................................... 20 
3.1 
Study Objectives ............................................................................................................................. 20 
3.2 
Study Assessments .......................................................................................................................... 20 
4 STUDY POPULATION ..................................................................................................................... 21 
4.1 
Number of Subjects ........................................................................................................................ 21 
4.2 
Inclusion Criteria ........................................................................................................................... 21 
4.3 
Exclusion Criteria .......................................................................................................................... 22 
5 INVESTIGATIONAL PRODUCT (IP) ............................................................................................ 23 
5.1 
Storage of Investigational Product ............................................................................................... 24 
5.2 
Instructions for Use and Administration of Investigational Product ........................................ 24 
5.3 
Instructions for the Subjects ......................................................................................................... 25 
5.4 
Procedures for Blinding and Unblinding ..................................................................................... 26 
6 CONCOMITANT MEDICATIONS/TREATMENTS .................................................................... 26 
6.1 
Permissible Medications/Treatments ........................................................................................... 26 
6.2 
Prohibited Medications/Treatments ............................................................................................. 27 
7 PROCEDURES ................................................................................................................................... 27 
7.1 
Time and Events Table .................................................................................................................. 29 
7.2 
Visit-Specific Procedures ............................................................................................................... 31 
7.2.1 
Visit 1: Screening (Days -31 to 0) ............................................................................................. 31 
7.2.2 
Visits 2 and 3: GSP1 and GSP2 ................................................................................................ 32 
7.2.3 
Visit 4: GSP3 (Day 1; Rescreening/Baseline) +14 Days of Visit 2 ......................................... 32 
7.2.4 
Visit 5: Day 8 ± 2 Days .............................................................................................................. 33 
7.2.5 
Visit 6: Day 15 ± 2 Days ............................................................................................................ 33 


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7.2.6 
Visit 7: Day 22 ± 2 Days ............................................................................................................ 34 
7.2.7 
Visit 8: Day 29 ± 2 Days ............................................................................................................ 34 
7.2.8 
Visit 9: Day 36 ± 2 Days ............................................................................................................ 35 
7.2.9 
Visits 10 and 11: GSP4 (Day 41) ± 2 Days and GSP 5 (Day 42) ± 2 Days ............................ 35 
7.2.10 
Visit 12: GSP6 (Day 43; End of Treatment) ± 2 Days ............................................................ 36 
7.2.11 
Visit 13: Follow-up (Day 57) ± 3 Days ..................................................................................... 36 
7.3 
Unscheduled Visits ......................................................................................................................... 37 
7.4 
Early Discontinuation of Subjects ................................................................................................ 37 
8 RESPONSE MEASURES AND SUMMARY OF DATA COLLECTION METHODS .............. 37 
8.1 
Safety Measures .............................................................................................................................. 37 
8.1.1 
Physical Examination ................................................................................................................ 38 
8.1.2 
Vital Signs .................................................................................................................................. 38 
8.1.3 
Clinical Laboratory Assessments ............................................................................................. 38 
8.1.4 
Adverse Events .......................................................................................................................... 39 
8.1.5 
Local Tolerability Assessments ................................................................................................ 39 
8.1.6 
Subject Assessments .................................................................................................................. 39 
8.2 
Summary of Methods of Data Collection ..................................................................................... 40 
8.3 
Efficacy Measures .......................................................................................................................... 40 
9 ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE) .................................... 40 
9.1 
Safety Evaluations .......................................................................................................................... 40 
9.2 
Adverse Events ............................................................................................................................... 40 
9.2.1 
Definitions of Adverse Events .................................................................................................. 40 
9.3 
Serious Adverse Events ................................................................................................................. 43 
9.3.1 
Definition and Reporting Procedures ...................................................................................... 43 
9.4 
Follow-up of Adverse Events and Laboratory Test Abnormalities .......................................... 44 
9.5 
Pregnancy Reporting ..................................................................................................................... 44 
9.5.1 
Time Period for Collecting Pregnancy Information .............................................................. 45 
9.5.2 
Action to Be Taken If Pregnancy Occurs ................................................................................ 45 
9.6 
Other Safety Measures .................................................................................................................. 46 
10 STATISTICAL PROCEDURES ....................................................................................................... 46 
10.1 Analysis Populations ...................................................................................................................... 46 
10.1.1 
Intent-to-Treat Population ....................................................................................................... 46 


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10.1.2 
Per-Protocol Population ........................................................................................................... 46 
10.1.3 
Safety Population ....................................................................................................................... 46 
10.2 Efficacy Endpoints ......................................................................................................................... 47 
10.2.1 
Definitions .................................................................................................................................. 47 
10.2.2 
Co-Primary Efficacy Endpoints ............................................................................................... 47 
10.2.3 
Secondary Efficacy Endpoints ................................................................................................. 47 
10.2.4 
Exploratory Efficacy Endpoints .............................................................................................. 48 
10.3 Analysis Methods ........................................................................................................................... 49 
10.3.1 
Primary and Secondary Analysis of the HDSM-Ax-7 Co-Primary Endpoint ..................... 49 
10.3.2 
Primary and Secondary Analyses of the GSP Co-Primary Endpoint .................................. 50 
10.3.3 
Method of Pooling Sites to Generate Analysis Centers ......................................................... 52 
10.3.4 
Handling of Missing Data for the Co-Primary Efficacy Endpoints in the ITT Population 52 
10.3.5 
Sensitivity Analyses of the Co-Primary Efficacy Endpoints ................................................. 52 
10.3.6 
Analysis of the Secondary Efficacy Endpoints ....................................................................... 54 
10.3.7 
Analysis of Exploratory Efficacy Endpoints ........................................................................... 54 
10.3.8 
Psychometric Analysis of the HDSM-Ax-7 ............................................................................. 54 
10.4 Safety Analyses ............................................................................................................................... 55 
10.5 Sample Size ..................................................................................................................................... 55 
11 STUDY ADMINISTRATION PROCEDURES ............................................................................... 56 
11.1 Subject Entry Procedures ............................................................................................................. 56 
11.1.1 
Overview of Entry Procedures ................................................................................................. 56 
11.1.2 
Informed Consent and Subject Privacy .................................................................................. 56 
11.1.3 
Method for Assignment to Study Product Groups ................................................................ 56 
11.2 Compliance with Protocol ............................................................................................................. 57 
11.3 Study Termination ......................................................................................................................... 57 
12 ADMINISTRATIVE ISSUES ............................................................................................................ 57 
12.1 Posting of Information on Clinicaltrials.gov ............................................................................... 57 
12.2 Protection of Human Subjects ...................................................................................................... 57 
12.2.1 
Compliance with Informed Consent Regulations (US 21 CFR Part 50) and Relevant 
Country Regulations ................................................................................................................. 57 
12.2.2 
Compliance with IRB Regulations ........................................................................................... 57 
12.2.3 
Compliance with Good Clinical Practice ................................................................................ 58 


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12.3 Changes to the Protocol ................................................................................................................. 58 
12.4 Subject Confidentiality .................................................................................................................. 58 
12.4.1 
Subject Privacy .......................................................................................................................... 58 
12.5 Documentation ............................................................................................................................... 58 
12.5.1 
Source Documents ..................................................................................................................... 58 
12.5.2 
Electronic Case Report Form Completion .............................................................................. 58 
12.5.3 
Retention of Documentation ..................................................................................................... 58 
12.6 Labelling, Packaging, Storage, and Return or Disposal of Investigational Product ............... 59 
12.6.1 
Labeling/Packaging ................................................................................................................... 59 
12.6.2 
Storage of Investigational Product .......................................................................................... 59 
12.6.3 
Clinical Supply Inventory ......................................................................................................... 59 
12.6.4 
Return or Disposal of Investigational Product ....................................................................... 59 
12.7 Monitoring by the Sponsor ............................................................................................................ 59 
12.8 Publications ..................................................................................................................................... 60 
13 REFERENCES .................................................................................................................................... 61 
14 APPENDICES ..................................................................................................................................... 62 
APPENDIX 1:  GRAVIMETRICALLY MEASURED SWEAT PRODUCTION ............................. 63 
APPENDIX 2:  HYPERHIDROSIS DISEASE SEVERITY MEASURE-AXILLARY (HDSM-
AX), ≥ 12 YEARS OF AGE (VERSION 1.3) ................................................................................. 64 
APPENDIX 3:  HYPERHIDROSIS DISEASE SEVERITY MEASURE-AXILLARY, CHILD (≥9 
TO ˂12 YEARS OF AGE) ................................................................................................................. 67 
APPENDIX 4:  DERMATOLOGY LIFE QUALITY INDEX-AXILLA; FOR SUBJECTS ≥17 
YEARS OF AGE ................................................................................................................................. 70 
APPENDIX 5:  TOLERABILITY ASSESSMENTS ............................................................................. 73 
APPENDIX 6:  STUDY DRUG APPLICATION & SUBJECT INSTRUCTIONS ........................... 74 
APPENDIX 7:  PROTOCOL AMENDMENTS .................................................................................... 77 


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SYNOPSIS 
Protocol Title 
A Multicenter, Randomized, Double-Blinded, Vehicle-Controlled Study to Evaluate the Safety and Efficacy 
of Topically Applied Sofpironium Bromide Gel, 15% in Subjects with Axillary Hyperhidrosis (the 
“Cardigan I Study”) 
Study Objectives 
• To evaluate the safety and local tolerability of sofpironium bromide gel, 15% when applied topically 
to subjects with primary axillary hyperhidrosis.  
• To evaluate the effect of sofpironium bromide gel, 15% on hyperhidrosis disease severity as it 
relates to sweat production, patient-reported outcomes, and quality of life self-assessments. 
Study Population 
Subjects aged 9 years with a diagnosis of axillary hyperhidrosis.  
Inclusion Criteria 
Subjects must fulfill all the following criteria to be eligible for study admission: 
1. 0DOHRUIHPDOHVXEMHFW9 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. Hyperhidrosis Disease Severity Measure-Axillary (HDSM-Ax 7-Item1 [HDSM-Ax-7]) of 3 
– 4 inclusive at both of the Screening Visits (Visits 1 and 4). 
b. Gravimetric test indicating a minimum of 50 mg of sweat production at rest in each axilla 
with a two-axilla combined total of at least 150 mg of sweat production in five (5) minutes at 
room temperature, 20°C to 25°C (68°F to 77°F), at Screening Visit 1 and at least one of 
Visits 2, 3, or 4. 
c. Symptoms of axillary hyperhidrosis for ≥6 months’ duration. 
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 form (if the subject reaches the 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. 
                                                 
1 The HDSM-Ax-7 scale will be conducted using 7 of the 11 items in the HDSM-Ax scale. More specifically, the mean of the 2 items in 
Section 1 and the first 5 items in Section 2 (7 sub-items total) will be used. The mean will be derived by dividing the sum of the 7 item 
scores by 7. For each of the HDSM-Ax sub-items, missing values at EOT will be imputed. HDSM-Ax-7 at EOT will be derived from 
the imputed values. 


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6. Sexually active females of childbearing potential (FOCBP)* who are engaging in sexual activity 
that can cause pregnancy must agree to periodic pregnancy testing and use a medically acceptable 
method of contraception for the duration of the study. This includes perimenopausal women who are 
less than 12 months from their last menses. Acceptable contraceptive methods include the 
following: 
a. Abstinence for the duration of the study, or where partner is sterile (e.g., vasectomy); OR 
b. Hormonal contraception, including oral, injectable, or implantable methods started ≥2 
months prior to screening; OR 
c. Non-hormonal contraception, including intrauterine devices (≥1-week status post 
placement), or properly used barrier methods (e.g., male or female condoms with or without 
spermicide, cervical cap/diaphragm with spermicide). 
* 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).  
Exclusion Criteria 
The following criteria will exclude a subject from participating in this study: 
1. In the Investigator’s opinion, diagnosis of 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) for the treatment of axillary hyperhidrosis 
within the specified timeframe: 
a. Botulinum toxin to the axillary area within 9 months of GSP1 (Visit 2). 
b. Prior treatment with axillary iontophoresis within 4 weeks of GSP1 (Visit 2). 
c. Axillary thermolysis, sympathectomy, or any other treatment with a medical device or 
surgical procedure of the axillary area at any time in the past. Prior axillary laser hair 
removal is permitted if more than 28 days prior to GSP1 (Visit 2). 
d. 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 GSP1 (Visit 2). 
However, a subject who has been on a stable dose (in the opinion of the Principal 
Investigator) 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 may be included. Doses of these 
agents should not be altered during the course of the study. 
e. Any topical treatment for hyperhidrosis, requiring a prescription, within 28 days of GSP1 
(Visit 2). 
f. Any over-the-counter topical antiperspirant/deodorant (applied directly to the axilla[e]) 
within 7 days of GSP1 (Visit 2). Non-antiperspirant deodorant will be provided by the 
Sponsor. 
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, oral, inhaled, topical, etc.) within 28 days of GSP1 (Visit 2). 


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4. All oral or topical homeopathic or herbal treatment (i.e., alternative therapies such as sage tablets, 
chamomile, valerian root, and St. John’s wort) within 28 days of GSP1 (Visit 2). 
5. Use of any cholinergic drug (e.g., bethanechol) within 28 days of GSP1 (Visit 2). 
6. Use of any anti-anxiety and/or anti-depressant drugs, psychostimulants (e.g., amphetamine), or 
drugs with known anticholinergic side effects is prohibited with the following exceptions: 
a. A subject who 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 may be 
included. 
b. Psychostimulants may be allowed if the dose has been stable for ≥3 months without change 
in hyperhidrosis frequency or severity. 
c. Drugs with known anticholinergic side effects (taken within the last 28 days), including dry 
mouth or 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 
electronic case report form. The doses of these agents should not be altered during the course 
of the study. 
7. Known cause of hyperhidrosis or known history of a condition that may cause hyperhidrosis 
(i.e., hyperhidrosis secondary to any known cause such as hyperthyroidism, diabetes mellitus, 
medications, etc.). 
8. Subjects with hyperhidrosis symptoms initiated or exacerbated with menopause. 
9. Subjects with unstable type 1 or type 2 diabetes mellitus or thyroid disease, 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. 
10. Subjects with known hypersensitivity to glycopyrrolate, anticholinergics, or any of the components 
of the topical formulation. 
11. Subject is pregnant, lactating, or is planning to become pregnant during the study. 
12. Participating in a study or used an investigational drug or device within 28 days prior to GSP1 
(Visit 2). 
13. Any major illness within 28 days before the screening examination. 
14. 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. 
15. 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 
Approximately 350 subjects, at up to approximately 45 clinical sites in the United States, will be 
randomized to receive either sofpironium bromide gel, 15% or vehicle gel (placebo) in a balanced 1:1 ratio 
in order to obtain approximately 300 evaluable subjects at the end of study. 


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Subjects will apply the investigational product (either sofpironium bromide gel, 15% or vehicle gel) once 
daily at bedtime to each axilla for 42 consecutive days. 
Gravimetric measurements of sweat production and patient-reported outcomes HDSM-Ax-7 and 
Dermatology Life Quality Index (DLQI) (via electronic clinical outcomes assessment [eCOA] technology) 
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 Day 43 visit (End of Treatment) only. Vital signs, local 
tolerability assessments, and adverse events will be collected at each visit. Blood and urine samples will be 
collected and analyzed at the Screening Visit and at the End of Treatment Visit for routine hematology, 
chemistry, and urinalysis parameters. Urine pregnancy testing for FOCBP will be performed at the 
Screening Visit, Baseline Visit, Visit 8 and End of Treatment. 
A total of 13 scheduled visits will take place over approximately 11 to 15 weeks, depending on when the 
Baseline Visit (treatment) is scheduled after the three (3) screening period visits: initial screening, GSP1, 
and GSP2. 
Test Product, Dose, and Mode of Administration 
Either sofpironium bromide gel, 15%; or vehicle gel (placebo) topically applied to the axillae 
Duration of Treatment 
Forty-two days followed by a 14-day post-treatment follow-up visit 
Safety Assessments 
• Physical examination 
• Vital signs 
• Clinical laboratory assessments 
• Urinalysis 
• Collection of adverse events  
• Subject-reported local tolerability assessments  
• Investigator-reported local tolerability assessments  
Efficacy Assessments 
The following assessment measures will be conducted to evaluate the efficacy of sofpironium bromide gel: 
• Hyperhidrosis Disease Severity Measurement-Axillary (HDSM-Ax-7) as measured by the subject 
(for subjects 12 years of age) 
• Hyperhidrosis Disease Severity Measurement-Axillary, Child (HDSM-Ax-7, Child) as measured by 
the subject (for subjects 9 to <12 years of age) 
• Gravimetrically measured sweat production (GSP) 
• Dermatology Life Quality Index (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 as Question #6 of HDSM-Ax at each assessment  
† Administered as Question #7 of HDSM-Ax at the Day 43 visit only 
 


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Statistical Methods 
Analysis Populations 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) Population will include all subjects who were randomized. Subjects will be 
analyzed according to the treatment group to which they were randomized, regardless of post randomization 
protocol deviations, including no treatment or wrong treatment received. 
Per-Protocol Population 
The Per-Protocol (PP) Population will be a subset of the ITT Population and will include subjects who meet 
the following criteria: 
• Meets all inclusion/exclusion criteria 
• Has not taken or applied any interfering concomitant medications 
• Completed the following visits: 
o Visit 2 GSP 1, and the required GSP data collection  
o Visit 3 GSP 2, and the required GSP data collection  
o Visit 4 (Day 1) Re-screening/Baseline GSP 3 and HDSM-Ax, and the required GSP and HDSM-
Ax data collection  
o Visit 10 (GSP 4) Day 41 (± 2 days), and the required GSP data collection  
o Visit 11 (GSP 5) Day 42 (± 2 days), and the required GSP data collection 
o Visit 12 (GSP 6) Day 43 (± 2 days) and HDSM-Ax, and the required GSP and HDSM-Ax data 
collection  
Safety Population 
The Safety Population will include all subjects randomized in the study who received study drug at least 
once. Subjects will be analyzed according to the treatment actually received. If a subject receives any 
sofpironium bromide gel, 15%, the subject will be analyzed in the sofpironium bromide gel group. 
Otherwise, the subject will be included in the vehicle group. 
Efficacy 
Co-Primary Efficacy Endpoints: 
• The proportion of subjects achieving at least a 2-point improvement in the HDSM-Ax-7 scale score 
from baseline to end of treatment (EOT). 
• The change in GSP from baseline to EOT. 
Primary Efficacy Analyses: 
The primary efficacy analysis will be performed on the ITT population. Both comparisons will be 
conducted using two-sided tests at an alpha=0.05 level. Both endpoints will need to demonstrate a 
statistically significant positive result in favor of the sofpironium bromide gel, 15% for the study to be 
considered successful.  
The HDSM-Ax-7 co-primary endpoint will be analyzed using a logistic regression model with the 
following covariates: treatment, baseline HDSM-Ax-7 total score, and analysis center. 


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The GSP co-primary endpoint will be analyzed using an analysis of covariance (ANCOVA) model with 
fixed effects for treatment, baseline ranked GSP, and analysis center. The ANCOVA may use rank-
transformed or continuous data, pending the outcome of the Shapiro Wilk Normality test. The normality 
test will be performed prior to multiple imputation and separately for each arm. Should the normality 
assumption be violated for either arm, the primary analysis will use rank-transformed GSP data. If the 
normality assumption holds for both arms, the primary analysis will use continuous GSP data. 
Methods for handling missing data for the Co-Primary Efficacy Endpoints 
Before performing the primary analysis for the ITT population, missing EOT HDSM-Ax-7 and GSP values 
for the sofpironium bromide gel, 15% arm will be imputed for the co-primary efficacy endpoints by 
multiple imputations using a control-based imputation (CBI) model approach. Whereas, multiple 
imputations for missing values in the vehicle group will be performed assuming missing at random (MAR). 
For the GSP endpoint in particular, in order to ensure that the missing data imputation method is robust to 
outliers, data from subjects that meet the criterion for being an outlier will be removed from the imputation 
sampling database (i.e., the existing vehicle database).  
Sensitivity Analyses of the Co-Primary Efficacy Endpoints 
To further explore the robustness of the primary analysis results to different missing data assumptions, 
analyses using two more imputation methods will be performed: a missing data imputed to failure approach 
for the HDSM-Ax-7 co-primary endpoint, and a tipping point analysis for both the HDSM-AX-7 and GSP 
co-primary endpoints. Additionally, the ranked GSP and non-rank transformed GSP ANCOVA analyses 
will be repeated without imputing missing data, and again after removing outlier data. To further support 
the results of the co-primary endpoint HDSM-Ax-7, analysis of the 7 individual items in the scale will be 
conducted. 
Secondary Efficacy Endpoints: 
• The proportion of subjects achieving at least a 1-point improvement in the HDSM-Ax-7 scale score 
from baseline to EOT. 
• The proportion of subjects achieving at least a 2-point improvement in the HDSM-Ax-7 scale score 
from baseline to EOT and achieving at least a 70% reduction in GSP from baseline to EOT. 
• The proportion of subjects achieving at least a 1-point improvement in the HDSM-Ax-7 scale score 
from baseline to EOT and achieving at least a 50% reduction in GSP from baseline to EOT. 
A gated, fixed-sequence testing procedure will be used to control the overall familywise error rate for the 
primary and secondary analyses. Testing will be performed first for the two co-primary endpoints. If both 
null hypotheses are rejected at the 2-sided 0.05 significance level in favor of sofpironium bromide gel, 15%, 
secondary efficacy endpoints will be tested in the order as specified above. Testing will continue only if all 
previously tested null hypotheses of no difference have been rejected at the 2-sided 0.05 significance level 
in favor of sofpironium bromide gel, 15%.  
The secondary efficacy endpoints will be analyzed using methods similar to what is described for the 
co-primary endpoints. 
Method of Pooling Sites to Generate Analysis Centers 
Subjects from low enrolling sites will be pooled in order to generate analysis centers. The minimum number 
of subjects per analysis center is 10. The lowest enrolling site will be combined with the largest enrolling 


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site that does not meet the minimum requirement, and then the second lowest enrolling site and the second 
largest enrolling site will be combined, and so on. Further combining will be done until all analysis centers 
have at least 10 subjects. All analyses that are controlled for site will use this analysis center designation. 
Full details will be provided in the statistical analysis plan. 
Psychometric Analysis of the HDSM-Ax-7-Item 
In parallel to the traditional statistical analysis, psychometric evaluation of the HDSM-Ax-7-Item will be 
carried out to confirm the most appropriate HDSM-Ax-7-Item 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 variables such as items 4 and 5 of the HDSM-Ax-7-Item, PGI-S, PGI-C, and GSP), stability, 
reliability, ability to detect change, and interpretability of clinical trial results. 
Safety 
Safety analysis will be performed by treatment received for the Safety Population. Treatment-emergent 
adverse event (TEAE) descriptions will be mapped to standard terms, i.e., Medical Dictionary for 
Regulatory Activities (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 cumulatively 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, (d) TEAEs leading to protocol treatment discontinuation, (e) protocol treatment-related 
serious TEAEs, (f) severe TEAEs, (g) TEAEs leading to dose interruption, (h) TEAEs of special interest, 
and (i) anticholinergic TEAEs.   
At each visit, local tolerability assessments will be descriptively summarized by severity. An overall 
summary table will also be presented with subject incidences tabulated according to the worst severity 
experienced while on study. In addition, at each post-baseline visit, local tolerability will be summarized as 
cumulative shift tables versus 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, median, minimum, 
maximum) for values obtained at Visit 1 and Visit 12.  Whereas, vital signs will be summarized in a similar 
manner at each visit.  
Sample Size and Power Estimation  
Sample size estimation was performed for the co-primary efficacy endpoints based on the results of a 
Phase 2b study (BBI-4000-CL-203): 
• HDSM-Ax-7 responder analysis: 2-point improvement response rates of 29.8% and 53.7% were 
assumed for the vehicle and sofpironium bromide gel, 15% arms, respectively. The power is 0.95 
with 116 subjects per arm and a total of 232 subjects. 
• GSP: using rank transformed GSP data for change from baseline to EOT, a difference of 16.6 in 
mean ranks between the vehicle and sofpironium bromide gel, 15% arms, with a pooled standard 
deviation of approximately 39.5, was used for this purpose. Normal approximation yielded a sample 
size estimate of 296 subjects for the study, 148 each arm, in order to achieve 0.95 power for the GSP 
co-primary endpoint. 


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A chi-square test for the HDSM-Ax-7 endpoint and a two-sample t-test for the GSP endpoint were used to 
estimate the above sample size and power for each endpoint. With approximately 300 evaluable subjects, 
the overall study power to demonstrate a statistically significant treatment effect (two-sided p < 0.05) for 
both co-primary efficacy endpoints simultaneously is greater than 0.90 (with greater than 0.95 power for 
each of HDSM-Ax-7 and GSP).  
Additionally, sample size estimation was also performed using non-rank-transformed GSP data. An 
expected mean treatment difference of 73 mg with a pooled standard deviation of approximately 170 was 
used for this purpose. This yielded a reduced sample size estimate compared with the target of 300 subjects 
completing the co-primary efficacy assessments in order to achieve 0.95 power for GSP, further indicating 
that our sample size estimations are conservative. 
Assuming missing data from approximately 15% of subjects, a total of 350 subjects will be targeted for 
enrollment.   
 
 


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ABBREVIATIONS 
ADME 
Absorption, distribution, metabolism, excretion 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
BPH 
Benign prostatic hyperplasia 
CBI 
Control-based imputation 
CFR 
Code of Federal Regulations 
CRF 
Case report form 
CRO 
Contract research organization 
DLQI 
Dermatology Life Quality Index 
ECG 
Electrocardiogram 
eCOA 
Electronic clinical outcome assessment 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
FOCBP 
Female of childbearing potential 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transpeptidase 
GSP 
Gravimetric sweat production 
HDSM-Ax 
Hyperhidrosis Disease Severity Measure-Axillary 
HDSS 
Hyperhidrosis Disease Severity Scale 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
Heart rate 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
I/E 
Inclusion/exclusion 
IEC 
Institutional Ethics Committee 
IRT 
Interactive Response Technology 
IND 
Investigational New Drug Application 


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IP 
Investigational product 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IUD 
Intrauterine device 
IV 
Intravenous  
LS 
Least squares 
MAR 
Missing at random 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 
MNAR 
Missing not at random 
NF 
National Formulary 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
PK 
Pharmacokinetic(s) 
PT 
Preferred term 
RBC 
Red blood cell 
REML 
Restricted maximum likelihood 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAR 
Suspected adverse reaction 
SOC 
System organ class 
SSRI 
Selective serotonin re-uptake inhibitor 
TEAE 
Treatment-emergent adverse event 
UPT 
Urine pregnancy test 
US 
United States 
USP 
United States Pharmacopeia 
WBC 
White blood cell 
 


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1 
BACKGROUND AND CLINICAL RATIONALE 
Hyperhidrosis is a disorder of excessive sweating beyond what is expected for thermoregulatory needs and 
environmental conditions. Primary hyperhidrosis (excessive sweating without an alternative origin) is localized, 
characteristically symmetric, and may involve several anatomic areas such as armpits, hands, and feet. It affects 
approximately 4.8% of the United States (US) population (Doolittle, 2016) and is believed to be caused by an 
overactive cholinergic response of the sweat glands. Current therapies have limited efficacy, significant side 
effects, and/or are invasive and costly.  
Oral and topical anticholinergic drugs, such as glycopyrrolate, have been used to treat hyperhidrosis. The main 
limitations of these drugs are systemic anticholinergic side effects (e.g., blurred vision, dizziness, dry mouth, 
constipation, urinary retention, and tachycardia). Sofpironium bromide is a novel, soft-anticholinergic ester 
analog of glycopyrrolate and is in development for the topical treatment of axillary 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, and as a soft drug, is designed to provide maximal therapeutic 
effect with minimal side effects. Please refer to the sofpironium bromide gel Investigator’s Brochure for more 
information. 
In the current multicenter, randomized, double-blinded, vehicle-controlled, pivotal, Phase 3 study, Brickell is 
studying the safety, tolerability, and efficacy of topically applied sofpironium bromide gel, 15%, in subjects with 
primary axillary hyperhidrosis over a 6-week period, followed by a 2-week follow-up period.  
Nonclinical Safety Conclusions 
A comprehensive battery of pharmacology, safety pharmacology, absorption, distribution, metabolism, excretion 
(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 topical clinical 
route of administration. 
Overall, the results of the nonclinical program support the safe use of sofpironium bromide gel at the intended 
maximum dosage for the treatment of primary axillary hyperhidrosis. Please refer to the sofpironium bromide gel 
Investigator’s Brochure for additional information pertaining to the nonclinical studies. 
Prior Human Experience 
Brickell and its partner company (Kaken Pharmaceutical, Japan) have conducted multiple clinical studies of 
sofpironium bromide gel that encompass over 1300 subject exposures. These studies have evaluated the safety, 
tolerability, pharmacokinetics (PK), and efficacy of sofpironium bromide gel in adult and pediatric primary 
hyperhidrosis patients and healthy adult subjects. Please refer to the sofpironium bromide gel Investigator’s 
Brochure for more detailed descriptions and results of the clinical studies. 
Clinical Safety Conclusions  
In studies conducted to date, three concentrations of sofpironium bromide gel, 5%, 10%, and 15%, demonstrated 
comparably acceptable safety and tolerability. Treatment-emergent adverse events (TEAEs) were mostly mild or 
moderate in severity with fewer subjects reporting TEAEs in the 5% gel group relative to the 10% and 15% gel 
groups. No deaths or drug-related serious adverse reactions have been reported in any sofpironium bromide gel 
clinical studies. Six serious adverse events have been reported and all were determined to be unrelated to 


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sofpironium bromide gel administration. 
Consistent with the soft drug design, a low incidence of systemic anticholinergic adverse events (AEs) has been 
found in all clinical studies of sofpironium bromide gel. The most common anticholinergic AE was dry mouth, 
and all anticholinergic AEs were expected. Of note, the anticholinergic AEs were predominantly mild or 
moderate in severity and transient in duration (i.e., resolving gradually with continued use). All TEAEs 
completely resolved spontaneously with treatment discontinuation. Local application site tolerability reactions of 
burning, itching, pain, erythema, and dryness at the axillae were predominantly minimal in severity and typically 
transient.  
Clinical Efficacy Conclusions  
Overall, all three sofpironium bromide gel concentrations, 5%, 10%, and 15%, have exhibited a larger absolute 
mean reduction in gravimetric sweat production (GSP) from baseline to end of treatment (EOT) compared with 
vehicle. Better improvement in GSP response was associated with higher concentrations of sofpironium bromide. 
However, while there was a slight trend toward dose response, all gel concentrations were essentially equivalent 
in patient-reported outcome measures based on the Hyperhidrosis Disease Severity Measure-Axillary 
(HDSM-Ax), Dermatology Quality of Life Index (DLQI), and Hyperhidrosis Disease Severity Score (HDSS), 
suggesting that all three concentrations are efficacious. The response was seen as early as Day 8 and remained 
consistent throughout the applicable treatment period. 
Clinical Pharmacokinetics Conclusions  
In PK studies conducted to date, both sofpironium and its major metabolite BBI-4010 could be measured in the 
majority of subjects. Systemic exposure to sofpironium and BBI-4010 appeared to increase in an approximately 
dose-proportional manner when comparing 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). Sofpironium accumulation after Day 1 was not observed. Plasma concentrations of 
BBI-4010 appeared to be lower than those of sofpironium. Steady state is likely reached within the first 24 hours. 
In general, 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 0.05 ng/mL for both sofpironium and BBI-4010.  
Risk to Subjects  
As an anticholinergic drug, administration of sofpironium bromide gel could be associated with signs or 
symptoms typical of anticholinergic effect such as dry mouth, blurred vision, dizziness, constipation, urinary 
retention, or tachycardia. The previous sofpironium bromide exposure to humans has demonstrated a low 
incidence of these effects, which are generally mild in severity. All such effects have been observed, and as 
expected, to be transient. 
2 
STUDY DESIGN 
This is a multicenter, randomized, double-blinded, vehicle-controlled, Phase 3 study to evaluate the safety and 
efficacy of topically applied sofpironium bromide gel, 15% in subjects with primary axillary hyperhidrosis. 
Approximately 350 subjects, at up to approximately 45 clinical sites in the US, will be enrolled to obtain 
approximately 300 evaluable subjects at the end of study. 


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Subjects will be randomized 1:1 to receive sofpironium bromide gel, 15% or vehicle gel (175 subjects dosed with 
15% gel and 175 subjects dosed with vehicle gel). Subjects will apply the investigational product once daily at 
bedtime to their axillae for 42 consecutive days. 
Patient-reported outcomes HDSM-Ax, Patient Global Impression of Severity (PGI-S), Patient Global Impression 
of Change (PGI-C; EOT only), and DLQI, as well as Investigator-reported GSP, will be recorded during the 
study at predefined time points. Vital signs and local tolerability assessments will be collected at Visits 4 through 
9 and Visits 12 (EOT) and 13. Adverse events will be collected at each post-Screening visit. Blood and urine 
samples will be collected and analyzed at Screening and Visit 12/EOT for routine hematology, chemistry, and 
urinalysis parameters. Additionally, a urine pregnancy test (UPT) for females of child-bearing potential (FOCBP) 
will be collected and analyzed at Visits 1, 4, 8, and 12. 
A total of 13 scheduled visits will take place over approximately 11 to 15 weeks, depending on when the Baseline 
Visit (treatment) is scheduled after the three (3) screening period visits: initial screening, GSP1, and GSP2. See 
Section 7.1 for an events table of this study.   
3 
STUDY OBJECTIVES AND ASSESSMENTS 
The purpose of this Phase 3 study is to assess the safety, local tolerability, and efficacy of sofpironium bromide 
gel, 15% when applied topically in subjects with primary axillary hyperhidrosis.  
3.1 
Study Objectives 
• To evaluate the safety and local tolerability of sofpironium bromide gel, 15% when applied topically to 
subjects with primary axillary hyperhidrosis.  
• To evaluate the effect of sofpironium bromide gel, 15% on hyperhidrosis disease severity as it relates to 
sweat production, patient-reported outcomes, and quality of life self-assessments. 
3.2 
Study Assessments 
Safety Measures: 
The following safety assessment measures will be conducted to evaluate the safety and local tolerability of 
sofpironium bromide gel, 15%: 
• Physical examination 
• Vital signs 
• Clinical laboratory assessments 
• Urinalysis 
• Collection of AEs 
• Subject-reported local tolerability assessments 
• Investigator-reported local tolerability assessments 
Efficacy Assessments: 
The following assessment measures will be conducted to evaluate the efficacy of sofpironium bromide gel, 15%: 
• HDSM-Ax 7-Item (HDSM-Ax-7) as measured by the subject (for subjects 12 years of age) 
• Hyperhidrosis Disease Severity Measurement-Axillary, Child (HDSM-Ax-7, Child) as measured by the 
subject (for subjects 9 to <12 years of age) 


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• GSP 
• 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 as Question #6 of HDSM-Ax at each assessment  
† Administered as Question #7 of HDSM-Ax at the Day 43 visit only 
 
4 
STUDY POPULATION 
4.1 
Number of Subjects  
Approximately 350 subjects, at up to approximately 45 clinical sites, will be randomized to receive either 
sofpironium bromide gel, 15% or vehicle gel in a 1:1 ratio to obtain approximately 300 evaluable subjects at the 
end of study. 
4.2 
Inclusion Criteria 
Subjects must fulfill all of the following criteria to be eligible for study admission: 
1. 0DOHRUIHPDOHVXEMHFW9 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-72 of 3-4 inclusive at both of the Screening visits (Visits 1 and 4) 
b. Gravimetric test indicating a minimum of 50 mg of sweat production at rest in each axilla with a 
two-axilla combined total of at least 150 mg of sweat production in five (5) minutes at room 
temperature, 20°C to 25°C (68°F to 77°F), at Screening Visit 1 and at least one of Visits 2, 3, or 4 
c. Symptoms of axillary hyperhidrosis for ≥6 months’ duration 
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 form (if the subject reaches the 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)* who are engaging in sexual activity that can 
cause pregnancy  must agree to periodic pregnancy testing and use a medically acceptable method of 
                                                 
2 The HDSM-Ax-7 scale will be conducted using 7 of the 11 items in the HDSM-Ax scale. More specifically, the mean of the 2 items in 
Section 1 and the first 5 items in Section 2 (7 sub-items total) will be used. The mean will be derived by dividing the sum of the 7 item 
scores by 7. For each of the HDSM-Ax sub-items, missing values at EOT will be imputed. HDSM-Ax-7 at EOT will be derived from 
the imputed values. 


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contraception for the duration of the study. This includes perimenopausal women who are less than 12 
months from their last menses. Acceptable contraceptive methods include the following:  
a. Abstinence for the duration of the study, or where partner is sterile (e.g., vasectomy); OR 
b. Hormonal contraception, including oral, injectable, or implantable methods started ≥2 months 
prior to screening; OR 
c. Non-hormonal contraception, including intrauterine devices (IUD; ≥1 week status post 
placement), or properly used barrier methods (e.g., male or female condoms with or without 
spermicide, cervical cap/diaphragm with spermicide). 
*  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).  
4.3 
Exclusion Criteria 
Meeting any of the following criteria will exclude a subject from participating in this study: 
1. In the Investigator’s opinion, diagnosis of 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, boils or sinus tracts, significant scarring, or open wounds). 
2. Prior use of any prohibited medication(s) or procedure(s) for the treatment of axillary hyperhidrosis 
within the specified timeframe: 
a. Botulinum toxin to the axillary area within 9 months of GSP1 (Visit 2). 
b. Prior treatment with axillary iontophoresis within 4 weeks of GSP1 (Visit 2) 
c. Axillary thermolysis, sympathectomy, or any other treatment with a medical device or surgical 
procedure of the axillary area at any time in the past. Prior axillary laser hair removal is permitted 
if more than 28 days prior to GSP1 (Visit 2). 
d. 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 GSP1 (Visit 2). However, a subject 
who has been on a stable dose (in the opinion of the Principal Investigator) 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 may be included. Doses of these agents should not be altered during the 
course of the study. 
e. Any topical treatment for hyperhidrosis, requiring a prescription, within 28 days of GSP1 
(Visit 2). 
f. Any over-the-counter topical antiperspirant/deodorant (applied directly to the axilla[e]) within 
7 days of GSP1 (Visit 2). Non-antiperspirant deodorant will be provided by the Sponsor. 
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 GSP1 (Visit 2).   
4. All oral or topical homeopathic or herbal treatment (i.e., alternative therapies such as sage tablets, 
chamomile, valerian root, and St. John’s wort) within 28 days of GSP1 (Visit 2). 


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5. Use of any cholinergic drug (e.g., bethanechol) within 28 days of GSP1 (Visit 2). 
6. Use of any anti-anxiety and/or antidepressant drugs, psychostimulants (e.g., amphetamine), or drugs with 
known anticholinergic side effects is prohibited with the following exceptions: 
a. A subject who has been on a stable dose of an anti-anxiety and/or antidepressant drug and has not 
had a recent change in hyperhidrosis frequency or severity for 3 months may be included.   
b. Psychostimulants may be allowed if the dose has been stable for 3 months without change in 
hyperhidrosis frequency or severity. 
c. Drugs with known anticholinergic side effects (taken within the last 28 days) including dry mouth 
or 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 electronic case 
report form (eCRF). The doses of these agents should not be altered during the course of the study. 
7. Known cause of hyperhidrosis or known history of a condition that may cause hyperhidrosis 
(i.e., hyperhidrosis secondary to any known cause such as hyperthyroidism, diabetes mellitus, 
medications, etc.). 
8. Subjects with hyperhidrosis symptoms initiated or exacerbated with menopause. 
9. Subjects with unstable type 1 or type 2 diabetes mellitus or thyroid disease, 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. 
10. Subjects with known hypersensitivity to glycopyrrolate, anticholinergics, or any of the components of the 
topical formulation. 
11. Subject is pregnant, lactating, or is planning to become pregnant during the study.  
12. Participating in a study or used an investigational drug or device within 28 days prior to GSP1 (Visit 2). 
13. Any major illness within 28 days before the screening examination. 
14. 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. 
15. 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 
hydroxypropyl 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 


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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 
(Visit 4) and Day 22 (Visit 7).  
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. 
Investigational product should be stored at controlled room temperature 68oF to 77oF (20oC to 25oC) with brief 
excursions 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. 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, 15%, or vehicle gel (placebo) to topically apply, once daily at bedtime, to each axilla 
using the supplied applicators for 42 consecutive days. 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 axilla dose application. Each full actuation of the pump corresponds to 
approximately 86.5 mg of sofpironium bromide in 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., Visit 12). 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, and dispensed at both the Baseline Visit (Visit 4, Day 1) and Visit 7 (Day 22) for a total of 2 containers 


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dispensed. Each of the 2 containers previously dispensed will be returned by the subject at a next respective visit 
(Visit 7 and Visit 12 [EOT]), weighed with the cap on, and weight recorded per the unique bottle number. At the 
End of Treatment visit (Visit 12), the subject will bring the 2nd 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. 
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. Thoroughly wash both hands and rinse the plastic applicator. 
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 grooming habits as follows: 
o 
Do not shower, shave, or wash the underarm area for at least 8 hours AFTER study product 
application. 
o 
Shaving of the underarm area should be done at least 8 hours BEFORE study product application. 
o 
If the subject takes a shower or washes the underarm area at night then it should be at least 
30 minutes before study product application. 
o 
Subjects should 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 the supplied non-antiperspirant 
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. 


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• 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. 
On the day of a clinic study visit: 
• Showering and shaving in the morning is permissible. 
• Do not apply any product to the axilla (including Sponsor-supplied non-antiperspirant deodorant). 
• Exercise is to be avoided (e.g., gym, jogging, etc.). 
• Avoid caffeine and tea until the gravimetric assessments are completed. 
5.4 
Procedures for Blinding and Unblinding 
This is a double-blind study. All study treatments (sofpironium bromide gel, 15%, and vehicle gel) are identical in 
color, shape, size, and packaging in order to maintain the blind.  
Subjects, Sponsor personnel, Investigator staff, persons performing the assessments, clinical operations personnel, 
data analysts, and personnel at central laboratories will remain blinded to the identity of the treatment from the time of 
randomization until database lock and unblinding, using the following methods: (1) randomization data will be 
maintained by a third party, kept strictly confidential until the time of unblinding, and will not be accessible by anyone 
involved in the study; (2) the identity of the treatments will be concealed by the use of study treatments that are 
identical in packaging, labeling, schedule of administration, and appearance. 
The treatment assignments for all enrolled subjects will be unblinded only after the conclusion of the study. 
Specifically, the blind will be broken only after all data are verified, entered into the database, and validated; subject 
evaluability assessments are performed and entered into the database; and the database is locked. In the case of a 
medical emergency, the Investigator can break the blind for the subject involved preferably by first discussing the 
situation with the medical monitor and the Sponsor (or designee) immediately. After confirmation, the Investigator 
will be contacted with unblinding information by a Sponsor representative. The Investigator will record the code break 
in the subject’s source documents. 
6 
CONCOMITANT MEDICATIONS/TREATMENTS 
Information will be recorded on concomitant medications/treatments (e.g., aspirin, Tylenol, birth control pills, 
intrauterine device [IUD], vitamins) taken during study participation, or which may require a washout for study 
participation. 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). The Sponsor-supplied non-antiperspirant deodorant should not be applied within 8 hours following 
the application of study product (suggest applying in the morning). 


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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.  
Prior to the inclusion of a subject in the study, as specified in Sections 4.2 and 4.3 (inclusion/exclusion 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 
o iontophoresis 
• 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 
(inclusion/exclusion criteria) including the following: 
o serotonergic agonists (or drugs that increase serotonin activity including SSRIs)  
o beta-blockers  
o alpha-adrenergic agonists (clonidine)  
o dopamine partial agonists  
o tricyclic antidepressants  
o anti-anxiety and/or other anti-depressant drugs  
o amphetamine products 
o drugs with known anticholinergic side effects. 
7 
PROCEDURES 
The timing of each assessment is listed in the Time and Events Table (Section 7.1).   
Each subject will report for 13 distinct visits (over 11-15 weeks).  
All Screening assessment results must be completed and reviewed prior to the GSP1 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 GSP1 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 


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phase of the study, the Investigator or designee will contact the Medical Monitor to address such subjects on a 
case-by-case basis. 
 
In the event of restrictions due to COVID-19, or any other pandemic, the Sponsor may, with IRB approval where 
required, during the study implement some or all study assessments and procedures associated with patient visits 
to be conducted remotely or by home visits (per FDA Guidance on Conduct of Clinical Trials of Medical 
Products during COVID-19 Public Health Emergency, March 2020) when the patients’ ability to visit 
investigator sites is impacted. 
 


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7.1 
Time and Events Table 
Visit  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10  
11  
12  
13  
PROCEDURE  
Screening 
 
 
Rescreening / 
Baseline 
 
 
 
 
 
 
 
End of 
Treatment 
Follow-up 
Gravimetric Timepoint  
 
GSP 
11 
GSP 
21 
GSP 
31 
 
 
 
 
 
GSP 
4 
GSP 
5 
GSP 
6 
 
Day  
(allowable window)  
Up to  
 31 days 
prior to  
GSP1   
  
(Day 1) 
Day   
8   
(± 2)  
Day  
15   
(± 2)  
Day  
22   
(± 2)  
Day  
29   
(± 2)  
Day  
36   
(± 2)  
Day  
41   
(±2)  
Day  
42   
(± 2)  
Day  
43   
(± 2)  
Day  
57   
(± 3)  
Informed Consent/Assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History, Demographics 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
Physical Exam 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Vital Signs (blood pressure, heart rate, 
respiratory rate, and temperature) 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
I/E Criteria 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
Gravimetric Assessments2,3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HDSM-Ax4,5 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DLQI6 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
Local Tolerability Assessments7 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization8 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Non-antiperspirant Deodorant Dispensed9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Investigational Product10 (IP) Dispensed / 
Returned 
 
 
 
X 
 
 
X 
 
 
 
   
X 
 
IP Weight11 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
Compliance Evaluation 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Safety Labs (hematology, chemistry, and 
urinalysis) 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
UPT (females of childbearing potential 
only)12 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Optional End of Study Patient Survey13  
 
 
 
 
 
 
 
 
 
 
 
 
X 


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Abbreviations: DLQI = Dermatology Life Quality Index; FOCBP = females of child-bearing potential; HDSM-Ax = Hyperhidrosis Disease Severity 
Measure-Axillae; I/E = inclusion/exclusion; IP = investigational product; PGI-C = Patient Global Impression of Change; PGI-S = Patient Global 
Impression of Severity; UPT = urine pregnancy test 
1 Visit 2 should occur no more than 31 days after the initial screening visit (Visit 1); both Visits 2 and 3 should occur within 14 days of 
rescreening/baseline Visit 4. Visit 4 will correspond to Day 1. 
2 Gravimetric assessments for all visits will be conducted from 7:00am-11:00am.  
3 One 5-minute gravimetric assessment will be conducted for each axilla.  
4 PGI-S will be administered as Question #6 of HDSM-Ax at every assessment; PGI-C will be administered as Question #7 of HDSM-Ax at the Day 43 
visit only. 
5 Version of HDSM-Ax questionnaire to EHDGPLQLVWHUHGDFFRUGLQJWRVXEMHFWDJHWRޒ\HDUVRU\HDUVof age). 
6 7KH'/4,ZLOOEHDGPLQLVWHUHGWRVXEMHFWV\HDUVRIDJH. 
7 Investigator assessments to be performed after the Subject assessments.  
8 Randomization will take place only after the subject is qualified at the Rescreening Visit (Visit 4).   
9 Non-antiperspirant deodorant will be dispensed at the Screening Visit (Visit 1) and resupplied as needed throughout the study. 
10 Pump container 1 of 2 to be primed, weighed, and dispensed to subject at Baseline (Visit 4). Pump 2 of 2 to be primed, weighed, and dispensed to 
subject at Day 22 (Visit 7). Written instructions for nightly dosing will be given to the subject. Subjects will apply their first dose of gel prior to 
bedtime the night of their Baseline visit. Instruct the subjects to return Pump container 1 of 2 at Day 22 (Visit 7) and Pump container 2 of 2 at 
Day 43 (Visit 12, End of Treatment).    
11 Pump container 1 of 2 will be weighed with the applicator cap on after priming at Baseline prior to dispensing to the subject and upon return at 
Day 22 (Visit 7). Pump container 2 of 2 will be weighed with the applicator cap on after priming at Day 22 (Visit 7) prior to dispensing to the 
subject and upon return at Day 43 (Visit 12, End of Treatment).    
12 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). 
13 2SWLRQDOHQGRIVWXG\VXUYH\ZLOOEHRIIHUHGWRVXEMHFWV\HDUVRIDJH.


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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 45 days prior to Visit 4 (Rescreening/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.   
• Subject to complete the GSP assessment. 
o GSP assessments for all visits will be conducted from 7:00 am to 11:00 am. 
o One 5-minute GSP assessment will be conducted for each axilla. 
o Refer to Appendix 1 for instructions and requirements of sample collection and handling. 
• Subject to complete the HDSM-Ax assessment.  
o Five multi-part questions and PGI-S question (administered as Question #6 at the end of the 
HDSM-Ax questionnaire) to be completed by the subject prior to other assessments.  
o Refer to Appendix 2 (HDSM-Ax) and Appendix 3 (HDSM-Ax Child) 
• 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 8.1.3).  
• Review concomitant medications/treatments and assess for washouts.  
• Provide subject with the Sponsor-provided non-antiperspirant deodorant. Resupply as needed throughout 
subject study participation.  
• Schedule the subject to return for Visit 2 (GSP1) after any washout has been completed; must be within 
31 days of Visit 1 (Screening).  
In the event a subject does not satisfy the sweat production eligibility (Inclusion criterion 2b) at the Screening 
Visit but is otherwise eligible to continue (i.e., satisfies all other eligibility requirements including HDSM-Ax 
severity but may still require a washout), the Screening GSP may be retested once during the screening period at 
the discretion of the Investigator:   
• 
Retest must occur within the 31 days from Screening (Visit 1) and must occur prior to GSP1 
(Visit 2).   
• 
HDSM-Ax must also be completed at the time of the Screening GSP retest.   
• 
If subject does not meet inclusion based on GSP and HDSM-Ax results at the time of the retest, the 
subject shall be screen failed and may not be rescreened.  
The subject shall be reminded that, on the day of each clinic study visit:   
• Showering in the morning is permissible.  
• Do not apply any product to the axilla (including Sponsor-supplied deodorant).  
• Exercise is to be avoided (e.g., gym, jogging, etc.).  
• Avoid caffeine and tea until the gravimetric assessments are completed. 


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7.2.2 
Visits 2 and 3: GSP1 and GSP2  
Visit 2 should occur no more than 31 days after the initial screening visit (Visit 1); both Visits 2 and 3 should 
occur within 14 days of Rescreening/Baseline Visit 4. Any washouts required for prohibited medications (see 
Section 4.3) must be completed prior to Visit 2 (GSP1).  
The following activities will be conducted: 
• Subject to complete the GSP assessment; will be conducted from 7:00 am to 11:00 am. 
• Review the subject’s health (AEs). 
• Review concomitant medications/treatments. 
• Schedule the subject to return for the next study visit.  
7.2.3 
Visit 4: GSP3 (Day 1; Rescreening/Baseline) +14 Days of Visit 2 
No more than 14 days may elapse between Visit 2 (GSP1) and Visit 4 (GSP3; Day 1).    
The following activities will be conducted: 
• Collect and review subject medical history and demographics.  
• Perform physical examination 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 
VHDWHGIRUPLQXWHV 
• Assess inclusion/exclusion criteria.   
• Subject to complete the GSP assessment; will be conducted from 7:00 am to 11:00 am. 
• Subject to complete the HDSM-Ax assessment.  
o Subject to complete PGI-S administered as Question #6 at the end of the HDSM-Ax questionnaire. 
• Subjects  17 years of age to complete the DLQI questionnaire. 
o 10 questions to be completed by the subject. 
o Refer to Appendix 4. 
• Perform local tolerability assessments (see Section 8.1.5).  
• 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. 
• Provided the subject has passed all inclusion/exclusion criteria, randomize the subject according to 
separate instructions.   
• Pull from inventory the pump container whose unique identifier matches that assigned by the IRT system 
at randomization. Record the unique IP gel pump container number on the source document. Dispense 
study product container 1 (of 2) to the subject as follows: 
o Write subject number and initials on the study product container label.  
o Prime the pump (5 actuations) and discard expressed gel.   
o Weigh the primed pump with the applicator cap on 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 subject 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 6). 


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o Instruct subject to apply the first application of study medication at home the evening of Visit 4 
(Baseline visit). 
• Review concomitant medications/treatments. 
• Schedule the subject to return for the next study visit.  
7.2.4 
Visit 5: Day 8 ± 2 Days 
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 (see Section 8.1.2). 
• Subject to complete the GSP assessment; will be conducted from 7:00 am to 11:00 am. 
• Subject to complete HDSM-Ax assessment.   
o Subject to complete PGI-S administered as Question #6 at the end of the HDSM-Ax questionnaire. 
• Perform local tolerability assessments.  
• Review changes to the subject’s health (AEs). 
• Evaluate subject compliance:  
o Ask subjects whether 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.   
• Review concomitant medications/treatments. 
• Schedule the subject to return for the next study visit.   
7.2.5 
Visit 6: Day 15 ± 2 Days  
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 the GSP assessment; will be conducted from 7:00 am to 11:00 am. 
• Subject to complete HDSM-Ax assessment.  
o Subject to complete PGI-S administered as Question #6 at the end of the HDSM-Ax questionnaire. 
• Subject to complete the DLQI questionnaire. 
• Perform local tolerability assessments.  
• Review changes to the subject’s health (AEs). 
• Evaluate subject compliance:  
o Ask subjects whether 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.   
• Review concomitant medications/treatments. 
• Remind subject to bring their study medication to next visit.  
• Schedule the subject to return for the next study visit.   


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7.2.6 
Visit 7: Day 22 ± 2 Days  
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 the GSP assessment; will be conducted from 7:00 am to 11:00 am. 
• Subject to complete HDSM-Ax assessment.  
o Subject to complete PGI-S administered as Question #6 at the end of the HDSM-Ax questionnaire. 
• Perform local tolerability assessments.  
• Review changes to the subject’s health (AEs). 
• Evaluate subject compliance:  
o Ask subjects whether 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 subject’s previously dispensed study product container, weigh with the applicator cap on, and 
record weight of container. 
• Dispense study product container (2 of 2). 
o Access the IRT system to obtain the number of the next assigned pump container to dispense. Pull 
from inventory the pump container whose unique identifier matches that assigned by the IRT 
system. Record the unique IP gel pump container number on the source document.  
o Write subject number and initials on the study product container label.  
o Prime the pump (5 actuations) and discard expressed gel.   
o Weigh the primed pump with the applicator cap on and record in source prior to dispensing to the 
subject.  
• Review concomitant medications/treatments. 
• Schedule the subject to return for the next study visit.   
7.2.7 
Visit 8: Day 29 ± 2 Days  
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 the GSP assessment; will be conducted from 7:00 am to 11:00 am. 
• Subject to complete HDSM-Ax assessment.  
o Subject to complete PGI-S administered as Question #6 at the end of the HDSM-Ax questionnaire. 
• Perform local tolerability assessments.  
• Review changes to the subject’s health (AEs). 
• Evaluate subject compliance:  
o Ask subjects whether 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.   


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• Perform UPT if applicable (FOCBP only). If positive, the subject shall be withdrawn from the study.   
• Review concomitant medications/treatments. 
• Schedule the subject to return for the next study visit.   
7.2.8 
Visit 9: Day 36 ± 2 Days  
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 the GSP assessment; will be conducted from 7:00 am to 11:00 am. 
• Subject to complete HDSM-Ax assessment.  
o Subject to complete PGI-S administered as Question #6 at the end of the HDSM-Ax questionnaire. 
• Perform local tolerability assessments.  
• Review changes to the subject’s health (AEs). 
• Evaluate subject compliance:  
o Ask subjects whether 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.   
• Review concomitant medications/treatments. 
• Schedule the subject to return for the next study visit.   
7.2.9 
Visits 10 and 11: GSP4 (Day 41) ± 2 Days and GSP 5 (Day 42) ± 2 Days  
Visits 10 and 11 will occur as separate visits on Days 41 and 42.      
The following activities will be conducted: 
• Subject to complete the GSP assessment; will be conducted from 7:00 am to 11:00 am. 
• Subject to complete HDSM-Ax assessment.  
o Subject to complete PGI-S administered as Question #6 at the end of the HDSM-Ax questionnaire. 
• Review changes to the subject’s health (AEs). 
• Evaluate subject compliance:  
o Ask subjects whether 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.   
• Review concomitant medications/treatments. 
• At Visit 11, remind subject to bring their study medication to next visit.  
• Schedule the subject to return for the next study visit.   


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7.2.10 
Visit 12: GSP6 (Day 43; End of Treatment) ± 2 Days  
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 the GSP assessment; will be conducted from 7:00 am to 11:00 am. 
• Subject to complete HDSM-Ax assessment.  
o Subject to complete PGI-S administered as Question #6 at the end of the HDSM-Ax questionnaire. 
o Subject to complete PGI-C administered as Question #7 at the end of the HDSM-Ax 
questionnaire. 
• Subject to complete the DLQI questionnaire. 
• Perform local tolerability assessments.  
• Review changes to the subject’s health (AEs). 
• Collect subject’s previously dispensed study product container, weigh with the applicator cap on, and 
record weight of container. 
• Evaluate subject compliance:  
o Ask subjects whether 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).   
• Perform UPT if applicable (FOCBP only). If positive, the subject shall be withdrawn from the study.   
• Review concomitant medications/treatments. 
• Schedule the subject to return for the next study visit.   
7.2.11 
Visit 13: Follow-up (Day 57) ± 3 Days  
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 the GSP assessment; will be conducted from 7:00 am to 11:00 am. 
• Subject to complete HDSM-Ax assessment.  
o Subject to complete PGI-S administered as Question #6 at the end of the HDSM-Ax questionnaire. 
• SubjectV\HDUVRIDJH to complete optional End of Study Survey. 
• Perform local tolerability assessments.  
• Review changes to the subject’s health (AEs). 
• Review concomitant medications/treatments. 
• Discharge subject from the study. 


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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 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. 
• 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, attempt to identify the reason the subject 
withdrew consent and document with particular attention paid to whether an underlying AE is at cause.  
• The subject becomes pregnant. 
• If for any reason per the Investigator’s or the Sponsor’s judgment, discontinuation is in the subject’s best 
interest. 
Subjects who discontinue the study prior to the completion of all treatment visits will be asked to complete the 
evaluations corresponding to Visit 12 (Day 43, 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. 
• Physical examination 
• Vital signs (blood pressure, pulse rate, respiratory rate, and temperature) 
• Laboratory tests (hematology, chemistry, urinalysis) and pregnancy testing in FOCBP 
• Collection of AEs 
• Local tolerability assessments 


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8.1.1 
Physical Examination 
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 
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. 
8.1.3 
Clinical Laboratory Assessments 
Hematology, clinical chemistry, urinalysis, and additional parameters to be tested are listed below: 
Hematology 
Platelet count  
RBC Indices: 
Automated WBC Differential: 
Red blood cell (RBC) count 
Mean corpuscular volume (MCV) 
Neutrophils 
White blood cell (WBC) count  
Mean corpuscular hemoglobin (MCH) 
Lymphocytes 
Reticulocyte count 
Mean corpuscular hemoglobin concentration 
(MCHC) 
Monocytes 
Hemoglobin 
 
Eosinophils 
Hematocrit 
 
Basophils 
 
Clinical Chemistry 
Blood urea nitrogen 
Chloride 
Alkaline phosphatase 
Creatinine 
Aspartate aminotransferase (AST) 
Total and direct bilirubin 
Sodium 
Alanine aminotransferase (ALT) 
 
Potassium 
Gamma glutamyl transferase (GGT) 
 
 
Routine Urinalysis 
Bilirubin, color, appearance, glucose, ketones, leukocyte esterase, nitrite, occult blood, pH, protein, specific gravity, and 
urobilinogen  
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). 


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All results will be reported and must be reviewed by the Investigator or designee. Abnormal results shall be 
assessed for clinical significance. Repeat laboratory 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. 
8.1.4 
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 8.1.5), 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?” 
8.1.5 
Local Tolerability Assessments 
Local tolerability assessments (see Appendix 5) will be evaluated through assessment of symptoms at the drug 
application site. These assessments are to be performed for both axillae individually. Subject assessments will be 
made prior to the Investigator assessments.  
Subject Local Tolerability Assessments: Subjects will be queried about whether any symptoms occurred at the 
study drug application site within the previous 24 hours and further whether any such symptoms persisted longer 
than 1 hour following study drug application. Standardized scales will be used to describe specifically the 
severity of any burning, stinging, or itching.  
Investigator Local Tolerability Assessments: Investigators will observe for the existence of any significant 
local symptoms at the study drug application site. Significant local symptoms are defined as those not ordinarily 
observed following application of a topical product. Standardized scales will be used to describe specifically the 
severity of any erythema or scaling. 
Local tolerability signs and symptoms that result in a subject requiring a concomitant therapy, interruption of 
treatment, or discontinuation from the study, will be reported as AEs.  
8.1.6 
Subject Assessments 
Subjects must complete ALL self-assessments while at the clinic (i.e., HDSM-Ax, DLQI, PGI-S, PGI-C) prior to 
assessments being made by the Investigator. Please see Appendix 2 and Appendix 3 (HDSM-Ax by age; also 
includes PGI-S and PGI-C) and Appendix 4 (DLQI) for a full description of these assessments. Subjects will also 
have the option to complete an End of Study Survey. The HDSM-Ax, DLQI, PGI-S, and PGI-C assessments, as 
well as the optional End of Study Survey, will be collected electronically using a tablet device. Site personnel 
will be trained and a separate electronic clinical outcomes assessment (eCOA) manual will be supplied. 


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8.2 
Summary of Methods of Data Collection 
This protocol will utilize validated 21 Code of Federal Regulations (CFR) Part 11 compliant electronic data 
capture (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 EDC 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 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, 15% as indicated in the Procedures Section 7.1: 
• HDSM-Ax as measured by the subject  
• GSP as measured by the Investigator 
• DLQI as measured by the subject (for subjects 17 years of age) 
• Patient Global Impression Scales; Severity (PGI-S) and Change (PGI-C)  
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 CRO (see Section 9.3.1). Contact information for the Sponsor’s Medical Monitor is provided on 
the protocol cover page.  
9.2 
Adverse Events 
9.2.1 
Definitions of Adverse Events  
According to 21 CFR Parts 312.32 and 320.32 (IND Safety Reporting, Applicability of Requirements Regarding 
an "Investigational New Drug Application"), Food and Drug Administration (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 International Council on Harmonisation (ICH) E2A (Clinical Safety and Data 
Management: Definitions and Standards for Expedited Reporting): 
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 (SAR) means any AE for which there is a reasonable possibility that the drug 
caused the AE. 


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The following information should be considered when determining whether or not to classify a test result, 
medical condition, or other incident as an AE: 
Adverse events will be recorded from the time of informed consent. 
Abnormal laboratory values should not generally be recorded as AEs unless an intervention is required, the 
laboratory abnormality results in an SAE, 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 AE 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 AE (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 study drug visit will be 
recorded on the appropriate Adverse Events 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 9.4). 
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.  
Severity 
Grade 
Description 
Mild  
1 
Awareness of sign or symptom, but easily tolerated 
Moderate  
2 
Discomfort enough to cause interference with usual activity 


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Severity 
Grade 
Description 
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. 
 


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Outcome 
Each AE will be characterized according to the outcomes described in the following table: 
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  
• Dose reduction 
• Unknown 
• Not applicable 
• Other (specify on eCRF) 
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 CRO Medical Monitor 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 CRO 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: 
Fatal: 
The adverse event resulted in death. 
Life Threatening: 
The adverse event placed the subject at immediate risk of death. This classification does not 
apply to an adverse event that hypothetically might cause death if it were more severe. 


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Fatal: 
The adverse event resulted in death. 
Hospitalization: 
The adverse event 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 subject’s ability to carry out 
activities of daily living. 
Congenital Anomaly or Birth 
Defect: 
An adverse outcome in a child or fetus of a subject 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 
subject 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 CRO Medical Monitor 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 CRO Medical Monitor within 24 
hours of becoming aware of the new or follow-up information. The new or follow-up information should be 
faxed to 919-313-1412 (US toll-free: 1-866-761-1274) or e-mailed to safety-inbox.biotech@iqvia.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 
(21 CFR 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. 
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 acceptable 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. 


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FOCBP must agree to periodic pregnancy testing and use a medically acceptable method of contraception for the 
duration of the study. 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); OR  
• Hormonal contraception, including oral, injectable, or implantable methods started ≥2 months prior to 
screening; OR 
• Non-hormonal contraception, including IUD (≥1-week status post placement) or properly used barrier 
methods (e.g., male or female condoms with or without spermicide, cervical cap/diaphragm with 
spermicide). 
* 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).   
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 acceptable 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 CRO Medical Monitor of this event, and record the pregnancy on the appropriate pregnancy surveillance 
form. The form will be sent to the CRO Medical Monitor by fax to 919-313-1412 (US toll-free: 1-866-761-1274) 
or e-mailed to safety-inbox.biotech@iqvia.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 
CRO Medical Monitor, on the appropriate pregnancy surveillance form(s), any follow-up information regarding 
the 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, 
elective or spontaneous, will be reported as a SAE. 


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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. 
10 
STATISTICAL PROCEDURES 
A detailed statistical analysis plan (SAP) 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 
The three analysis populations for this study are defined below. Identification of the subjects to be included in 
each analysis population will be determined and finalized prior to database unmasking.  
10.1.1 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) Population will include all subjects who were randomized. Subjects will be analyzed 
according to the treatment group to which they were randomized, regardless of post-randomization protocol 
deviations, including no treatment or wrong treatment received. 
10.1.2 
Per-Protocol Population 
The PP Population will be a subset of the ITT Population and will include subjects who meet the following 
criteria: 
• Meets all inclusion/exclusion criteria 
• Has not taken or applied any interfering concomitant medications 
• Completed the following visits: 
o Visit 2 GSP 1, and the required GSP data collection  
o Visit 3 GSP 2, and the required GSP data collection  
o Visit 4 (Day 1) Re-screening/Baseline GSP 3 and HDSM-Ax, and the required GSP and HDSM-Ax 
data collection 
o Visit 10 (GSP 4) Day 41 (± 2 days), and the required GSP data collection  
o Visit 11 (GSP 5) Day 42 (± 2 days), and the required GSP data collection 
o Visit 12 (GSP 6) Day 43 (± 2 days) and HDSM-Ax, and the required GSP and HDSM-Ax data 
collection  
 
10.1.3 
Safety Population 
The Safety Population will include all subjects randomized in the study who received study drug, either vehicle 
or sofpironium bromide gel, 15%, at least once. If a subject received any sofpironium bromide gel, 15%, the 
subject will be analyzed in the sofpironium bromide gel, 15%, treatment group. Otherwise the subject will be 
included in the vehicle group. 


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10.2 
Efficacy Endpoints 
10.2.1 
Definitions 
For the purposes of analysis, Baseline and End of Treatment (EOT) definitions for the two primary efficacy 
assessment measures, HDSM-Ax-7 and Gravimetric Sweat Production (GSP), are defined below. 
HDSM-Ax  
•
Baseline = Visit 4 (Day 1) assessment
•
EOT = Visit 12 (Day 43) assessment
GSP 
•
Baseline = the median of GSP1, GSP2, and GSP3 measurements obtained on Visit 2, Visit 3, and Visit 4,
respectively
•
EOT = the median of GSP4, GSP5, and GSP6 measurements obtained on Visit 10, Visit 11, and Visit 12,
respectively
Note that at each timepoint, GSP will be defined as the sum of both axillae measurements. If 1 axilla value is 
missing at a timepoint, then the non-missing observed value will be multiplied by 2. The values for baseline 
or EOT will not be regarded as missing as long as the measurement is available at least for one of the three 
timepoints. 
10.2.2 
Co-Primary Efficacy Endpoints 
The following co-primary efficacy endpoints will be analyzed to assess the efficacy of sofpironium bromide gel, 
15%: 
•
The proportion of subjects achieving at least a 2-point improvement in the HDSM-Ax-7 scale score from
baseline to EOT.
•
The change in GSP from baseline to EOT.
Note that the assessment of the first co-primary efficacy endpoint will be conducted using 7 of the 11 items on 
the HDSM-Ax scale. More specifically, the mean of the 2 items in section 1 and the first 5 items in section 2 
(7 sub-items in total) will be used. The mean will be derived by taking the sum of 7 item scores and dividing it by 
7.For each of the HDSM-Ax sub-items, missing values at EOT will be imputed as described briefly in
Section 10.3.1. HDSM-Ax-7 at EOT will be derived from the imputed values. Further details on imputation
methods will be provided in the SAP.
10.2.3 
Secondary Efficacy Endpoints 
The following secondary efficacy endpoints will be analyzed: 
•
The proportion of subjects achieving at least a 1-point improvement in the HDSM-Ax-7 scale score from
baseline to EOT.
•
The proportion of subjects achieving at least a 2-point improvement in the HDSM-Ax-7 scale score from
baseline to EOT and achieving at least a 70% reduction in GSP from baseline to EOT.


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• The proportion of subjects achieving at least a 1-point improvement in the HDSM-Ax-7 scale score from 
baseline to EOT and achieving at least a 50% reduction in GSP from baseline to EOT. 
10.2.4 
Exploratory Efficacy Endpoints  
Exploratory efficacy endpoints to be analyzed include the following: 
• The proportion of subjects achieving at least a 1-point improvement in the HDSM-Ax-7 scale score from 
baseline to Days 8, 15, 22, 29, 36, 41, 42, 43 (EOT), and 57. 
• The proportion of subjects achieving at least a 1-point improvement in the HDSM-Ax 11-Item 
(HDSM-Ax-11) scale score from baseline to Days 8, 15, 22, 29, 36, 41, 42, 43 (EOT), and 57. 
• The proportion of subjects achieving at least a 2-point improvement in the HDSM-Ax-7 scale score from 
baseline to Days 8, 15, 22, 29, 36, 41, 42, 43 (EOT), and 57. 
• The proportion of subjects achieving at least a 2-point improvement in the HDSM-Ax-11 scale score from 
baseline to Days 8, 15, 22, 29, 36, 41, 42, 43 (EOT), and 57. 
• The proportion of subjects achieving at least a 1-point improvement in the HDSM-Ax Question 4 score 
from baseline to Days 8, 15, 22, 29, 36, 41, 42, 43 (EOT), and 57. 
• The proportion of subjects achieving at least a 2-point improvement in the HDSM-Ax Question 4 score 
from baseline to Days 8, 15, 22, 29, 36, 41, 42, 43 (EOT), and 57. 
• The proportion of subjects achieving at least a 1-point improvement in the HDSM-Ax Question 5 score 
from baseline to Days 8, 15, 22, 29, 36, 41, 42, 43 (EOT), and 57. 
• The proportion of subjects achieving at least a 2-point improvement in the HDSM-Ax Question 5 score 
from baseline to Days 8, 15, 22, 29, 36, 41, 42, 43, (EOT), and 57.  
• Change in PGI-S from baseline to Days 8, 15, 22, 29, 36, 41, 42, 43 (EOT), and 57.  
• PGI-C score on Day 43 (EOT).  
• The proportion of subjects achieving at least a 2-point improvement in the HDSM-Ax-11 scale score from 
baseline to EOT and achieving at least a 70% reduction in GSP from baseline to EOT. 
• The proportion of subjects achieving at least a 1-point improvement in the HDSM-Ax-11 scale score from 
baseline to EOT and achieving at least a 50% reduction in GSP from baseline to EOT. 
• The proportion of subjects achieving at least a 2-point improvement in the HDSM-Ax-7 scale score and 
achieving at least a 70% reduction in GSP from baseline to Days 8, 15, 22, 29, 36, 41, 42, 43, EOT, and 
Day 57. 
• The proportion of subjects achieving at least a 2-point improvement in the HDSM-Ax-11 scale score and 
achieving at least a 70% reduction in GSP from baseline to Days 8, 15, 22, 29, 36, 41, 42, 43, EOT, and 
Day 57. 
• The proportion of subjects achieving at least a 1-point improvement in the HDSM-Ax-7 scale score and 
achieving at least a 50% reduction in GSP from baseline to Days 8, 15, 22, 29, 36, 41, 42, 43, EOT, and 
Day 57. 
• The proportion of subjects achieving at least a 1-point improvement in the HDSM-Ax-11 scale score and 
achieving at least a 50% reduction in GSP from baseline to Days 8, 15, 22, 29, 36, 41, 42, 43, EOT, and 
Day 57. 


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• Change in HDSM-Ax-7 scale score from baseline to Days 8, 15, 22, 29, 36, 41, 42, 43 (EOT), and 57 as a 
continuous measure. 
• Change in HDSM-Ax-11 scale score from baseline to Days 8, 15, 22, 29, 36, 41, 42, 43 (EOT), and 57 as 
a continuous measure.  
• The proportion of subjects achieving at least a 70% reduction in GSP from baseline to Days 8, 15, 22, 29, 
36, 41, 42, 43, EOT, and Day 57.  
• The proportion of subjects achieving at least a 50% reduction in GSP from baseline to Days 8, 15, 22, 29, 
36, 41, 42, 43, EOT, and Day 57. 
• The rank-based GSP change from baseline to Days 8, 15, 22, 29, 36, 41, 42, 43, EOT, and Day 57. 
• The absolute GSP change from baseline to Days 8, 15, 22, 29, 36, 41, 42, 43, EOT, and Day 57. 
• The percent change from baseline in GSP from baseline to Days 8, 15, 22, 29, 36, 41, 42, 43, EOT, and 
Day 57. 
• The change in the modified DLQI from baseline to Day 15 and Day 43 (EOT). 
10.3 
Analysis Methods 
The primary efficacy analysis will be performed on the ITT population with missing values imputed. The co-
primary efficacy endpoints are: 
• The proportion of subjects achieving at least a 2-point improvement in the HDSM-Ax-7 scale score from 
baseline to EOT in the sofpironium bromide gel, 15% group versus vehicle; and 
• The change in GSP from baseline to EOT in the sofpironium bromide gel, 15% group versus vehicle. 
Both comparisons will be conducted using two-sided tests at an alpha=0.05 level. Both endpoints will need to 
demonstrate a statistically significant positive result in favor of sofpironium bromide gel, 15% for the study to be 
considered successful.  
The key elements of the primary efficacy analysis for each co-primary endpoint are described below. 
10.3.1 
Primary and Secondary Analysis of the HDSM-Ax-7 Co-Primary Endpoint    
Data: HDSM-Ax-7  total scores 2-point responder status (0, 1) at EOT. Missing data will be imputed first before 
analysis is performed. 
Imputation Model: Imputation will be item-level. If a subject is missing values for any of items 1a, 1b, 2a, 2b, 
2c, 2d, or 2e at Visit 4 (Day 1), the Visit 1 (Screening) value will be used as Baseline. If the Visit 1 (Screening) 
value is also missing, the subject will be excluded from all HDSM-Ax-7 change from baseline analyses. If a 
subject is missing Day 43 value, the closest (in time) available non-missing value from Day 41 (±2 days) or Day 
42 (±2 days) will be used as the first level of imputation. Should none of the Days 41, 42, and 43 values be 
available, multiple imputations of missing EOT item-level scores will be performed on the sofpironium bromide 
gel, 15% arm values using a control-based imputations (CBI) methodology (see Section 10.3.4). Multiple 
imputations assuming missing at random will be performed for missing data for vehicle subjects. The HDSM-
Ax-7 score will be calculated using the imputed item-level values. Further details on imputation methods will be 
provided in the SAP. 
Analysis Model:  Logistic Regression Model 
Covariates:  The following covariates are planned: 


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• Treatment (class effect: sofpironium bromide gel, 15% group, vehicle group) 
• Baseline HDSM-Ax-7 total score 
• Analysis center (see Section 10.3.3) 
Hypothesis Tested: 
The null hypothesis: 
H0: The proportion of subjects achieving at least a 2-point improvement in the HDSM-Ax-7 scale score 
from baseline to EOT is the same in the sofpironium bromide gel, 15%, and vehicle arms  
will be tested against the two-sided alternative hypothesis: 
H1: The proportion of subjects achieving at least a 2-point improvement in the HDSM-Ax-7 scale score 
from baseline to EOT is not the same in the sofpironium bromide gel, 15%, and vehicle arms. 
Estimand:  The estimand of this co-primary efficacy analysis is the difference in proportions between 
sofpironium bromide gel, 15%, and vehicle arms with a 2-point improvement from baseline to EOT in 
HDSM-Ax-7 total scores among all ITT subjects, regardless of treatment adherence. 
As a secondary, supportive analysis, change from baseline to EOT will be analyzed as a continuous measure.  
The analysis model will be an ANCOVA model with treatment, baseline HDSM-Ax-7 score, and analysis center 
as covariates.  The estimand for this analysis is the difference in mean baseline to EOT changes in HDSM-Ax-7 
total scores between sofpironium bromide gel, 15%, and vehicle arms among all ITT subjects, regardless of 
treatment adherence.  
In addition, a separate site poolability analysis will be performed with analysis center-by-treatment interaction 
terms added to the primary analysis model. An overall p < 0.10 for the combined interaction terms will be 
regarded as an indication of potential heterogeneity among the analysis centers. A mixed model analysis will then 
be performed with analysis center as a random effect to account for the potential heterogeneity. 
10.3.2 
Primary and Secondary Analyses of the GSP Co-Primary Endpoint    
Data: Either rank-based GSP change from baseline to EOT or continuous GSP change from baseline to EOT will 
be analyzed. The GSP assessment is known to be a highly variable measure, and as such, the Shapiro Wilk test of 
normality will be performed to determine if the co-primary endpoint will be continuous or rank transformed. The 
normality test will be performed prior to multiple imputation for missing data and separately for each arm. 
Should the normality assumption be violated for either arm, the co-primary endpoint will be analyzed using rank-
transformed GSP data. If the normality assumption holds for both arms, then the co-primary endpoint will be 
analyzed using continuous GSP data.  
For the rank transformation of GSP measurements at a particular time point, continuous data for all subjects 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. For determination of baseline value for a subject, the continuous GSP data will be 
ranked separately at each of Visits 2, 3, and 4; the median of the three ranks will be used as baseline value of the 
subject.  Using the measurement data from Visits 10, 11, and 12, the rank-transformed GSP value at EOT will be 
derived in the same manner. For each subject, the difference between the rank-transformed baseline and EOT 
GSP values (EOT – baseline) will serve as the outcome value for the rank-based GSP ANCOVA analysis.     
Missing EOT GSP data (continuous data) will be imputed before analysis is performed. 


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Imputation Model: Imputation will be done using continuous data prior to rank-transformation, should the 
normality assumption be violated. For continuous data, subjects with results (see Section 10.3.3) meeting the 
criterion for “outlier” will be removed from imputation sampling database (i.e., data for vehicle patients) prior to 
missing data imputation. From the remaining imputation sampling database of continuous GSP measurements, 
multiple imputations of missing EOT sofpironium bromide, 15% arm GSP values will be performed using a CBI 
methodology (see Section 10.3.4). Multiple imputations assuming MAR will be performed for missing EOT data 
Vehicle subjects. Further details on multiple imputations will be provided in the SAP. 
Analysis Model: ANCOVA model (either non-ranked or ranked, pending outcome of normality test) 
Fixed effects: The following fixed effects are planned: 
• Treatment (class effect: sofpironium bromide gel, 15% group, vehicle group) 
• Baseline GSP (either non-ranked or ranked, pending outcome of normality test) 
• Analysis center (see Section 10.3.3) 
Hypothesis Tested: 
The null hypothesis: 
H0: The rank-based GSP changes from baseline to EOT are the same in the sofpironium bromide gel, 
15%, and vehicle groups  
will be tested against the two-sided alternative hypothesis: 
H1: The rank-based GSP changes from baseline to EOT are not the same in the sofpironium bromide gel, 
15%, and vehicle groups. 
Estimand:  The estimand of this co-primary efficacy analysis is the mean difference between treatments, 
sofpironium bromide gel, 15%, versus vehicle, in the change from baseline to EOT for GSP among all ITT 
subjects, regardless of treatment adherence. 
Additionally, the following secondary and supportive analyses will be performed for the GSP co-primary 
endpoint:  
(a) Using the same methodology as described above, an ANCOVA analysis will be performed for either the non-
rank transformed, continuous GSP data, or the rank transformed GSP data, pending the results of the normality 
test. If the normality assumption is violated and the rank-transformed data are used as the co-primary endpoint, 
analysis of the continuous data will be supportive. If the normality assumption holds and the continuous data are 
used as the co-primary endpoint, then analysis of the rank-transformed data will be supportive.   
(b) To further address the potential large variations in GSP data, mixed model repeated measures (MMRM) 
analyses will be performed to estimate the average sofpironium bromide gel, 15% treatment effect over the 
6-week course of treatment, i.e. the average sofpironium bromide gel, 15% versus vehicle difference from 
baseline to Days 8, 15, 22, 29, 36, and EOT, using both rank-based and non-rank-based data. As the MMRM 
methodology is known to be robust to missing data, missing data will not be imputed for this analysis.  In 
addition, based on the BBI-4000 CL-203 results, treatment versus visit interactions are not expected.  Details of 
the analysis models will be provided in the SAP.   
(c) For the primary endpoint of either ranked or continuous GSP (pending normality test results), a separate site 
poolability analysis will be performed with analysis center-by-treatment interaction terms added to the primary 
analysis model. An overall p < 0.10 for the combined interaction terms will be regarded as an indication of 


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potential heterogeneity among the analysis centers. A mixed model analysis will then be performed with analysis 
center as a random effect to account for the potential heterogeneity.    
10.3.3 
Method of Pooling Sites to Generate Analysis Centers 
Subjects from low enrolling sites will be pooled in order to generate analysis centers. The minimum number of 
subjects per analysis center is 10. For sites with <10 enrollments, the lowest enrolling site will be combined with 
the largest enrolling site, and then the second lowest enrolling site and the second largest enrolling site will be 
combined, and so on. Further combining will be done as necessary until all analysis centers have at least 
10 subjects. All analyses that are controlled for site will use this analysis center designation. Site poolability 
will also be assessed as described in Sections 10.3.1 and 10.3.2. Full details will be provided in the SAP. 
10.3.4 
Handling of Missing Data for the Co-Primary Efficacy Endpoints in the ITT Population 
For both HDSM-Ax-7 and GSP, multiple imputations for missing values in the vehicle group will be performed 
assuming MAR.  For the sofpironium bromide gel, 15% group, multiple imputations using the CBI model will be 
employed as the primary imputation method to handle missing data. This approach will adopt a missing not at 
random (MNAR) assumption and missing values in the sofpironium bromide gel, 15%, group will be imputed 
based on a distribution with estimated values at visits lost to follow-up similar to that of subjects in the vehicle 
group. This approach further assumes that for the treatment effect observed in sofpironium bromide gel, 15% 
arm, subjects with missing data gradually trends towards the estimated mean in the vehicle group, i.e., any 
treatment benefit gained is not immediately lost upon withdrawal. The same co-primary analysis models will be 
applied to the multiple imputed datasets and the results combined via Rubin’s rules (Rubin, 1976).  
Furthermore, in order to ensure that the missing data imputation method proposed is robust to outliers for the 
GSP co-primary endpoint, data from subjects that meet the criterion for being an outlier will be removed from the 
imputation sampling database as follows. Combining the vehicle and sofpironium bromide gel, 15% arms, the 
mean and standard deviation will be calculated for the non-missing GSP change from baseline to EOT data. Data 
values more than 3 standard deviations away from the mean will be regarded as outliers. However, since the 
outliers are included in the original mean and standard deviation calculations and would have inflated their 
values, the outliers will be set aside and the mean and standard deviation will be re-calculated to see if any 
additional outliers are identified. This process will be repeated until no more outliers are identified. Prior to 
performing imputation for missing GSP change from baseline data in the ITT population, data values 
contributing to the outlying observations will be removed from the imputation sampling database, i.e. the non-
missing vehicle data. With this approach, outlying data will not be propagated during missing data imputation. 
Once an imputation is complete, all original non-missing data and the imputed, previously missing data will be 
used for the GSP ITT analysis. Further details for this approach will be included in the SAP. 
10.3.5 
Sensitivity Analyses of the Co-Primary Efficacy Endpoints 
To further explore the robustness of the primary analysis results to different missing data assumptions, analyses 
using two additional imputation methods will be performed as presented below. Furthermore, the ranked GSP 
and non-rank transformed GSP ANCOVA analyses will be repeated without imputing missing data, and again 
after removing outlier data. Additionally, the 7 items in the HDSM-Ax-7 scale will be analyzed individually to 
support the primary analysis for this co-primary endpoint. 


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Summary of Sensitivity Analyses of the Co-Primary Efficacy Endpoints 
 
Co-Primary Efficacy Endpoint Assessed 
Sensitivity Analysis 
1 
GSP change from baseline to EOT 
Analysis performed on available data 
only without imputing missing data; 
using both ranked and non-ranked data. 
2 
GSP change from baseline to EOT 
Subjects with outlying data removed 
from analysis; using both ranked and 
non-ranked data (multiple imputations 
for missing data). 
3 
HDSM-Ax-7 2-point improvement from baseline 
to EOT 
Missing data imputed as failure/non-
response (single imputation only) 
4 
HDSM-Ax-7 2-point improvement and GSP 
change from baseline to EOT 
Tipping point analysis (multiple 
imputations for missing data) 
5 
HDSM-Ax-7 2-point improvement from baseline 
to EOT 
Analysis of the 7 individual items in 
the HDSM-Ax-7 scale (multiple 
imputations for missing data) 
Unless otherwise specified, sensitivity analyses pertain to the primary analyses for the co-primary endpoints only. 
A brief description of each sensitivity analysis is provided below; complete details will be included in the final 
SAP. 
Sensitivity Analysis 1: To further investigate the robustness of the GSP co-primary efficacy endpoint, the ranked 
and non-rank transformed GSP analyses will be repeated on all available data only without imputing missing 
data. The methodology will be similar to the primary analysis of the GSP co-primary endpoint. 
Sensitivity Analysis 2: To further investigate the robustness of the GSP co-primary efficacy outcome, the ranked 
and non-rank transformed GSP analyses will be repeated after removing outlier data (as defined in 
Section 10.3.4). The methodology will be similar to the primary analysis of the GSP co-primary endpoint, except 
that outlier data will be removed from the imputed database for these analyses. 
Sensitivity Analysis 3: Missing post-baseline HDSM-Ax-7 data will be imputed as failure/non-response in both 
treatment groups. The co-primary efficacy HDSM-Ax-7 analysis will be re-run on the so-imputed HDSM-Ax-7 
dataset and treatment success proportion estimates will be produced.   
Sensitivity Analysis 4: A tipping point analysis will be conducted to investigate the robustness of the co-primary 
efficacy outcomes. Tipping point analyses will be conducted separately for the HDSM-Ax-7 and GSP co-primary 
endpoints. 
For the GSP co-primary endpoint, missing data in the vehicle arm will be assumed to be MAR, while missing 
data from the sofpironium bromide gel, 15%, arm will be imputed assuming that subjects with missing data have 
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this study. The GSP co-primary efficacy outcome analysis methodology will be applied to the imputed datasets 
and repeated until statistical significance no longer holds. The tipping point will be identified and the results will 
be summarized graphically. 
For the HDSM-Ax-7 co-primary endpoint, identical imputation methodology to that described above for the GSP 
will be applied to the HDSM-Ax-7 total scores, and the resulting values will be dichotomized into responders 


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versus non-responders using the 2-point improvement criterion. $ǻLQFUHPHQWRIon a 0-4 scale) will be 
used for this study. The HDSM-Ax-7 co-primary efficacy outcome analysis methodology will be applied to the 
imputed datasets and repeated until statistical significance no longer holds. The tipping point will be identified 
and the results will be summarized graphically. 
Sensitivity Analysis 5: A sensitivity analysis will be conducted to investigate whether any of the individual 
items in the HDSM-Ax-7 scale are overly influencing changes observed in the total score. First, a subject will be 
counted as a responder if they achieve at least a 2-point improvement in the individual question from baseline to 
EOT. The logistic regression model for the primary analysis for HDSM-Ax-7 will be repeated for each of the 7 
individual items, and each individual question will be analyzed separately. Secondly, one of the 7 items will be 
omitted, and the HDSM-Ax-7 total score will be calculated as the average of the remaining 6 items. The primary 
logistic regression analysis for 2-point improvement response rate will be performed on this 6-item scale. This 
process will be repeated 7 times, each time with a different item of the HDSM-Ax-7 scale removed from 
calculation of the overall score. 
10.3.6 
Analysis of the Secondary Efficacy Endpoints 
A gated, fixed-sequence testing procedure will be used in this protocol to control the overall familywise false 
positive error rate for the primary and secondary endpoints analyses. As described above, the primary analysis 
will be regarded as positive and the trial will be successful for the co-primary efficacy endpoints if both null 
hypotheses in Section 10.3.1 and Section 10.3.2 of no difference are rejected in favor of sofpironium bromide gel, 
15% at the 2-sided 0.05 level of significance. 
If both co-primary analyses yield statistically significant results in favor of the sofpironium bromide gel, 15% 
group, the three secondary efficacy endpoints specified in Section 10.2.3 will be tested in a fixed sequence in the 
order presented in Section 10.2.3. Testing will continue only if all previously tested null hypotheses have been 
rejected at the 2-sided alpha=0.05 significance level in favor of sofpironium bromide gel, 15%.     
The HDSM-Ax-7 1-point improvement responder secondary endpoint analysis will be conducted using the same 
logistic regression model as that used for the HDSM-Ax-7 co-primary efficacy analysis. For the composite 
endpoints, both baseline HDSM-Ax-7 score and baseline GSP value will be included as covariates.    
10.3.7 
Analysis of Exploratory Efficacy Endpoints 
PGI-S and PGI-C endpoints will be analyzed using a Cochran-Mantel-Haenszel test. All other exploratory 
efficacy endpoints that involve a proportion of responders will be analyzed using methods similar to what was 
described for the HDSM-Ax-7 co-primary endpoint. All other exploratory endpoints that involve a change from 
baseline to a single timepoint will be analyzed using methods similar to what is described for the GSP co-primary 
endpoint. P-values for exploratory efficacy endpoints will be provided for descriptive purposes only and no 
formal hypothesis testing will occur. All exploratory efficacy analyses will be based on available data and 
missing GSP and HDSM-Ax EOT data imputed. 
10.3.8 
Psychometric Analysis of the HDSM-Ax-7 
In parallel to the traditional statistical analysis, psychometric evaluation of the HDSM-Ax-7 will be carried out to 
confirm the most appropriate HDSM-Ax-7 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 variables such as 
Questions 4 and 5 of the HDSM-Ax-7, PGI-S, PGI-C, and GSP), stability, reliability, ability to detect change, 
and interpretability of clinical trial results. 


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The details regarding psychometric analyses will be described in a separate statistical analysis plan. 
10.4 
Safety Analyses 
Safety assessments of interest are local tolerability assessments, AEs, laboratory evaluations, and vital signs. 
Safety analysis will be performed by treatment received for the Safety Population. Treatment-emergent adverse 
event descriptions will be mapped to standard terms, i.e., Medical Dictionary for Regulatory Activities 
(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 cumulatively 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, (d) TEAEs leading to protocol 
treatment discontinuation, (e) protocol treatment-related serious TEAEs, (f) severe TEAEs, (g) TEAEs leading to 
dose interruption, (h) TEAEs of special interest, and (i) anticholinergic TEAEs. 
At each visit, local tolerability assessments will be descriptively summarized by severity. For any symptoms, 
subject severity is the worst severity of the two axillae.  
An overall summary table will also be presented with subject incidences tabulated according to the worst severity 
experienced while on study. In addition, at each post-baseline visit, local tolerability will be summarized as 
cumulative shift tables versus 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, median, minimum, 
maximum) for values obtained at Visit 1 and Visit 12.  Whereas, vital signs will be summarized in a similar 
manner at each visit.  
10.5 
Sample Size 
Sample size estimation was performed for the co-primary efficacy endpoints based on the results of a Phase 2b 
study (BBI-4000-CL-203): 
• HDSM-Ax-7 responder analysis: 2-point improvement response rates of 29.8% and 53.7% were assumed 
for the vehicle and  sofpironium bromide gel, 15% arms, respectively. The power is 0.95 with 116 
subjects per arm and a total of 232 subjects. 
• GSP: using rank-transformed GSP data for change from baseline to EOT, a difference of 16.6 in mean 
ranks between the vehicle and sofpironium bromide gel, 15% arms, with a pooled standard deviation of 
approximately 39.5, was used for this purpose. Normal approximation yielded a sample size estimate of 
296 subjects for the study, 148 each arm, in order to achieve 0.95 power for the GSP co-primary endpoint.   
A chi-square test for the HDSM-Ax-7 endpoint and a two-sample t-test for the GSP endpoint were used to 
estimate the above sample size and power for each endpoint. With approximately 300 evaluable subjects, the 
overall study power to demonstrate a statistically significant treatment effect (two-sided p < 0.05) for both co-
primary efficacy endpoints simultaneously is greater than 0.90 (with greater than 0.95 power for each of HDSM-
Ax-7 and GSP). 
Assuming missing data from approximately 15% of subjects, a total of 350 subjects will be targeted for 
enrollment. 


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Additionally, sample size estimation was also performed using non-rank-transformed GSP data. An expected 
mean treatment difference of 73 mg with a pooled standard deviation of approximately 170 was used for this 
purpose. This yielded a reduced sample size estimate compared with the target of 300 subjects completing the co-
primary efficacy assessments in order to achieve 0.95 power for GSP, further indicating that our sample size 
estimations are conservative. 
11 
STUDY ADMINISTRATION PROCEDURES 
11.1 
Subject Entry Procedures 
11.1.1 
Overview of Entry Procedures 
Subjects with hyperhidrosis as defined by the criteria in 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 8-digit subject screening number composed of a 1-digit study 
number (1), a 3-digit site number, followed by a 4-digit sequentially assigned number starting at 0001, at each 
site. For instance, the first subject from site 001 will have 10010001 as their assigned subject screening number; 
the subsequent subject from this site will have 10010002 as their assigned subject screening number. The first 
subject from site 002 will have 10020001 as their assigned subject screening number; the subsequent subject 
from this site will have 10020002 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. 
The randomization for this study will be stratified by investigator site. Therefore, each site will be treated as a 
block and a randomization schedule will be prepared in order to balance the 1:1 treatment assignment within the 
site. Randomization details, including block size, will be prespecified in a randomization plan. 
After subjects qualify for the study (as determined by the Investigator at the Screening/Rescreening Visits), they 
will be randomized to sofpironium bromide, 15% or vehicle gel, and notified that their screening number 
becomes their post-randomization subject number. Each kit carton will contain a treatment plastic pump, which 
will be labeled with a unique bottle number displayed on the label. A kit 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 
site-specific randomization schedule. After obtaining the kit numbers assigned from the EDC system, the 
Investigator will document the kit numbers dispensed to the subject by tearing off the perforated portion of the 
carton label and placing it on the study subject source document. 


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Approximately 350 subjects will be randomized to receive either sofpironium bromide gel, 15%, or vehicle gel 
(placebo) in a ratio of 1:1. 
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 whether 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 whether they experienced any problems dispensing the investigational 
product. 
• Subjects will be asked whether they used any other products on their axillae. 
• Site staff will review concomitant medication use since the previous visit and determine whether 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 any study-related procedures. Potential 
subjects will be screened within 45 days prior to Visit 4 (Rescreening/Baseline) to assess their eligibility to enter 
the study. Only eligible subjects with axillary hyperhidrosis will be enrolled. 
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. 


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12.2.3 
Compliance with Good Clinical Practice 
This protocol is to be conducted in accordance with the applicable GCP regulations and guidelines, e.g., the ICH 
Guideline on GCP. 
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) are to be obtained from each subject prior to enrollment into the study, in 
accordance with the applicable privacy requirements (e.g., 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 


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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. 
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 brief 
excursions 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 prepared 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. In the event of interruptions to site accessibility due to COVID-19 or other pandemics 
conditions, alternative means of monitoring the study documents may be implemented, as allowed by local and 
federal requirements, such as remote monitoring and/or data verification. 


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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. 
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. 


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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. 
2. 
Ayele BT, Lipkovich I, Molenberghs G, Mallinckrodt CH. A Multiple-Imputation-Based Approach to 
Sensitivity Analyses and Effectiveness Assessments in Longitudinal Clinical Trials. J Biopharm Stat. 
2016;24(2):211-228. 
3. 
Rubin DB. Inference and missing data. Biometrika. 1976;63(3):581–590. 
4. 
FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health 
Emergency. US Department of Health and Human Services. Food and Drug Administration.  July 2020. 
FDA website.   


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14 
APPENDICES 
 
 


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APPENDIX 1:  GRAVIMETRICALLY MEASURED SWEAT 
PRODUCTION 
Method: Axilla Filter Paper Gravimetric Sweat Production Measurements  
Set Up  
IMPORTANT:  Make sure that you distinguish each gravimetric collection packet Right (R) from 
Left (L) throughout the gravimetric measurement (i.e., during set up, measurement).  
• 
Clip or shave axilla hair if present. Use an electric razor or clippers so a short stubble (<1 mm) is 
present (blade shaving may irritate the skin or cause folliculitis; ok for men and women who use a 
manual razor routinely). Wash and clean the axilla to remove all loose hair or stubble. Towel dry 
the axilla(e).  
• 
Place the subject in a room with controlled humidity and temperature between 20°C and 25°C 
(68°F to 77°F) for at least 30 minutes. During acclimation, the subject should remain in a 
semirecumbent position.   
• 
Measurements will be done in the same room throughout the study.  
• 
To the best of their ability, the same Study Site Staff member will perform the evaluation for each 
subject both within and across subjects. If this is not possible due to extenuating circumstances 
(e.g., vacation, illness, etc.), another qualified Study Site Staff Member cross-trained by the 
originally assigned staff member may perform these activities.   
• 
Refer to the detailed study training manual and video for step-by-step directions.   
Filter Paper Measurement  
• 
Prepare the cotton towel, filter paper, and conical tube for the assessment.    
• 
Place one filter paper and the conical tube with lid on the Sponsor-provided balance sensitive to 
1 mg and record its weight. Tare the weight of the filter paper and conical tube.   
• 
Have subject assume a semi-reclining position with the axilla fully exposed and the arm resting 
comfortably above the head.    
• 
Dry the axilla gently with the cotton towel.  
• 
Using talc-free gloves, place the preweighed filter paper in the center of the axilla against the 
subject’s skin, and have the patient carefully fold their axilla down to hold the filter paper in 
place. Immediately start the timer for 5 minutes. Immediately after 5 minutes, ask the patient to 
lift his/her arm and gently lift the filter paper out of the axillary vault and place it into the conical 
tube and replace lid to avoid evaporative loss of fluid.    
• 
Record the time and  weight.   
• 
Refer to detailed study training manual and video for step-by-step directions.   


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APPENDIX 2:  HYPERHIDROSIS DISEASE SEVERITY MEASURE-
AXILLARY (HDSM-AX), ≥ 12 YEARS OF AGE 
(VERSION 1.3) 
Hyperhidrosis Disease Severity Measure--Axillary 
(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 


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c) 
Underarm sweating after little or no 
physical exercise? 
0 
1 
2 
3 
4 
d) Underarm wetness? 
0 
1 
2 
3 
4 
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 
 


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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) 
 
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 as Question #6 of HDSM-Ax at each assessment 
† Administered as Question #7 of HDSM-Ax at the Day 43 (EOT) visit only. 


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APPENDIX 3:  HYPERHIDROSIS DISEASE SEVERITY MEASURE-
AXILLARY, CHILD (≥9 TO ˂12 YEARS OF AGE) 
HDSM-Ax Child (version 28 FEB 2018)* 
INSTRUCTIONS:  We are interested in finding out about your underarm sweating.   
• 
Circle the best answer to each question. 
o Think about sweating in your underarms only. 
o Think about your sweating this morning and yesterday. 
• 
Please answer ALL questions. 
______________________________________________________________________ 
1. Since you woke up yesterday, how often did you have these things?   
 
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 clothes from underarm 
sweating? 
0 
1 
2 
3 
4 
b) Underarm sweating for no reason? 
0 
1 
2 
3 
4 
2. Since you woke up yesterday, how much did you have these things? 
 
I did not 
have this  
A tiny 
amount 
A little 
A lot 
A great 
amount 
a) Underarm sweating when you felt 
nervous, scared, or worried? 
0 
1 
2 
3 
4 
b) Damp or wet clothing from underarm 
sweating? 
0 
1 
2 
3 
4 
c) 
Underarm sweating after sitting 
quietly? 
0 
1 
2 
3 
4 
d) Underarm wetness? 
0 
1 
2 
3 
4 
e) Underarm sweating for no reason? 
0 
1 
2 
3 
4 
f) 
Underarm sweating that you could 
not hide? 
0 
1 
2 
3 
4 
g) Underarm sweating when you were 
not hot? 
0 
1 
2 
3 
4 


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3. Since you woke up yesterday, how much did you want to do these things? 
 
Not at all  
A tiny 
amount  
A little 
A lot 
A great 
amount 
a) Change clothes because of underarm 
sweating? 
0 
1 
2 
3 
4 
b) Wipe sweat from your underarms? 
0 
1 
2 
3 
4 
 
4. Since you woke up yesterday, how much of the time did you have underarm sweating?  
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. Describe your underarm sweating AT ITS WORST since you woke up yesterday?  
0 
I did not have underarm sweating 
1 
I had a tiny amount of underarm sweating  
2 
I had some underarm sweating  
3 
I had a lot of underarm sweating  
4 
I had a great amount of underarm sweating  
 
 
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.** 


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  None 
  Mild 
  Moderate 
  Severe 
  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 as Question #6 of HDSM-Ax at each assessment 
† Administered as Question #7 of HDSM-Ax at the Day 43 (EOT) visit only 
 
 
 
 
 


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APPENDIX 4:  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 



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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 




 
 

7. 
Over the last week, has your underarm sweating 
prevented you from working or studying? 
Yes 
 
No 
 
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 

 
 



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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. 
 
 
 
 
 


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APPENDIX 5:  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 eCRFs 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): As reported by the Subject to the Investigator, the severity of any 
symptoms of burning, stinging, or itching at the application-site within the previous 24 hours, and 
further any such symptoms persisting longer than 1 hour following study drug application, will be 
described specifically by severity using the following standardized scales: 
Score 
Burning 
Stinging 
Itching 
0 = Absent 
Normal, no discomfort 
Normal, no discomfort 
Normal, no discomfort 
1 = Minimal 
An awareness, but no 
discomfort  
An awareness, but no 
discomfort  
An awareness, but no 
discomfort  
2 = Mild 
Noticeable discomfort 
causing intermittent 
awareness 
Noticeable discomfort 
causing intermittent 
awareness 
Noticeable discomfort 
causing intermittent 
awareness 
3 = Moderate 
Noticeable discomfort 
causing continuous 
awareness 
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 
Definite discomfort 
causing continuous 
awareness, interfering 
occasionally with normal 
daily activities 
Local tolerability (Investigator): The Investigator will assess the drug application site for the 
existence of significant local symptoms. Significant local symptoms are defined as those not ordinarily 
observed following application of a topical product. The following standardized scales will be used to 
describe specifically the severity of any erythema or scaling:  
Score 
Scaling 
Erythema 
0 = Absent 
No scaling 
No redness 
1 = Minimal 
Fine scaling, barely perceptible 
Faint red or pink coloration, barely 
perceptible 
2 = Mild 
Slight scaling, noticeable only with light 
scratching 
Light red or pink coloration 
3 = Moderate 
Definitely noticeable scaling 
Medium red coloration 
4 = Severe 
Extensive scaling 
Beet red coloration 


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APPENDIX 6:  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. Thoroughly wash both hands and rinse the plastic applicator. 
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 as follows:   
o Do not shower, shave, or wash the underarm area for at least 8 hours AFTER study 
product application. 
o Shaving of the underarm area should be done at least 8 hours BEFORE study product 
application. 
o If the subject takes a shower or washes the underarm area at night, then it should be at 
least 30 minutes before study product application. 
o Subjects should 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 Sponsor-provided 
non-antiperspirant 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. 
 


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On the day of all clinic study visits you may shower but are NOT permitted to: 
• Apply any product to your axilla (including Sponsor-provided non-antiperspirant deodorant). 
• Exercise. 
• Consume caffeine containing food or beverage until the gravimetric assessments are completed. 


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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. 
• Apply the study product each evening before bedtime. 
• Not shower, shave, or wash the underarm area for at least 8 hours after study product application. 
• Not shave underarm area at least 8 hours prior to applying study product in the evening. 
• Do not apply any other product to the axillary area (including Sponsor-provided non-antiperspirant 
deodorant) 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 an acceptable 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). 
• Wear a T-shirt while sleeping or similar pajama and avoid touching the underarm area. 
• 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 4 (Baseline): Visit 7 (Day 22) and Visit 12 (End of Treatment; Day 43).  
 


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APPENDIX 7:  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-301/01 on all 
pages) 
 
Footer: Added the amendment date to all pages 
 
Change Number 
Section # / Name 
Details of Change 
2 
Title Page 
Added the date of amendment  
 
Original Text 
VERSION: Original September 20, 2019 
 
Revised Text 
ORIGINAL PROTOCOL: September 20, 2019  
AMENDMENT 01: November 08, 2019 
 
Change Number 
Section # / Name 
Details of Change 
3 
SYNOPSIS,  
Inclusion Criteria 
Revised text regarding acceptable contraceptive 
methods, duration of contraception, and definition 
of postmenopausal. 
 
Original Text 
6.  Sexually active females of childbearing potential 
(FOCBP)* who are engaging in sexual activity that 
can cause pregnancy 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 less than 12 months from their last 
menses. Acceptable contraceptive methods include 
the following: 
a. Abstinence for the duration of the study, or 
where partner is sterile (e.g., vasectomy); 
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 


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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, 
ELODWHUDOWXEDOOLJDWLRQ>6 months prior to 
baseline] or bilateral oophorectomy) or is 
not postmenopausal (defined as amenorrhea 
FRQVHFXWLYHPRQWKV LQZRPHQ
years of age). 
 
Revised Text 
6.  Sexually active females of childbearing potential 
(FOCBP)* who are engaging in sexual activity that 
can cause pregnancy must agree to periodic 
pregnancy testing and use a medically acceptable 
method of contraception for the duration of the 
study. This includes perimenopausal women who 
are less than 12 months from their last menses. 
Acceptable contraceptive methods include the 
following: 
a. Abstinence for the duration of the study, or 
where partner is sterile (e.g., vasectomy); 
OR 
b. Hormonal contraception, including oral, 
injectable, or implantable methods started 
PRQWKVSULRUWRVFUHHQLQJ25 
c. Non-hormonal contraception, including 
LQWUDXWHULQHGHYLFHV-week status post 
placement), or properly used barrier 
methods (e.g., male or female condoms with 
or without spermicide, cervical 
cap/diaphragm with spermicide). 
 
* FOCBP for this study includes any 
premenopausal female capable of becoming 
pregnant who has not undergone successful 
surgical sterilization (hysterectomy, 
ELODWHUDOWXEDOOLJDWLRQ>6 months prior to 
baseline] or bilateral oophorectomy) or is 
not postmenopausal (defined as amenorrhea 
FRQVHFXWLve months). 


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Change Number 
Section # / Name 
Details of Change 
4 
SYNOPSIS, Study 
Design 
Revised the number of clinical sites from 80 to 65 
 
Original Text 
Approximately 450 subjects, at approximately 80 
clinical sites in the United States will be 
randomized to receive either sofpironium bromide 
gel, 15% or vehicle gel (placebo) in a balanced 1:1 
ratio in order to obtain approximately 406 
evaluable subjects at the end of study. 
 
Revised Text 
Approximately 450 subjects, at up to approximately 
65 clinical sites in the United States, will be 
randomized to receive either sofpironium bromide 
gel, 15% or vehicle gel (placebo) in a balanced 1:1 
ratio in order to obtain approximately 406 
evaluable subjects at the end of study. 
 
Change Number 
Section # / Name 
Details of Change 
5 
SYNOPSIS, Study 
Design 
Removed Hyperhidrosis Quality of Life Index from 
the list of assessments. 
 
Original Text 
Gravimetric measurements of sweat production and 
patient-reported outcomes HDSM-Ax-7, 
Hyperhidrosis Quality of Life Index, and 
Dermatology Life Quality Index (DLQI) (via 
electronic clinical outcomes assessment [eCOA] 
technology) will be recorded during the study at 
predefined time points. 
 
Revised Text 
Gravimetric measurements of sweat production and 
patient-reported outcomes HDSM-Ax-7 and 
Dermatology Life Quality Index (DLQI) (via 
electronic clinical outcomes assessment [eCOA] 
technology) will be recorded during the study at 
predefined time points. 
 
Change Number 
Section # / Name 
Details of Change 
6 
Section 2, Study 
Design 
Revised text to reflect the change in number of 
clinical sites from 80 to 65 


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Original Text 
Approximately 450 subjects at 80 clinical sites in 
the US will be enrolled to obtain approximately 406 
evaluable subjects at the end of study. 
 
Revised Text 
Approximately 450 subjects, at up to approximately 
65 clinical sites in the US, will be enrolled to obtain 
approximately 406 evaluable subjects at the end of 
study. 
 
Change Number 
Section # / Name 
Details of Change 
7 
Section 4.1, Number 
of Subjects 
Revised text to reflect the change in number of 
clinical sites from 80 to 65 
 
Original Text 
Approximately 450 subjects, at approximately 80 
clinical sites, will be randomized to receive either 
sofpironium bromide gel, 15% or vehicle gel in a 
1:1 ratio to obtain approximately 406 evaluable 
subjects at the end of study. 
 
Revised Text 
Approximately 450 subjects, at up to approximately 
65 clinical sites, will be randomized to receive 
either sofpironium bromide gel, 15% or vehicle gel 
in a 1:1 ratio to obtain approximately 406 evaluable 
subjects at the end of study. 
 
Change Number 
Section # / Name 
Details of Change 
8 
Section 4.2, 
Inclusion Criteria 
Revised text regarding acceptable contraceptive 
methods, duration of contraception, and definition 
of postmenopausal. 
 
Original Text 
6.  Sexually active females of childbearing potential 
(FOCBP)* who are engaging in sexual activity that 
can cause pregnancy 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 less than 12 months from their last 
menses. Acceptable contraceptive methods include 
the following: 
a. Abstinence for the duration of the study, or 
where partner is sterile (e.g., vasectomy); 


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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, 
ELODWHUDOWXEDOOLJDWLRQ>PRQWKVSULRUWR
baseline] or bilateral oophorectomy) or is 
not postmenopausal (defined as amenorrhea 
!FRQVHFXWLYHPRQWKVLQZRPHQ
years of age). 
 
Revised Text 
6.  Sexually active females of childbearing potential 
(FOCBP)* who are engaging in sexual activity that 
can cause pregnancy must agree to periodic 
pregnancy testing and use a medically acceptable 
method of contraception for the duration of the 
study. This includes perimenopausal women who 
are less than 12 months from their last menses. 
Acceptable contraceptive methods include the 
following: 
a. Abstinence for the duration of the study, or 
where partner is sterile (e.g., vasectomy); 
OR 
b. Hormonal contraception, including oral, 
injectable, or implantable methods started 
2 months prior to screening; OR 
c. Non-hormonal contraception, including 
intrauterine devices (IUD; 1 week status 
post placement), or properly used barrier 
methods (e.g., male or female condoms with 
or without spermicide, cervical 
cap/diaphragm with spermicide). 
*  FOCBP for this study includes any 
premenopausal female capable of becoming 
pregnant who has not undergone successful 
surgical sterilization (hysterectomy, 


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bilateral WXEDOOLJDWLRQ>PRQWKVSULRUWR
baseline] or bilateral oophorectomy) or is 
not postmenopausal (defined as amenorrhea 
12 consecutive months). 
 
Change Number 
Section # / Name 
Details of Change 
9 
Section 7.1, Time 
and Events Table 
Table footnote 12 updated to reflect changes 
regarding acceptable contraceptive methods and 
definition of postmenopausal. 
 
Original Text 
12.FOCBP for this study includes any premenopausal female capable 
of becoming pregnant who has not undergone successful surgical 
VWHULOL]DWLRQK\VWHUHFWRP\ELODWHUDOWXEDOOLJDWLRQ>PRQWKVSULRU
to baseline], or bilateral oophorectomy) or is not postmenopausal 
GHILQHGDVDPHQRUUKHDFRQVHFXWLYHPRQWKVLQZRPHQ\HDUV
of age). 
 
Revised Text 
12.FOCBP for this study includes any premenopausal female capable 
of becoming pregnant who has not undergone successful surgical 
sterilization (hysterectomy, biODWHUDOWXEDOOLJDWLRQ>PRQWKVSULRU
to baseline], or bilateral oophorectomy) or is not postmenopausal 
GHILQHGDVDPHQRUUKHDFRQVHFXWLYHPRQWKV 
 
Change Number 
Section # / Name 
Details of Change 
10 
Section 8.1.3, 
Clinical Laboratory 
Assessments 
Additional assessments added to the Routine 
Urinalysis Table, and specific gravity grouped with 
these additional assessments 
 
Original Text 
pH, glucose, protein, blood and ketones by dipstick 
 
Revised Text 
Bilirubin, color, appearance, glucose, ketones, 
leukocyte esterase, nitrite, occult blood, pH, 
protein, specific gravity, and urobilinogen 
 
Change Number 
Section # / Name 
Details of Change 
11 
Section 8.1.3, 
Clinical Laboratory 
Assessments 
Text in other screening tests section revised to 
reflect changes to the definition of postmenopausal 
 
Original Text 
* 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 


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oophorectomy) or is not postmenopausal (defined 
as amenorrhea >12 consecutive months in women 
55 years of age). 
 
Revised Text 
* 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). 
 
Change Number 
Section # / Name 
Details of Change 
12 
Section 9.5, 
Pregnancy Reporting 
Changed occurrences of the word “effective” to 
“acceptable” when describing adequacy of 
contraception  
 
Change Number 
Section # / Name 
Details of Change 
13 
Section 9.5, 
Pregnancy Reporting 
Text revised to reflect changes in criteria for 
acceptable contraception and definition of 
postmenopausal. 
 
Original Text 
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 


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pregnant who has not undergone successful surgical 
sterilization (hysterectomy, bilateral tubal ligation 
>PRQWKVSULRUWREDVHOLQH@RUELODWHUDO
oophorectomy) or is not postmenopausal (defined 
DVDPHQRUUKHDFRQVHFXWLYHPRQWKVLQZRPHQ
\HDUVRIDJH 
 
Revised Text 
FOCBP must agree to periodic pregnancy testing 
and use a medically acceptable method of 
contraception for the duration of the study. 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); 
OR  
• Hormonal contraception, including oral, 
injectable, or implantable methods started 
2 months prior to screening; OR 
• Non-hormonal contraception, including 
IUD (1-week status post placement) or 
properly used barrier methods (e.g., male or 
female condoms with or without 
spermicide, cervical cap/diaphragm with 
spermicide). 
* FOCBP for this study includes any 
premenopausal female capable of becoming 
pregnant who has not undergone successful surgical 
sterilization (hysterectomy, bilateral tubal ligation 
>PRQWKVSULRUWREDVHOLQH@RUELODWHUDO
oophorectomy) or is not postmenopausal (defined 
DVDPHQRUUKHDFRQVHFXWLYHPRQWKV 
 
Change Number 
Section # / Name 
Details of Change 
14 
Appendix 1 
Revised text under set up section for 
gravimetrically measured sweat production 
methods 
 
Original Text 
The same Study Site Staff member will perform the 
evaluation for each subject both within and across 
subjects. If this is not possible due to extenuating 
circumstances (e.g., vacation, illness, etc.), another 


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qualified Study Site Staff Member cross-trained by 
the originally assigned staff member may perform 
these activities.   
 
Revised Text 
To the best of their ability, the same Study Site 
Staff member will perform the evaluation for each 
subject both within and across subjects. If this is 
not possible due to extenuating circumstances (e.g., 
vacation, illness, etc.), another qualified Study Site 
Staff Member cross-trained by the originally 
assigned staff member may perform these 
activities.   
 
Change Number 
Section # / Name 
Details of Change 
15 
Appendix 7 
Added new Appendix 7 to detail changes made in 
AMENDMENT 01 


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AMENDMENT 02 SUMMARY OF CHANGES 
Change Number 
Section # / Name 
Details of Change 
1 
Section 10.5, 
Sample Size 
Text revised to reflect changes in the sample size 
calculation. Corresponding text in the synopsis and 
the following sections from the main body text 
revised accordingly: Section 2, Study Design; 
Section 4.1, Number of Subjects; and Section 
11.1.3, Method for Assignment to Study Product 
Groups. 
 
Original Text 
Based on analysis of results from a previous Phase 
2b study (CL-203), the following treatment 
differences (and variation) are expected in this 
protocol for the co-primary efficacy endpoints: 
 
• HDSM-Ax-7 responder analysis: an 
expected treatment difference of 23.9% with 
a reference (vehicle group) response rate of 
approximately 29.8%. However, to be 
conservative, the lower limit of a 1-sided 
75% confidence interval for the difference 
estimate, 18%, was used for sample size and 
power estimation.  
 
• GSP: an expected mean treatment 
difference of 73 mg for the continuous 
measurement data, with a pooled standard 
deviation of approximately 170. However, 
to be conservative, the lower limit of a 
1-sided 62.5% confidence interval for the 
difference estimate, 61 mg, was used for 
sample size and power estimation. 
 
A chi-square test for the HDSM-Ax-7 endpoint and 
a two-sample t-test for the GSP endpoint were used 
to estimate power for each endpoint. It is estimated 
that 450 total subjects will need to be randomized 
(in a 1:1 allocation) with 406 subjects completing 
the co-primary efficacy assessments (approximately 
10% drop-out rate). With 406 evaluable subjects, 
the overall study power to demonstrate a 
statistically significant treatment effect (two-sided 
p < 0.05) for both co-primary endpoints 


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simultaneously is greater than 0.90 (with greater 
than 0.95 power for each of HDSM-Ax-7 and 
GSP). 
 
Additionally, sample size estimation was also 
performed using rank-transformed GSP data. A 
difference of 16.6 in mean ranks with a pooled 
standard deviation of approximately 42 was used 
for this purpose. This yielded a reduced sample size 
estimate compared with the target of 406 subjects 
completing the co-primary efficacy assessments in 
order to achieve 0.95 power for GSP, further 
indicating that our sample size estimations are 
conservative. 
 
Revised Text 
Sample size estimation was performed for the co-
primary efficacy endpoints based on the results of a 
Phase 2b study (BBI-4000-CL-203): 
 
• HDSM-Ax-7 responder analysis: 2-point 
improvement response rates of 29.8% and 
53.7% were assumed for the vehicle and 
sofpironium bromide gel, 15% arms, 
respectively. The power is 0.95 with 116 
subjects per arm and a total of 232 subjects. 
 
• GSP: using rank-transformed GSP data for 
change from baseline to EOT, a difference 
of 16.6 in mean ranks between the vehicle 
and sofpironium bromide gel, 15% arms, 
with a pooled standard deviation of 
approximately 39.5, was used for this 
purpose. Normal approximation yielded a 
sample size estimate of 296 subjects for the 
study, 148 each arm, in order to achieve 
0.95 power for the GSP co-primary 
endpoint.   
With approximately 300 evaluable subjects, the 
overall study power to demonstrate a statistically 
significant treatment effect (two-sided p < 0.05) for 
both co-primary efficacy endpoints simultaneously 
is greater than 0.90 (with greater than 0.95 power 
for each of HDSM-Ax-7 and GSP). 


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Assuming missing data from approximately 15% of 
subjects, a total of 350 subjects will be targeted for 
enrollment. 
 
Change Number 
Section # / Name 
Details of Change 
2 
Section 2, 
Study Design 
The number of potential sites was changed from up 
to 65 to up to 45, and the number of subjects in 
each treatment arm was adjusted to 175.  
Corresponding text in the synopsis and Section 4.1, 
Number of Subjects also revised.  
 
Original Text 
Approximately 450 subjects, at up to approximately 
65 clinical sites in the US, will be enrolled to obtain 
approximately 406 evaluable subjects at the end of 
study. 
 
Subjects will be randomized 1:1 to receive 
sofpironium bromide gel, 15% or vehicle gel 
(225 subjects dosed with 15% gel and 225 subjects 
dosed with vehicle gel).  
 
Revised Text 
Approximately 350 subjects, at up to approximately 
45 clinical sites in the US, will be enrolled to obtain 
approximately 300 evaluable subjects at the end of 
study. 
 
Subjects will be randomized 1:1 to receive 
sofpironium bromide gel, 15% or vehicle gel 
(175 subjects dosed with 15% gel and 175 subjects 
dosed with vehicle gel).  


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AMENDMENT 03 SUMMARY OF CHANGES 
Change Number 
Section # / Name 
Details of Change 
1 
SYNOPSIS, 
Study Objectives; 
Section 2, 
Study Design; 
Section 3, Study 
Objectives and 
Assessments 
Text was revised in multiple sections to specify 
primary axillary hyperhidrosis as the indication 
throughout the protocol. 
 
Original Text 
… subjects with axillary hyperhidrosis.  
 
Revised Text 
…subjects with primary axillary hyperhidrosis. 
 
Change Number 
Section # / Name 
Details of Change 
2 
SYNOPSIS, 
Inclusion Criteria, 
Footnote 1 
Text was revised to indicate imputation details 
regarding HDSM-Ax-7 values. 
 
Original Text 
Subjects must answer all of the 7 sub items to be 
evaluable for the HDSM-Ax-7 scale assessment. 
 
Revised Text 
For each of the HDSM-Ax sub-items, missing 
values at EOT will be imputed. HDSM-Ax-7 at 
EOT will be derived from the imputed values. 
 
Change Number 
Section # / Name 
Details of Change 
3 
SYNOPSIS, 
Statistical Methods, 
Efficacy 
Details were added regarding normality testing and 
the use of rank-transformed versus continuous GSP 
data. 
 
Original Text 
The GSP co-primary endpoint will be analyzed 
using a rank based analysis of covariance 
(ANCOVA) model with fixed effects for treatment, 
baseline ranked GSP, and analysis center. 
 
Revised Text 
The GSP co-primary endpoint will be analyzed 
using an analysis of covariance (ANCOVA) model 
with fixed effects for treatment, baseline ranked 
GSP, and analysis center. The ANCOVA may use 
rank-transformed or continuous data, pending the 
outcome of the Shapiro Wilk Normality test. The 
normality test will be performed prior to multiple 
imputation and separately for each arm. Should the 
normality assumption be violated for either arm, the 


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primary analysis will use rank-transformed GSP 
data. If the normality assumption holds for both 
arms, the primary analysis will use continuous GSP 
data. 
 
Change Number 
Section # / Name 
Details of Change 
4 
SYNOPSIS, 
Statistical Methods, 
Safety 
Additional TEAE tables were included in the safety 
analyses. 
 
Original Text 
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, 
 
Revised Text 
Separate tables will be constructed for (a) all 
reported TEAEs, (b) protocol treatment-related 
TEAEs, (c) serious TEAEs, (d) TEAEs leading to 
protocol treatment discontinuation, (e) protocol 
treatment-related serious TEAEs, (f) severe 
TEAEs, (g) TEAEs leading to dose interruption, (h) 
TEAEs of special interest, and (i) anticholinergic 
TEAEs.   
 
Change Number 
Section # / Name 
Details of Change 
5 
SYNOPSIS, 
Statistical Methods, 
Sample Size and 
Power Estimation 
Additional details were added regarding sample 
size estimation.   
 
Original Text 
With approximately 300 evaluable subjects, the 
overall study power to demonstrate a statistically 
significant treatment effect (two-sided p < 0.05) for 
both co-primary efficacy endpoints simultaneously 
is greater than 0.90 (with greater than 0.95 power 
for each of HDSM-Ax-7 and GSP).  
Assuming missing data from approximately 15% of 
subjects, a total of 350 subjects will be targeted for 
enrollment. 
 
Revised Text 
A chi-square test for the HDSM-Ax-7 endpoint and 
a two-sample t-test for the GSP endpoint were used 
to estimate the above sample size and power for 
each endpoint. With approximately 300 evaluable 


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subjects, the overall study power to demonstrate a 
statistically significant treatment effect (two-sided 
p < 0.05) for both co-primary efficacy endpoints 
simultaneously is greater than 0.90 (with greater 
than 0.95 power for each of HDSM-Ax-7 and 
GSP).  
Additionally, sample size estimation was also 
performed using non-rank-transformed GSP data. 
An expected mean treatment difference of 73 mg 
with a pooled standard deviation of approximately 
170 was used for this purpose. This yielded a 
reduced sample size estimate compared with the 
target of 300 subjects completing the co-primary 
efficacy assessments in order to achieve 0.95 power 
for GSP, further indicating that our sample size 
estimations are conservative. 
Assuming missing data from approximately 15% of 
subjects, a total of 350 subjects will be targeted for 
enrollment. 
 
Change Number 
Section # / Name 
Details of Change 
6 
Section 1, 
Background and 
Clinical Rationale, 
Prior Human 
Experience 
Text was updated to reflect the most current 
number of subject exposures; additionally, text was 
deleted pertaining to previously ongoing studies, 
which have now been completed. 
 
Change Number 
Section # / Name 
Details of Change 
7 
Section 7, 
Procedures 
Text was added following the introductory 
paragraphs in Section 7 to specify that some 
assessments may be conducted remotely due to 
COVID-19-related restrictions. 
 
Revised Text 
In the event of restrictions due to COVID-19, or 
any other pandemic, the Sponsor may, with IRB 
approval where required, during the study 
implement some or all study assessments and 
procedures associated with patient visits to be 
conducted remotely or by home visits (per FDA 
Guidance on Conduct of Clinical Trials of Medical 
Products during COVID-19 Public Health 


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Emergency, March 2020) when the patients’ ability 
to visit investigator sites is impacted. 
 
 
Change Number 
Section # / Name 
Details of Change 
8 
Section 10.2.2, Co-
Primary Efficacy 
Endpoints 
Imputation methods for the HDSM-Ax-7 endpoint 
were revised. 
 
Original Text 
The mean will be derived by taking the sum of 
7 item scores and dividing it by 7. Subjects must 
answer all of the 7 sub-items to be evaluable for the 
HDSM-Ax-7 endpoint. Data will be considered 
missing for non-evaluable subjects. 
 
Revised Text 
The mean will be derived by taking the sum of 
7 item scores and dividing it by 7. For each of the 
HDSM-Ax sub-items, missing values at EOT will 
be imputed as described briefly in Section 10.3.1. 
HDSM-Ax-7 at EOT will be derived from the 
imputed values. Further details on imputation 
methods will be provided in the SAP. 
 
Change Number 
Section # / Name 
Details of Change 
9 
Section 10.2.4, 
Exploratory Efficacy 
Endpoints 
Additional exploratory endpoints were included. 
 
Revised Text 
• The proportion of subjects achieving at least a 
2-point improvement in the HDSM-Ax 
Question 4 score from baseline to Days 8, 15, 
22, 29, 36, 41, 42, 43 (EOT), and 57. 
• The proportion of subjects achieving at least a 
1-point improvement in the HDSM-Ax 
Question 5 score from baseline to Days 8, 15, 
22, 29, 36, 41, 42, 43 (EOT), and 57. 
 
Change Number 
Section # / Name 
Details of Change 
10 
Section 10.3, 
Analysis Methods  
Text was added specifying that missing values will 
be imputed. 
 
Original Text 
The primary efficacy analysis will be performed on 
the ITT population. 


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Revised Text 
The primary efficacy analysis will be performed on 
the ITT population with missing values imputed. 
 
 
Change Number 
Section # / Name 
Details of Change 
11 
Section 10.3.1, 
Primary and 
Secondary Analysis 
of the HDSM-Ax-7 
Co-Primary 
Endpoint 
Revisions were made to the text pertaining to the 
imputation model. 
 
Original Text 
If a subject is missing Visit 4 (Day 1) value, Visit 1 
(Screening) value will be used as Baseline. If a 
subject is missing Day 43 value, the closest (in 
time) available non-missing HDSM-Ax-7 value 
from Day 41 (±2 days) or Day 42 (±2 days) will be 
used as the first level of imputation. Should none of 
the Days 41, 42, and 43 values be available, 
multiple imputations of missing EOT HDSM-Ax-7 
score will be performed on the sofpironium 
bromide, 15% arm values using a control-based 
imputations (CBI) methodology (see Section 
10.3.4). Multiple imputations assuming missing at 
random will be performed for missing data for 
vehicle subjects.  
 
 
Revised Text 
Imputation will be item-level. If a subject is 
missing values for any of items 1a, 1b, 2a, 2b, 2c, 
2d, or 2e at Visit 4 (Day 1), the Visit 1 (Screening) 
value will be used as Baseline. If the Visit 1 
(Screening) value is also missing, the subject will 
be excluded from all HDSM-Ax-7 change from 
baseline analyses. If a subject is missing Day 43 
value, the closest (in time) available non-missing 
value from Day 41 (±2 days) or Day 42 (±2 days) 
will be used as the first level of imputation. Should 
none of the Days 41, 42, and 43 values be 
available, multiple imputations of missing EOT 
item-level scores will be performed on the 
sofpironium bromide gel, 15% arm values using a 
control-based imputations (CBI) methodology (see 


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Section 10.3.4). Multiple imputations assuming 
missing at random will be performed for missing 
data for vehicle subjects. The HDSM-Ax-7 score 
will be calculated using the imputed item-level 
values. Further details on imputation methods will 
be provided in the SAP. 
 
 
Change Number 
Section # / Name 
Details of Change 
12 
Section 10.3.1, 
Primary and 
Secondary Analysis 
of the HDSM-Ax-7 
Co-Primary 
Endpoint 
Details regarding site poolability were added in the 
estimand sub-section. 
 
Revised Text 
In addition, a separate site poolability analysis will 
be performed with analysis center-by-treatment 
interaction terms added to the primary analysis 
model. An overall p < 0.10 for the combined 
interaction terms will be regarded as an indication 
of potential heterogeneity among the analysis 
centers.  A mixed model analysis will then be 
performed with analysis center as a random effect 
to account for the potential heterogeneity. 
 
 
Change Number 
Section # / Name 
Details of Change 
13 
Section 10.3.2, 
Primary and 
Secondary Analyses 
of the GSP 
Co-Primary 
Endpoint 
Text was added describing the methods for using 
either rank-based or continuous data for the 
co-primary endpoint analysis. 
 
Revised Text 
Either rank-based GSP change from baseline to 
EOT or continuous GSP change from baseline to 
EOT will be analyzed. The GSP assessment is 
known to be a highly variable measure, and as 
such, the Shapiro Wilk test of normality will be 
performed to determine if the co-primary endpoint 
will be continuous or rank transformed. The 
normality test will be performed prior to multiple 
imputation for missing data and separately for each 


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arm. Should the normality assumption be violated 
for either arm, the co-primary endpoint will be 
analyzed using rank-transformed GSP data. If the 
normality assumption holds for both arms, then the 
co-primary endpoint will be analyzed using 
continuous GSP data.  
 
 
Change Number 
Section # / Name 
Details of Change 
14 
Section 10.3.2, 
Primary and 
Secondary Analyses 
of the GSP 
Co-Primary 
Endpoint 
Text was revised to indicate changes to the 
imputation method regarding the use of continuous 
or ranked data. 
 
Original Text 
Imputation Model: Data from subjects (see 
Section 10.3.3) meeting the criterion for “outlier” 
will be removed from imputation sampling 
database (i.e., data for vehicle patients) prior to 
missing data imputation. From the remaining 
imputation sampling database of continuous GSP 
measurements, multiple imputations of missing 
EOT sofpironium bromide, 15% arm GSP values 
will be performed using a CBI methodology (see 
Section 10.3.4). Multiple imputations assuming 
MAR will be performed for missing EOT data 
vehicle subjects. 
Analysis Model: ANCOVA model (either non-
ranked or ranked, pending outcome of normality 
test) 
Fixed effects: The following fixed effects are 
planned: 
• Treatment (class effect: sofpironium bromide 
gel, 15% group, vehicle group) 
• Baseline ranked GSP 
• Analysis center (see Section 10.3.3) 
 
Revised Text 
Imputation Model: Imputation will be done using 
continuous data prior to rank-transformation, 
should the normality assumption be violated. For 
continuous data, subjects with results (see Section 
10.3.3) meeting the criterion for “outlier” will be 
removed from imputation sampling database (i.e., 


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data for vehicle patients) prior to missing data 
imputation. From the remaining imputation 
sampling database of continuous GSP 
measurements, multiple imputations of missing 
EOT sofpironium bromide, 15% arm GSP values 
will be performed using a CBI methodology (see 
Section 10.3.4). Multiple imputations assuming 
MAR will be performed for missing EOT data 
vehicle subjects. Further details on multiple 
imputations will be provided in the SAP. 
Analysis Model: ANCOVA model (either non-
ranked or ranked, pending outcome of normality 
test) 
Fixed effects: The following fixed effects are 
planned: 
• Treatment (class effect: sofpironium bromide 
gel, 15% group, vehicle group) 
• •Baseline GSP (either non-ranked or ranked, 
pending outcome of normality test) 
• •Analysis center (see Section 10.3.3) 
 
Change Number 
Section # / Name 
Details of Change 
15 
Section 10.3.2, 
Primary and 
Secondary Analyses 
of the GSP 
Co-Primary 
Endpoint 
Text in (a) was revised to indicate changes to the 
imputation method regarding the use of continuous 
or ranked data, and text was added to (c) regarding 
site poolability analysis. 
 
Original Text 
(a) Using the same methodology as described 
above, an ANCOVA analysis will be performed for 
either the non-rank transformed, continuous GSP 
data. 
 
Revised Text 
(a) Using the same methodology as described 
above, an ANCOVA analysis will be performed for 
either the non-rank transformed, continuous GSP 
data or the rank transformed GSP data, pending the 
results of the normality test. If the normality 
assumption is violated and the rank-transformed 
data are used as the co-primary endpoint, analysis 
of the continuous data will be supportive. If the 
normality assumption holds and the continuous 


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data are used as the co-primary endpoint, then 
analysis of the rank-transformed data will be 
supportive.  
(b)…. 
(c) For the primary endpoint of either ranked or 
continuous GSP (pending normality test results), a 
separate, site poolability analysis will be performed 
with analysis center-by-treatment interaction terms 
added to the primary analysis model. An overall p 
< 0.10 for the combined interaction terms will be 
regarded as an indication of potential heterogeneity 
among the analysis centers. A mixed model 
analysis will then be performed with analysis center 
as a random effect to account for the potential 
heterogeneity.    
 
Change Number 
Section # / Name 
Details of Change 
16 
Section 10.3.3, 
Method of Pooling 
Sites to Generate 
Analysis Centers 
Text was revised to indicate details regarding 
pooling of sites. 
 
Original Text 
The lowest enrolling site will be combined with the 
largest enrolling site that does not meet the 
minimum requirement, and then the second lowest 
enrolling site and the second largest enrolling site 
will be combined, and so on. Further combining 
will be done until all analysis centers have at least 
10 subjects. All analyses that are controlled for site 
will use this analysis center designation.   
 
Revised Text 
For sites with <10 enrollments, the lowest enrolling 
site will be combined with the largest enrolling site, 
and then the second lowest enrolling site and the 
second largest enrolling site will be combined, and 
so on. Further combining will be done as necessary 
until all analysis centers have at least 10 subjects. 
All analyses that are controlled for site will use this 
analysis center designation. Site poolability will 
also be assessed as described in Sections 10.3.1 and 
10.3.2. 
Change Number 
Section # / Name 
Details of Change 


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17 
Section 10.3.5, 
Sensitivity Analyses 
of the Co-Primary 
Efficacy Endpoints 
Text was added that specified increments used for 
the GSP co-primary endpoint for Sensitivity 
Analysis 4. 
 
Original Text 
Missing values will be multiply imputed via this 
PHWKRGZLWKLQFUHDVLQJǻYDOXHV The GSP co-
primary efficacy outcome analysis methodology 
will be applied to the imputed datasets and repeated 
until statistical significance no longer holds. The 
tipping point will be identified and the results will 
be summarized graphically. 
For the HDSM-Ax-7 co-primary endpoint, identical 
imputation methodology to that described above for 
the GSP will be applied to the HDSM-Ax-7 total 
scores, and the resulting values will be 
dichotomized into responders versus non-
responders using the 2-point improvement criterion.  
 
Revised Text 
Missing values will be multiply imputed via this 
PHWKRGZLWKLQFUHDVLQJǻYDOXHV$ǻLQFUHPHQWRI
5 mg will be used for this study. The GSP co-
primary efficacy outcome analysis methodology 
will be applied to the imputed datasets and repeated 
until statistical significance no longer holds. The 
tipping point will be identified and the results will 
be summarized graphically. 
For the HDSM-Ax-7 co-primary endpoint, identical 
imputation methodology to that described above for 
the GSP will be applied to the HDSM-Ax-7 total 
scores, and the resulting values will be 
dichotomized into responders versus non-
responders using the 2-point improvement criterion. 
$ǻLQFUHPHQWRIon a 0-4 scale) will be used 
for this study. 
 
Change Number 
Section # / Name 
Details of Change 
18 
Section 10.3.5, 
Sensitivity Analyses 
of the Co-Primary 
Efficacy Endpoints 
Details were added regarding the sensitivity 
analysis. 
 
Original Text 
Sensitivity Analysis 5: A sensitivity analysis will 
be conducted to investigate whether any of the 
individual items in the HDSM-Ax-7 scale are 


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overly influencing changes observed in the total 
score. The primary analysis for HDSM-Ax-7 will 
be repeated for each of the 7 individual items. 
 
Revised Text 
Sensitivity Analysis 5: A sensitivity analysis will 
be conducted to investigate whether any of the 
individual items in the HDSM-Ax-7 scale are 
overly influencing changes observed in the total 
score. First, a subject will be counted as a 
responder if they achieve at least a 2-point 
improvement in the individual question from 
baseline to EOT. The logistic regression model for 
the primary analysis for HDSM-Ax-7 will be 
repeated for each of the 7 individual items, and 
each individual question will be analyzed 
separately. Secondly, one of the 7 items will be 
omitted, and the HDSM-Ax-7 total score will be 
calculated as the average of the remaining 6 items. 
The primary logistic regression analysis for 2-point 
improvement response rate will be performed on 
this 6-item scale. This process will be repeated 7 
times, each time with a different item of the 
HDSM-Ax-7 scale removed from calculation of the 
overall score 
 
Change Number 
Section # / Name 
Details of Change 
19 
Section 10.3.7, 
Analysis of 
Exploratory Efficacy 
Endpoints 
Text was added to specify the method for PGI-S 
and PGI-C endpoints, and to clarify when 
imputation for missing data will be performed. 
 
Original Text 
All exploratory efficacy endpoints that involve a 
proportion of responders will be analyzed using 
methods similar to what was described for the 
HDSM-Ax-7 co-primary endpoint. All other 
exploratory endpoints that involve a change from 
baseline to a single timepoint will be analyzed 
using methods similar to what is described for the 
GSP co-primary endpoint. P-values for exploratory 
efficacy endpoints will be provided for descriptive 
purposes only and no formal hypothesis testing will 
occur. 
 
Revised Text 
PGI-S and PGI-C endpoints will be analyzed using 
a Cochran-Mantel-Haenszel test. All other 
exploratory efficacy endpoints that involve a 


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proportion of responders will be analyzed using 
methods similar to what was described for the 
HDSM-Ax-7 co-primary endpoint. All other 
exploratory endpoints that involve a change from 
baseline to a single timepoint will be analyzed 
using methods similar to what is described for the 
GSP co-primary endpoint. P-values for exploratory 
efficacy endpoints will be provided for descriptive 
purposes only and no formal hypothesis testing will 
occur. All exploratory efficacy analyses will be 
based on available data and missing GSP and 
HDSM-Ax EOT data imputed. 
 
Change Number 
Section # / Name 
Details of Change 
20 
Section 10.4, 
Safety Analyses 
Additional items were included [(e) through (i)], 
which specify tabulated summaries to be produced 
for TEAEs.  Additional text was added specifying 
the definition of subject severity. 
 
Revised Text 
(e) protocol treatment-related serious TEAEs, (f) 
severe TEAEs, (g) TEAEs leading to dose 
interruption, (h) TEAEs of special interest, and (i) 
anticholinergic TEAEs…For any symptoms, 
subject severity is the worst severity of the two 
axillae.  
 
Change Number 
Section # / Name 
Details of Change 
21 
Section 10.5, 
Sample Size 
 Additional details were included regarding 
estimation of sample size. 
 
Original Text 
With approximately 300 evaluable subjects, the 
overall study power to demonstrate a statistically 
significant treatment effect (two-sided p < 0.05) for 
both co-primary efficacy endpoints simultaneously 
is greater than 0.90 (with greater than 0.95 power 
for each of HDSM-Ax-7 and GSP). 
Assuming missing data from approximately 15% of 
subjects, a total of 350 subjects will be targeted for 
enrollment. 
 
Revised Text 
A chi-square test for the HDSM-Ax-7 endpoint and 
a two-sample t-test for the GSP endpoint were used 
to estimate the above sample size and power for 
each endpoint. With approximately 300 evaluable 


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subjects, the overall study power to demonstrate a 
statistically significant treatment effect (two-sided 
p < 0.05) for both co-primary efficacy endpoints 
simultaneously is greater than 0.90 (with greater 
than 0.95 power for each of HDSM-Ax-7 and 
GSP). 
Assuming missing data from approximately 15% of 
subjects, a total of 350 subjects will be targeted for 
enrollment. 
Additionally, sample size estimation was also 
performed using non-rank-transformed GSP data. 
An expected mean treatment difference of 73 mg 
with a pooled standard deviation of approximately 
170 was used for this purpose. This yielded a 
reduced sample size estimate compared with the 
target of 300 subjects completing the co-primary 
efficacy assessments in order to achieve 0.95 power 
for GSP, further indicating that our sample size 
estimations are conservative. 
 
Change Number 
Section # / Name 
Details of Change 
22 
Section 12.7, 
Monitoring by the 
Sponsor 
Text was added to specify that alternative means of 
monitoring may be implemented due to COVID-19 
conditions. 
 
Original Text 
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. 
 
Revised Text 
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, 


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design, complexity, size, and endpoints of the 
study. In the event of interruptions to site 
accessibility due to COVID-19 or other pandemics 
conditions, alternative means of monitoring the 
study documents may be implemented, as allowed 
by local and federal requirements, such as remote 
monitoring and/or data verification. 
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. 
 

SAP_001.pdf: 
Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-301 
 
30 July 2021 
Version:  2.0 
STATISTICAL ANALYSIS PLAN 
30 July 2021 Amendment, Version 2.0 
 
 
 
CONFIDENTIAL 
 
 
A Multicenter, Randomized, Double-Blinded, 
Vehicle-Controlled Study to Evaluate the Safety and Efficacy 
of Topically Applied Sofpironium Bromide Gel, 15% in 
Subjects with Axillary Hyperhidrosis (the “Cardigan I Study”) 
 
 
 
PROTOCOL NUMBER: BBI-4000-CL-301 
 
 
 
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. 
NCT03836287


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-301 
 
30 July 2021 
 
Version:  2.0 
 
Page 2 of 74 
 
DOCUMENT VERSION CONTROL 
 
Version 
Number 
Date 
Comments/Changes 
0.1 
16 January 2019 
First Draft 
0.2 
23 October 2019 
Second Draft, updated per final Sept 20th 2019 version of 
CSP 
0.3 
2 March 2020 
Third Draft, updated per January 2020 consensus meeting 
0.4 
13 April 2020 
Fourth Draft, updated per March 2020 consensus meeting 
0.5 
20 May 2020 
Fifth Draft, updated per May 2020 consensus meeting 
0.6 
18 June 2020 
Sixth draft, updated per comments 
0.7 
01 July 2020 
Seventh draft, updated per comments 
1.0 
10 July 2020 
Finalize 
1.1 
09 June 2021 
Changes: reference to protocol amendment in section 1 
updated; demographics age category updated; duplicate 
subjects section 3.3 added; mITT population added for 
primary and key secondary end points, as well as sensitivity 
analyses for primary end points; convention for negative 
GSP values added; subgroup analyses added; AE text added 
about date imputation algorithm, local site reactions, figures, 
and overall summary table; formatting updates; update to 
TLF list; text added to Section 13 
2.0 
30 July 2021 
Changes: Section 8.3.7 update to PP analyses – PP is a 
completers population, so no multiple imputation is needed; 
Section 8.2.2 - analysis center pooling updated to add further 
combinations should models not converge; Sections 8.3.1 
and 8.3.2 - method for combining p-values for site 
poolability added and method for selecting overall p-values 
for mixed effects model added; update to titles in TLF list  
 
 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-301 
 
30 July 2021 
 
Version:  2.0 
 
Page 3 of 74 
 
APPROVALS 
Approved: 
 
 
Date: 
 
 
Bridget Daly 
Senior Biostatistician I 
 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-301 
 
30 July 2021 
 
Version:  2.0 
 
Page 4 of 74 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .............................................................................................. 6 
LIST OF IN-TEXT TABLES .............................................................................................. 7 
1. 
PURPOSE OF THE ANALYSES ............................................................................... 8 
2. 
PROTOCOL SUMMARY ........................................................................................... 9 
2.1 
Study Objectives ............................................................................................ 9 
2.2 
Study Endpoints ............................................................................................. 9 
2.2.1 
Primary Endpoints ................................................................................. 9 
2.2.2 
Secondary Endpoints ............................................................................ 9 
2.2.3 
Exploratory Efficacy Endpoints ........................................................... 10 
2.2.4 
Safety Endpoints ................................................................................. 11 
2.3 
Overall Study Design and Plan .................................................................... 11 
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 
3.3 
Duplicate Subjects ........................................................................................ 16 
4. 
ANALYSIS POPULATIONS .................................................................................... 17 
5. 
STUDY SUBJECTS ................................................................................................. 18 
5.1 
Disposition of Subjects ................................................................................. 18 
5.2 
Protocol Violations ........................................................................................ 18 
6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ......................... 19 
7. 
MEASUREMENTS OF STUDY TREATMENT EXPOSURE ................................... 20 
8. 
EFFICACY EVALUATION ....................................................................................... 21 
8.1 
Efficacy Endpoints ........................................................................................ 21 
8.1.1 
Definitions ........................................................................................... 21 
8.1.2 
Co-Primary Efficacy Endpoints ........................................................... 23 
8.1.3 
Secondary Efficacy Endpoints ............................................................ 23 
8.1.4 
Exploratory Efficacy Endpoints ........................................................... 23 
8.2 
Overview of Efficacy Analysis Issues ........................................................... 25 
8.2.1 
Handling of Dropouts or Missing Data ................................................ 25 
8.2.1.1 
Multiple Imputations for Missing Data on Co-Primary 
Endpoints ............................................................................... 25 
8.2.1.2 
GSP Data Outlier ................................................................... 26 
8.2.1.3 
Missing Data for all other Efficacy Endpoints ......................... 26 
8.2.2 
Multicenter Studies ............................................................................. 26 
8.2.3 
Assessment Time Windows ................................................................ 27 
8.2.4 
Multiple Comparisons/Multiplicity ........................................................ 27 
8.2.5 
Electronic Clinical Assessment Data .................................................. 28 
8.3 
Analysis Methods ......................................................................................... 28 
8.3.1 
Primary Analysis of the HDSM-Ax-7 Co-Primary Endpoint ................. 28 
8.3.2 
Primary Analysis of the GSP Co-Primary Endpoint ............................ 30 


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CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-301 
 
30 July 2021 
 
Version:  2.0 
 
Page 5 of 74 
 
8.3.3 
Supportive Analysis of the HDSM-Ax-7 Co-Primary Endpoint ............ 31 
8.3.4 
Supportive Analysis of the GSP Co-Primary Endpoint ....................... 32 
8.3.5 
Sensitivity Analyses of the Co-Primary Efficacy Endpoints................. 33 
8.3.5.1 
Sensitivity Analysis 1: GSP, All Available Data, no 
Imputations ............................................................................ 34 
8.3.5.2 
Sensitivity Analysis 2: GSP, Outlying Data Removed, 
Multiple Imputations ............................................................... 34 
8.3.5.3 
Sensitivity Analysis 3: HDSM-Ax-7, Missing Data imputed to 
Failure/Non-Response ........................................................... 35 
8.3.5.4 
Sensitivity Analysis 4: HDSM-Ax-7 and GSP, Tipping Point 
Analysis .................................................................................. 35 
8.3.5.5 
Sensitivity Analysis 5: Analysis of the Influence of 7 
individual items in the HDSM-Ax-7 scale ............................... 36 
8.3.6 
Secondary Efficacy Analyses .............................................................. 36 
8.3.7 
Exploratory Efficacy Analyses ............................................................. 36 
8.4 
Examination of Subgroups ........................................................................... 37 
9. 
SAFETY EVALUATION ........................................................................................... 39 
9.1 
Overview of Safety Analysis Methods .......................................................... 39 
9.2 
Adverse Events ............................................................................................ 39 
9.3 
Local Tolerability Assessments .................................................................... 41 
9.4 
Clinical Laboratory Evaluation ...................................................................... 41 
9.5 
Vital Signs, Physical Findings, and Other Observations Related to Safety .. 42 
9.5.1 
Vital Signs ........................................................................................... 42 
9.5.2 
Physical Examinations ........................................................................ 42 
9.5.3 
Other Safety Measures ....................................................................... 42 
9.5.3.1 
Prior and Concomitant Medications ....................................... 42 
10. PHARMACOKINETIC/PHARMACODYNAMIC EVALUATION .............................. 44 
11. OTHER ANALYSES ................................................................................................ 45 
11.1 
Psychometric Analysis of the HDSM-Ax-7 ................................................... 45 
12. INTERIM ANALYSES AND DATA MONITORING .................................................. 46 
13. CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL ........................ 47 
14. REFERENCES ......................................................................................................... 48 
15. LIST OF PLANNED TABLES .................................................................................. 49 
16. LIST OF PLANNED FIGURES ................................................................................ 65 
17. LIST OF PLANNED DATA LISTINGS .................................................................... 68 
18. APPENDICES .......................................................................................................... 69 
18.1 
Schedule of Events ...................................................................................... 69 
18.2 
HDSM-Ax Imputation Flow Chart ................................................................. 71 
18.3 
GSP Imputation Flow Chart .......................................................................... 72 
19. ATTACHMENTS ...................................................................................................... 74 
 
 
 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-301 
 
30 July 2021 
 
Version:  2.0 
 
Page 6 of 74 
 
LIST OF ABBREVIATIONS 
AE 
Adverse event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomic Therapeutic Chemical 
BBI-4000 
Sofpironium bromide 
CBI 
Control Based Imputation 
CMH 
Cochran-Mantel-Haenszel 
CSR 
Clinical study report 
CRF 
Case report form 
DLQI 
Dermatology Life Quality Index 
eCOA 
Electronic clinical outcome assessment 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EOT 
End of Treatment 
GSP 
Gravimetric sweat production 
HDSM-Ax 
Hyperhidrosis Disease Severity Measure-Axillary 
ICH 
International Council on Harmonisation 
ITT 
Intent-to-Treat 
MAR 
Missing at Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified intent-to-treat 
MMRM 
Mixed model repeated measures 
NMAR 
Not Missing at Random 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
PP 
Per-protocol 
REML 
Restricted maximum likelihood 
SAE 
Serious adverse event 
SD 
Standard deviation 
SI 
Systeme International 
TEAE 
Treatment-emergent adverse event 
WHO 
World Health Organization 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-301 
 
30 July 2021 
 
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LIST OF IN-TEXT TABLES 
Table   8-2 
Summary of Sensitivity Analyses of the Co-Primary Efficacy 
Endpoints ...................................................................................... 33 
 
 
 
 


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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-301. 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, efficacy, 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 
amendment to Amendment 1.1 dated June 09, 2021 is based on Amendment 3 of the 
BBI-4000-CL-301 protocol dated August 6, 2020 (Original September 20, 2019). 
 
 
 
 


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2. 
PROTOCOL SUMMARY 
2.1 
Study Objectives 
The purpose of this Phase 3 study is to assess the safety, local tolerability, and efficacy of 
sofpironium bromide gel, 15% when applied topically to subjects with primary axillary 
hyperhidrosis. 
Primary: 
x To evaluate the safety and local tolerability of sofpironium bromide gel, 15% 
when applied topically to subjects with primary axillary hyperhidrosis.  
x To evaluate the effect of sofpironium bromide gel, 15% on hyperhidrosis disease 
severity as it relates to sweat production, patient-reported outcomes, and quality 
of life self-assessments. 
 
2.2 
Study Endpoints 
2.2.1 
Primary Endpoints 
There are 2 co-primary efficacy endpoints: 
1. The proportion of subjects achieving at least a 2-point improvement in 
Hyperhidrosis Disease Severity Measurement-Axillary, 7-item (HDSM-Ax-7) 
scale score from baseline to end of treatment (EOT). 
2. The change in gravimetric sweat production (GSP) from baseline to EOT. 
2.2.2 
Secondary Endpoints 
The following secondary efficacy endpoints will be analyzed: 
x The proportion of subjects achieving at least a 1-point improvement in the 
HDSM-Ax-7 scale score from baseline to EOT. 
x The proportion of subjects achieving at least a 2-point improvement in the 
HDSM-Ax-7 scale score from baseline to EOT and achieving at least a 70% 
reduction in GSP from baseline to EOT. 
x The proportion of subjects achieving at least a 1-point improvement in the 
HDSM-Ax-7 scale score from baseline to EOT and achieving at least a 50% 
reduction in GSP from baseline to EOT. 


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2.2.3 
Exploratory Efficacy Endpoints 
Exploratory efficacy endpoints to be analyzed include the following: 
x The proportion of subjects achieving at least a 1-point improvement in the 
HDSM-Ax-7 scale score from baseline to Days 8, 15, 22, 29, 36, 41, 42, 43 
(EOT), and 57. 
x The proportion of subjects achieving at least a 1-point improvement in the 
HDSM-Ax, 11-Item (HDSM-Ax-11) scale score from baseline to Days 8, 15, 22, 
29, 36, 41, 42, 43 (EOT), and 57. 
x The proportion of subjects achieving at least a 2-point improvement in the 
HDSM-Ax-7 scale score from baseline to Days 8, 15, 22, 29, 36, 41, 42, 43 
(EOT), and 57. 
x The proportion of subjects achieving at least a 2-point improvement in the 
HDSM-Ax-11 scale score from baseline to Days 8, 15, 22, 29, 36, 41, 42, 43 
(EOT), and 57. 
x The proportion of subjects achieving at least a 1-point improvement in the 
HDSM-Ax Question 4 score from baseline to Days 8, 15, 22, 29, 36, 41, 42, 43 
(EOT), and 57. 
x The proportion of subjects achieving at least a 2-point improvement in the 
HDSM-Ax Question 4 score from baseline to Days 8, 15, 22, 29, 36, 41, 42, 43 
(EOT), and 57. 
x The proportion of subjects achieving at least a 1-point improvement in the 
HDSM-Ax Question 5 score from baseline to Days 8, 15, 22, 29, 36, 41, 42, 43 
(EOT), and 57. 
x The proportion of subjects achieving at least a 2-point improvement in the 
HDSM-Ax Question 5 score from baseline to Days 8, 15, 22, 29, 36, 41, 42, 43 
(EOT), and 57. 
x Change in Patient Global Impression of Severity (PGI-S) from baseline to Days 8, 
15, 22, 29, 36, 41, 42, 43 (EOT), and 57.  
x Patient Global Impression of Change (PGI-C) score on Day 43 (EOT).  
x The proportion of subjects achieving at least a 2-point improvement in the 
HDSM-Ax-11 scale score from baseline to EOT and achieving at least a 70% 
reduction in GSP from baseline to EOT. 
x The proportion of subjects achieving at least a 1-point improvement in the 
HDSM-Ax-11 scale score from baseline to EOT and achieving at least a 50% 
reduction in GSP from baseline to EOT. 
x The proportion of subjects achieving at least a 2-point improvement in the 
HDSM-Ax-7 scale score and achieving at least a 70% reduction in GSP from 
baseline to Days 8, 15, 22, 29, 36, 41, 42, 43, EOT, and Day 57. 


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x The proportion of subjects achieving at least a 2-point improvement in the 
HDSM-Ax-11 scale score and achieving at least a 70% reduction in GSP from 
baseline to Days 8, 15, 22, 29, 36, 41, 42, 43, EOT, and Day 57. 
x The proportion of subjects achieving at least a 1-point improvement in the 
HDSM-Ax-7 scale score and achieving at least a 50% reduction in GSP from 
baseline to Days 8, 15, 22, 29, 36, 41, 42, 43, EOT, and Day 57. 
x The proportion of subjects achieving at least a 1-point improvement in the 
HDSM-Ax-11 scale score and achieving at least a 50% reduction in GSP from 
baseline to Days 8, 15, 22, 29, 36, 41, 42, 43, EOT, and Day 57. 
x Change in HDSM-Ax-7 scale score from baseline to Days 8, 15, 22, 29, 36, 41, 
42, 43 (EOT), and 57 as a continuous measure. 
x Change in HDSM-Ax-11 scale score from baseline to Days 8, 15, 22, 29, 36, 41, 
42, 43 (EOT), and 57 as a continuous measure.  
x The proportion of subjects achieving at least a 70% reduction in GSP from 
baseline to Days 8, 15, 22, 29, 36, 41, 42, 43, EOT, and Day 57.  
x The proportion of subjects achieving at least a 50% reduction in GSP from 
baseline to Days 8, 15, 22, 29, 36, 41, 42, 43, EOT, and Day 57. 
x The rank-based GSP change from baseline to Days 8, 15, 22, 29, 36, 41, 42, 43, 
EOT, and Day 57. 
x The absolute GSP change from baseline to Days 8, 15, 22, 29, 36, 41, 42, 43, 
EOT, and Day 57. 
x The percent change from baseline in GSP from baseline to Days 8, 15, 22, 29, 36, 
41, 42, 43, EOT, and Day 57. 
x The change in the Dermatology Life Quality Index (DLQI) (axilla) from baseline 
to Day 15 and Day 43 (EOT). 
2.2.4 
Safety Endpoints 
Safety assessments of interest are local tolerability assessments, adverse events, 
laboratory evaluations, and vital signs. 
2.3 
Overall Study Design and Plan 
This is a multicenter, randomized, double-blinded, vehicle-controlled, Phase 3 study to 
evaluate the safety and efficacy of topically applied sofpironium bromide gel, 15% in 
subjects with primary axillary hyperhidrosis. 
Approximately 350 subjects, at up to approximately 45 clinical sites in the United States, 
will be randomized to receive either sofpironium bromide gel, 15%, or vehicle gel 
(placebo) in a balanced 1:1 ratio in order to obtain approximately 300 evaluable subjects 
at the end of study. 


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Subjects will apply the investigational product (either sofpironium bromide gel, 15%, or 
vehicle gel) once daily at bedtime to each axilla for 42 consecutive days. 
Patient-reported outcomes HDSM-Ax, Patient Global Impression of Severity (PGI-S), 
Patient Global Impression of Change (PGI-C; EOT only), and Dermatology Life Quality 
Index (DLQI), as well as Investigator-reported GSP, will be recorded during the study at 
predefined timepoints. Vital signs and local tolerability assessments will be collected at 
Visits 4 through 9 and Visits 12 (EOT) and 13. Adverse events will be collected at each 
post-Screening visit. Blood and urine samples will be collected and analyzed at Screening 
and Visit 12 (EOT) for routine hematology, chemistry, and urinalysis parameters. 
Additionally, a urine pregnancy test  for females of child-bearing potential  will be 
collected and analyzed at Visits 1, 4, 8, and 12. 
A total of 13 scheduled visits will take place over approximately 11 to 15 weeks, 
depending on when the Baseline Visit (treatment) is scheduled after the three (3) 
screening period visits: initial screening, GSP1, and GSP2. 
2.4 
Study Population 
Subjects aged  years with a diagnosis of primary axillary hyperhidrosis. 
2.5 
Treatment Regimens 
Either sofpironium bromide gel, 15% or vehicle gel (placebo) topically applied to the 
axillae once daily at bedtime for 42 consecutive days. 
2.6 
Sample Size Determination 
Sample size estimation was performed for the co-primary efficacy endpoints based on the 
results of a Phase 2b study (BBI-4000-CL-203): 
x HDSM-Ax-7 responder analysis: 2-point improvement response rates of 29.8% 
and 53.7% were assumed for the vehicle and sofpironium bromide gel, 15% arms, 
respectively. The power is 0.95 with 116 subject per arm and a total of 232 
subjects. 
x GSP: using rank-transformed GSP data for change from baseline to EOT, a 
difference of 16.6 in mean ranks between vehicle and sofpironium bromide gel, 
15% arms, with a pooled standard deviation of approximately 39.5, was used for 
this purpose. Normal approximation yielded a sample size estimate of 296 
subjects for the study, 148 in each arm, in order to achieve 0.95 power for the 
GSP co-primary endpoint. 
A chi-square test for the HDSM-Ax-7 endpoint and a two-sample t-test for the GSP 
endpoint were used to estimate the above sample size and power for each endpoint. With 
approximately 300 evaluable subjects, the overall study power to demonstrate a 
statistically significant treatment effect (two-sided p < 0.05) for both co-primary 


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endpoints simultaneously is greater than 0.90 (with greater than 0.95 power for each of 
HDSM-Ax-7 and GSP). It is estimated that 350 total subjects will need to be randomized 
(in a 1:1 allocation) for there to be 300 subjects completing the co-primary efficacy 
assessments (approximately 15% drop-out rate).   
Additionally, sample size estimation was also performed using non-rank-transformed 
GSP data. An expected mean treatment difference of 73 mg with a pooled standard 
deviation of approximately 170 was used for this purpose. This yielded a reduced sample 
size estimate compared with the target of 300 subjects completing the co-primary 
efficacy assessments in order to achieve 0.95 power for GSP, further indicating that our 
sample size estimations are conservative. 
 


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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 file name and run date/time. Summary tables 
and data listings will be summarized by treatment, as appropriate. All data collected per-
protocol will be listed.  Derived variables may also 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, no percentage will be shown. 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 there are missing values, 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 eCRF), and the SD and other measures of variability (e.g. standard error) 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. 
Unless otherwise specified, all statistical tests will be 2-sided XVLQJĮ 0.05. Estimates 
and confidence intervals will be reported to 1 more decimal than the original data. P-
values will be reported to 4 decimal places. P-values less than 0.0001 will be displayed as 
“<0.0001”; p-values greater than 0.9999 will be displayed as “>0.9999”. 
Summary tables and data listings:  
x No preliminary rounding will be performed; rounding will only occur after 
analysis.  
x 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. 


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x 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.  
x Data listings will be sorted by site, subject, treatment, and week and/or time of 
assessment, unless otherwise noted. 
x When change from baseline is calculated, baseline is the last observation obtained 
prior to dosing of the study drug unless otherwise specified. 
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 Anatomical-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 of 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: 
x 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 
x 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. For 
example, Day 1 is defined as the date of the first dose of gel. 


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Note that if the subject is randomized but not treated then the randomization date will be 
Day 1 for Schedule of Event purposes. 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. 
Unless otherwise noted, values reported as greater than or less than some quantifiable 
limit (e.g., “< 2.0”) will be summarized as such in summary tables and figures. However, 
analysis will be performed using the numeric equivalent, e.g. “<2.0” will be analyzed as 
2.0. Summary tables and figures will be footnoted when such practices occur. 
Partial or missing dates used in calculations of duration may be imputed with logic 
similar to that of Adverse Events (Section 9.2). 
3.3 
Duplicate Subjects 
During the course of the BBI-4000-CL-301 study, some subjects were identified as 
having registered for study participation at more than one site and/or in the second Phase 
3 pivotal study (BBI-4000-CL-302); these subjects are said to be duplicate subjects. 
Duplicate subjects are identified as such in the individual study subject listings. 
For analyses using the Intent-to-treat (ITT) Population or the Safety Population: (a) 
duplicate subjects with repeat registrations in the same study will have each registration 
analyzed as a different study subject with his/her unique subject ID; (b) For subjects who 
registered to both BBI-4000-CL-301 and BBI-4000-CL-302, the registrations will remain 
in each study as subjects for the respective study.    
Duplicate subjects will be removed from the modified ITT (mITT) Population (See 
Section 4) for the co-primary efficacy endpoints, secondary efficacy endpoints and 
sensitivity analyses of the co-primary efficacy endpoints. 


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4. 
ANALYSIS POPULATIONS 
Identification of the subjects to be included in each analysis population will be 
determined and finalized prior to database lock and unblinding. Subjects will be 
classified into the Safety, Intent-to-Treat (ITT), Per-Protocol (PP), and modified Intent-
to-Treat (mITT) populations according to the following definitions: 
Safety Population 
The Safety Population will include all subjects randomized in the study who received 
study drug, either vehicle or sofpironium bromide, 15%, at least once. Subjects will be 
analyzed according to the treatment actually received. If a subject receives any 
sofpironium bromide gel, 15%, the subject will be analyzed in the sofpironium bromide 
gel group. Otherwise the subject will be included in the vehicle group. 
Intent-to-Treat (ITT) Population  
The ITT Population will include all subjects who were randomized. Subjects will be 
analyzed according to the treatment group to which they were randomized, regardless of 
post-randomization protocol deviations, including no treatment or wrong treatment 
received. 
Per-Protocol (PP) Population  
The PP Population will be a subset of the mITT Population and will include subjects who 
meet the following criteria: 
x Meets all inclusion/exclusion criteria 
x Has not taken or applied any interfering concomitant medications 
x Completed the following visits: 
o Visit 2 GSP 1, and the required GSP data collection 
o Visit 3 GSP 2, and the required GSP data collection 
o Visit 4 (Day 1) Re-screening/Baseline GSP 3 and HDSM-Ax, and the 
required GSP and HDSM-Ax data collection 
o Visit 10 (GSP 4) Day 41 (± 2 days), and the required GSP data collection 
o Visit 11 (GSP 5) Day 42 (± 2 days), and the required GSP data collection 
o Visit 12 (GSP 6) Day 43 (± 2 days) and HDSM-Ax, and the required GSP 
and HDSM-Ax data collection 
Modified Intent-to-Treat (mITT) Population  
The mITT Population will be a subset of the ITT Population and excludes subjects with 
duplicate enrollments either within BBI-4000-CL-301 or across BBI-4000-CL-301 and 
BBI-BL-4000-CL-302 (see Section 3.3). All other subjects will be analyzed according to 
the treatment group to which they were randomized, regardless of post-randomization 
protocol deviations, including no treatment or wrong treatment received. 
 


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5. 
STUDY SUBJECTS 
5.1 
Disposition of Subjects 
Subject disposition will be summarized by treatment group for Safety, ITT, mITT, and 
PP populations separately. Summaries will include the number and percentage of subjects 
completing treatment, completing the study, and discontinuing the study early by the 
primary reason for discontinuation. The number and percentage of subjects excluded and 
reason for exclusion will be included in the PP population disposition table. 
All subject disposition data will be listed by clinical site. 
5.2 
Protocol Violations 
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: 
x Not meeting eligibility criteria;  
x Randomization error;  
x Received no protocol treatment or wrong treatment; 
x Non-compliance with study drug dosing;  
x On-study administration of a prohibited medication;  
x 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 prior to 
database lock and prior to breaking the blind of the treatment group assignments. 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 presented.  
A per subject listing will be provided for all protocol violations, major or minor, for the 
Safety Population. 
 
 


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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, mITT, and PP Populations. 
Age will be summarized using descriptive statistics. Age will also be categorized into 9-
12, 13-16, 17-30, DQG31 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, mITT, 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) = Weight (lbs) / 2.2046. 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. 
 


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7. 
MEASUREMENTS OF STUDY TREATMENT EXPOSURE 
Extent of study treatment exposure will be summarized for the Safety Population by 
treatment group. The duration of exposure will be presented in days and calculated as the 
date of last dose of study drug minus the date of first dose of study drug, plus one.  
Study treatment exposure will be calculated for each subject by taking into account 
whether a subject took all doses of study drug as instructed through dosing deviations, 
including dose interruptions/modifications for AEs/tolerability, collected on the dosing 
page of the eCRF. For each dosing entry, study treatment exposure will be determined as 
the total number of doses received divided by the number of expected doses, multiplied 
by 100. As the standard dosing regimen is for study drug to be applied 1 time daily per 
axilla, the expected number of doses will be the number of days between the date of last 
dose of study drug minus the date of first dose of study drug, plus one, times two. The 
number of doses received will be the number of days between the date of last dose of 
study drug minus the date of first dose of study drug, plus one, multiplied by 2, minus the 
number of missed doses recorded on the dosing page of the eCRF.  
Study treatment exposure will be calculated at the subject-level (i.e. across all dosing 
entries) and will be 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. 
 
 
 


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8. 
EFFICACY EVALUATION 
8.1 
Efficacy Endpoints 
The following assessment measures will be conducted to evaluate the efficacy of 
BBI-4000:  
x Hyperhidrosis Disease Severity Measurement-Axillary (HDSM-Ax) as measured 
by the subject (for subjects 12 years of age) 
x Hyperhidrosis Disease Severity Measurement-Axillary, Child (HDSM-Ax, Child) 
as measured by the subject (for subjects 9 to <12 years of age) 
x Gravimetrically measured sweat production (GSP) 
x Dermatology Life Quality Index (DLQI) axilla, as measured by the subject (for 
subjects 17 years of age) 
x Patient Global Impression Scales*; Severity (PGI-S**) and Change (PGI-C†) 
* These questions will be included in the HDSM-Ax questionnaires  
** Administered as Question #6 of HDSM-Ax at each assessment  
† Administered as Question #7 of HDSM-Ax at the Day 43 visit only 
 
8.1.1 
Definitions 
For the purposes of analysis, Baseline and End of Treatment (EOT) definitions for the 
two primary efficacy assessment measures, HDSM-Ax and Gravimetric Sweat 
Production (GSP), as well as the other efficacy parameters of interest, are defined below. 
HDSM-Ax   
The HDSM-Ax-7 scale 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 apply to both 
WKH\HDUVRIDJHVFDOHDQGWKH9-11 year old scale. The mean will be derived by 
taking the sum of 7 item scores and dividing it by 7. Subjects must answer all of the 7 
sub-items for the HDSM-Ax-7 score to be evaluable/non-missing. 
The HDSM-Ax-11 scale 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 apply WRERWKWKH\HDUVRIDJH
scale and the 9-11 year old 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 for the HDSM-Ax-11 score to be evaluable/non-missing. 
Baseline and End of therapy HDSM-Ax values are defined as follows: 
x Baseline = Visit 4 (Day 1) assessment 
x EOT = Visit 12 (Day 43) assessment 


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GSP (both axillae combined total) 
Baseline and End of therapy values are defined as follows: 
x Baseline = the median of GSP1, GSP2, and GSP3 measurements obtained on 
Visit 2, Visit 3, and Visit 4, respectively  
x EOT = the median of GSP4, GSP5, and GSP6 measurements obtained on Visit 
10, Visit 11, and Visit 12, respectively 
Note that at each timepoint, GSP will be defined as the sum of both axillae 
measurements. If one axilla value is missing at a timepoint, then the non-missing 
observed value will be multiplied by 2. The values for baseline or EOT will not be 
regarded as missing as long as the measurement is available at least for one of the three 
timepoints. Negative GSP values will be treated as missing. 
DLQI (axilla) 
The DLQI total score is calculated by summing answers to questions 1 through 10, 
including both parts of Question 7. The answer to each individual question is scored as 
follows’: 
“Very much” = 3 
“A lot” = 2 
“A little” = 1 
“Not at all” = 0 
“Not relevant” = 0 
Question 7,  “prevented work or studying” = 3 
All questions must be answered at the first DLQI assessment. Subsequent DLQI 
assessments missing an answer for a single question will be scored 0 for that question and 
totaled. Question 7 will be considered answered if Part 2 is answered even if No is not 
checked for Part 1. Subjects missing data for more than one question will have the 
instrument dropped for that visit. 
Baseline and End of therapy values are defined as follows. 
x Baseline = Visit 4 (Day 1) assessment 
x EOT = Visit 12 (Day 43) assessment 
 
Patient Global Impression Scales; Severity (PGI-S) and Change (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. 
 


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8.1.2 
Co-Primary Efficacy Endpoints 
The following co-primary efficacy endpoints will be analyzed to assess the efficacy of 
sofpironium bromide gel, 15%: 
x The proportion of subjects achieving at least a 2-point improvement in the 
HDSM-Ax-7 scale score from baseline to EOT (responders). 
x The change in GSP from baseline to EOT. 
Note that the analysis of the HDSM-Ax co-primary efficacy endpoint will be conducted 
using 7 of the 11 items on the HDSM-Ax scale. More specifically, the mean of the 2 
items in section 1 and the first 5 items in section 2 (7 sub-items in total) will be used. The 
mean will be derived by taking the sum of 7 item scores and dividing it by 7. For each of 
the HDSM-Ax sub-items, missing values at EOT will be imputed per Section 8.2.1.1 and 
Appendix 18.2. HDSM-Ax-7 at EOT will be derived from the imputed values.  
8.1.3 
Secondary Efficacy Endpoints 
The following secondary efficacy endpoints will be analyzed: 
x The proportion of subjects achieving at least a 1-point improvement in the 
HDSM-Ax-7 scale score from baseline to EOT. 
x The proportion of subjects achieving at least a 2-point improvement in the 
HDSM-Ax-7 scale score from baseline to EOT and achieving at least a 70% 
reduction in GSP from baseline to EOT. 
x The proportion of subjects achieving at least a 1-point improvement in the 
HDSM-Ax-7 scale score from baseline to EOT and achieving at least a 50% 
reduction in GSP from baseline to EOT. 
8.1.4 
Exploratory Efficacy Endpoints 
Exploratory efficacy endpoints to be analyzed include the following: 
x The proportion of subjects achieving at least a 1-point improvement in the 
HDSM-Ax-7 scale score from baseline to Days 8, 15, 22, 29, 36, 41, 42, 43 
(EOT), and 57. 
x The proportion of subjects achieving at least a 1-point improvement in the 
HDSM-Ax 11-Item (HDSM-Ax-11) scale score from baseline to Days 8, 15, 22, 
29, 36, 41, 42, 43 (EOT), and 57. 
x The proportion of subjects achieving at least a 2-point improvement in the 
HDSM-Ax-7 scale score from baseline to Days 8, 15, 22, 29, 36, 41, 42, 43 
(EOT), and 57. 
x The proportion of subjects achieving at least a 2-point improvement in the 
HDSM-Ax-11 scale score from baseline to Days 8, 15, 22, 29, 36, 41, 42, 43 
(EOT), and 57. 


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x The proportion of subjects achieving at least a 1-point improvement in the 
HDSM-Ax Question 4 score from baseline to Days 8, 15, 22, 29, 36, 41, 42, 43 
(EOT), and 57. 
x The proportion of subjects achieving at least a 2-point improvement in the 
HDSM-Ax Question 4 score from baseline to Days 8, 15, 22, 29, 36, 41, 42, 43 
(EOT), and 57. 
x The proportion of subjects achieving at least a 1-point improvement in the 
HDSM-Ax Question 5 score from baseline to Days 8, 15, 22, 29, 36, 41, 42, 43 
(EOT), and 57. 
x The proportion of subjects achieving at least a 2-point improvement in the 
HDSM-Ax Question 5 score from baseline to Days 8, 15, 22, 29, 36, 41, 42, 43 
(EOT), and 57. 
x Change in PGI-S from baseline to Days 8, 15, 22, 29, 36, 41, 42, 43, and 57.  
x PGI-C score on Day 43.  
x The proportion of subjects achieving at least a 2-point improvement in the 
HDSM-Ax-11 scale score from baseline to EOT and achieving at least a 70% 
reduction in GSP from baseline to EOT. 
x The proportion of subjects achieving at least a 1-point improvement in the 
HDSM-Ax-11 scale score from baseline to EOT and achieving at least a 50% 
reduction in GSP from baseline to EOT. 
x The proportion of subjects achieving at least a 2-point improvement in the 
HDSM-Ax-7 scale score and achieving at least a 70% reduction in GSP from 
baseline to Days 8, 15, 22, 29, 36, 41, 42, 43, EOT, and Day 57. 
x The proportion of subjects achieving at least a 2-point improvement in the 
HDSM-Ax-11 scale score and achieving at least a 70% reduction in GSP from 
baseline to Days 8, 15, 22, 29, 36, 41, 42, 43, EOT, and Day 57. 
x The proportion of subjects achieving at least a 1-point improvement in the 
HDSM-Ax-7 scale score and achieving at least a 50% reduction in GSP from 
baseline to Days 8, 15, 22, 29, 36, 41, 42, 43, EOT, and Day 57. 
x The proportion of subjects achieving at least a 1-point improvement in the 
HDSM-Ax-11 scale score and achieving at least a 50% reduction in GSP from 
baseline to Days 8, 15, 22, 29, 36, 41, 42, 43, EOT, and Day 57. 
x Change in HDSM-Ax-7 scale score from baseline to Days 8, 15, 22, 29, 36, 41, 
42, 43 (EOT), and 57 as a continuous measure. 
x Change in HDSM-Ax-11 scale score from baseline to Days 8, 15, 22, 29, 36, 41, 
42, 43 (EOT), and 57 as a continuous measure.  
x The proportion of subjects achieving at least a 70% reduction in GSP from 
baseline to Days 8, 15, 22, 29, 36, 41, 42, 43, EOT, and Day 57.  
x The proportion of subjects achieving at least a 50% reduction in GSP from 
baseline to Days 8, 15, 22, 29, 36, 41, 42, 43, EOT, and Day 57. 


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x The rank-based GSP change from baseline to Days 8, 15, 22, 29, 36, 41, 42, 43, 
EOT, and Day 57. 
x The absolute GSP change from baseline to Days 8, 15, 22, 29, 36, 41, 42, 43, 
EOT, and Day 57. 
x The percent change from baseline in GSP from baseline to Days 8, 15, 22, 29, 36, 
41, 42, 43, EOT, and Day 57. 
x The change in the DLQI (axilla) from baseline to Day 15 and Day 43 (EOT). 
8.2 
Overview of Efficacy Analysis Issues 
8.2.1 
Handling of Dropouts or Missing Data 
8.2.1.1 
Multiple Imputations for Missing Data on Co-Primary 
Endpoints 
For both HDSM-Ax-7 (diagram in Appendix 18.2) and GSP (diagram in Appendix 18.3), 
multiple imputations for missing EOT values in the vehicle group will be performed 
assuming Missing at Random (MAR). For the sofpironium bromide gel, 15% group, 
multiple imputations using a control-based imputations (CBI) model will be employed as 
the primary imputation method to handle missing EOT data. This approach will adopt a 
missing not at random (MNAR) assumption. It assumes that, due to discontinuing 
treatment, a subject who has been benefiting from sofpironium bromide gel, 15%, would 
maintain its benefit up to the last known efficacy endpoint value and from then on behave 
like a subject on vehicle. That is, the subject’s efficacy trajectory after dropping out 
would be similar to that of a subject on vehicle with like subject characteristics and 
endpoint history up to the last observed visit for the sofpironium bromide gel, 15%, 
subject. 
Twenty imputed datasets will be generated for each of the co-primary efficacy endpoints. 
The same co-primary analysis models (Section 8.3) will be applied to the multiple 
imputed datasets and the results combined via Rubin’s rules (Rubin, 1976). 
 
HDSM-Ax individual missing items scores will be imputed. If the individual item score 
is missing at Visit 12, but non-missing at either Visits 10 and or/ 11, then the closest (in 
time) non-missing score will be carried forward.  If the individual item score is missing at 
all three visits of Visits 10, 11, and 12, then individual item scores will be imputed for all 
three visits. The mean will be derived from the imputed values. Further details are 
provided in Section 8.3.1 below. 
 
GSP at EOT will only be multiply imputed if both the right and left axilla weights are 
missing at all three visits of Visits 10, 11, and 12. Further details are provided in Section 
8.3.2 below. 
 


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8.2.1.2 
GSP Data Outlier 
The GSP assessment is known to be a highly variable measure. As such, two approaches 
will be applied to reduce the influence of large variations: 
 
1) Prior to performing missing data imputations, if Normality of the GSP change 
from baseline to EOT data is violated by the Shapiro-Wilk test for either the 
vehicle arm or the sofpironium bromide gel, 15% arm, the GSP data will be rank-
transformed at baseline and EOT and the difference in ranks will be used as the 
dependent variable in the primary efficacy model (Section 8.3.2) 
2) Outlying GSP values will be removed from the imputation sampling database for 
missing data imputation purposes, as described below 
 
In order to ensure that the missing data imputation method proposed is robust to outliers 
for the GSP co-primary endpoint, data from subjects that meet the criterion for being an 
outlier will be removed from the imputation sampling database as follows. Combining 
the vehicle and sofpironium bromide gel, 15% arms, the mean and standard deviation 
will be calculated for the non-missing GSP change from baseline to EOT data, i.e. the 
GSP primary outcome measure. Data values more than 3 standard deviations away from 
the mean will be regarded as outliers. However, since the outliers are included in the 
original mean and standard deviation calculations and would have inflated their values, 
the outliers will be set aside and the mean and standard deviation will be re-calculated to 
see if any additional outliers are identified. This process will be repeated until no more 
outliers are identified. Prior to performing imputation for missing GSP change from 
baseline data in the ITT population (Section 8.2.1.1) data values contributing to the 
outlying observations will be removed from the imputation sampling database, i.e. the 
non-missing vehicle data. With this approach, outlying data will not be propagated during 
missing data imputation. Once an imputation is complete, all original non-missing data 
(including outliers) and the imputed, previously missing, data will be used for the GSP 
ITT analysis.  
8.2.1.3 
Missing Data for all other Efficacy Endpoints 
Unless otherwise specified, missing GSP and HDSM-Ax EOT data will be imputed for 
all ITT efficacy analyses. 
8.2.2 
Multicenter Studies 
Subjects from low enrolling sites will be pooled in order to generate analysis centers. The 
minimum number of subjects per analysis center is 10. For sites with <10 enrollments, 
the lowest enrolling site will be combined with the largest enrolling site, and then the 
second lowest enrolling site and the second largest enrolling site will be combined, and 
so on. Further combining will be done as necessary until all analysis centers have at least 
10 subjects. All analyses that are controlled for site will use this analysis center 
designation. 


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Should convergence issues occur due to small cell size for the covariate corresponding to 
analysis center, the following approach will be followed: a) analysis center will first be 
re-defined, continuing to group the largest and smallest centers together until there are at 
least 35 subjects per center; b) If convergence issues still occur after step a) has been 
completed then analysis center will be re-defined again, continuing to group the largest 
and smallest centers together until there are at least 70 subjects per center; c) if 
convergence issues still remain after implementing steps a) and b), the term for analysis 
center will dropped from the MI algorithm/statistical model. 
If the convergence issue occurs in the generation of a MI dataset, all outcomes based on 
that dataset will use the same analysis center definition.   All sensitivity analysis datasets 
will use the same analysis center definition and the models based off of those datasets 
will use that analysis center definition. 
If the convergence issue occurs in modeling of an outcome, all models for that particular 
outcome will use the same analysis center definition.  For example, if the grouping of at 
least 70 subjects per analysis center is required for the (27DQDO\VLVRI-point 
improvement in HDSM-Ax-7, then all modHOVDWDOOWLPHSRLQWVRIWKH-point 
improvement in HDSM-Ax-7 will use that analysis center definition.  However, this 
would not impact the choice of DQDO\VLVFHQWHUIRU-point improvement in HDSM-Ax-
7, nor WKH-point improvement in HDSM-Ax-11. 
8.2.3 
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 collected. 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. 
8.2.4 
Multiple Comparisons/Multiplicity 
A gated, fixed-sequence testing procedure will be used in this protocol to control the 
overall familywise false positive error rate for the primary and secondary endpoints 
analyses. The primary analysis will be regarded as positive and the trial will be successful 
for the co-primary efficacy endpoints if both null hypotheses are rejected in favor of 
sofpironium bromide gel, 15% at the 2-sided alpha = 0.05 level of significance (see 
hypotheses defined in Sections 8.3.1 and 8.3.2). 
The three secondary efficacy endpoints are described in Section 8.1.3. If both co-primary 
analyses yield statistically significant results in favor of the sofpironium bromide gel, 
15%, group, the three secondary efficacy endpoints will be tested in a fixed sequence in 
the order presented in Section 8.1.3. Testing will continue only if all previously tested 


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null hypotheses have been rejected at the 2-sided alpha = 0.05 significance level in favor 
of sofpironium bromide gel, 15%.  
8.2.5 
Electronic Clinical Assessment Data  
Gravimetric measurements of sweat production (GSP) and patient-reported outcomes 
HDSM-Ax, PGI-S, PGI-C, and Dermatology Life Quality Index (DLQI) (via electronic 
clinical outcomes assessment [eCOA] technology) will be recorded during the study at 
predefined timepoints. In the event that the eCOA data is not able to be captured via a 
device, the assessments will be recorded manually and the data entered into EDC. It is 
not expected that a subject will record both an electronic and a manual assessment for an 
outcome at any given timepoint. However, if duplicate data do exist, then the eCOA 
value will be used in the analysis. 
8.3 
Analysis Methods 
With the exclusion of Section 8.3.7 Exploratory Efficacy Analyses, all other Section 8.3 
analyses will be repeated for the mITT population. 
The primary efficacy analysis will be performed on the ITT population with missing 
values imputed. The co-primary efficacy outcomes are: 
x The proportion of subjects achieving at least a 2-point improvement in the 
HDSM-Ax-7 scale score from baseline to EOT in the sofpironium bromide gel, 
15% group versus vehicle; and 
x The change in GSP from baseline to EOT in the sofpironium bromide gel, 15% 
group versus vehicle. 
Both comparisons will be conducted using two-sided tests at an alpha=0.05 level. Both 
endpoints will need to demonstrate a statistically significant positive result in favor of 
sofpironium bromide gel, 15% for the study to be considered successful.  
8.3.1 
Primary Analysis of the HDSM-Ax-7 Co-Primary Endpoint    
The primary analysis of the HDSM-Ax-7 co-primary endpoint will use the 2-point 
responder status at EOT. If a subject is missing any of items 1a, 1b, 2a, 2b, 2c, 2d, or 2e 
Visit 4 (Day 1) value, Visit 1 (Screening) value will be used as Baseline. If Visit 1 
(Screening) value is also missing, subject will be excluded from all HDSM-Ax-7 change 
from baseline analyses. If a subject is missing Day 43 value, the closest (in time) 
available non-missing value from Day 41 (±2 days) or Day 42 (±2 days) will be used as 
the first level of imputation. Should none of the Days 41, 42, and 43 values be available, 
multiple imputations of missing EOT (i.e. Day 43) item-level scores will be performed on 
the sofpironium bromide gel, 15% arm values using CBI methodology (Section 8.2.1.1 
and Appendix 18.2). Multiple imputations assuming MAR will be performed for missing 
data for Vehicle subjects. The HDSM-Ax-7 score will be calculated using the imputed 
item-level values. No other missing value imputation will be performed in this co-
primary analysis.  


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The analysis will use a logistic regression model. 
The following covariates are planned: 
x Treatment (class effect: sofpironium bromide gel, 15% group, vehicle) 
x Baseline HDSM-Ax-7 total score 
x Analysis center (see Section 8.2.2) 
The null hypothesis to be tested for the primary analysis of the HDSM-Ax-7 co-primary 
endpoint is as below: 
H0: The proportion of subjects achieving at least a 2-point improvement in the HDSM-
Ax-7 scale score from baseline to EOT is the same in the sofpironium bromide gel, 15%, 
and vehicle groups, i.e. 
H0: PA = PP ; 
where PA and PP represent the true underlying proportion of subjects achieving at least a 
2-point improvement in HDSM-Ax-7 for Treatment A (sofpironium bromide gel, 15%) 
and Treatment P (vehicle), respectively.  
The null hypothesis will be tested against the two-sided alternative hypothesis as below: 
H1: The proportion of subjects achieving at least a 2-point improvement in the HDSM-
Ax-7 scale score from baseline to EOT is not the same in the sofpironium bromide gel, 
15%, and vehicle groups, i.e. 
H1: PA  PP ; 
Within the model specified above, a comparison will be made of the proportion of 2-
point HDSM-Ax-7 responders at EOT in the sofpironium bromide gel, 15%, and vehicle 
groups. The estimand of this co-primary efficacy analysis is the difference in proportions 
between sofpironium bromide gel, 15%, and vehicle with a 2-point improvement from 
baseline to EOT in HDSM-Ax-7 total scores among all ITT subjects, regardless of 
treatment adherence. The comparison will be conducted using a two-sided test at an alpha 
= 0.05. 
A separate, site poolability analysis will be performed with analysis center-by-treatment 
interaction terms added to the primary analysis model. The overall p-value for the 
analysis center-by-treatment interaction terms will be determined by averaging the Chi-
squared test statistics across the 20 imputations, then calculating the p-value based on that 
average. An overall p < 0.10 for the combined interaction terms will be regarded as an 
indication of potential heterogeneity among the analysis centers.  A mixed effects logistic 
regression model analysis will then be performed with analysis center as a random effect 
to account for the potential heterogeneity.  The overall p-value for the analysis center 
random effect will be derived from the covariance parameter estimates across the 20 
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8.3.2 
Primary Analysis of the GSP Co-Primary Endpoint    
The primary analysis of the GSP co-primary endpoint will use all available GSP change 
from baseline scores at EOT. Missing baseline continuous GSP data (i.e. missing data for 
all Visits of 2, 3, 4) will be imputed using the Screening GSP data. If Screening GSP data 
is also missing, subject will be excluded from all GSP change from baseline analyses. 
For GSP change from baseline to EOT data, univariate checks will be performed prior to 
performing multiple imputations for missing data. The Shapiro-Wilk test will be applied 
to assess Normality of the model residuals separately for sofpironium bromide gel, 15% 
arm, and vehicle arm. Should the assumption of Normality not be violated for both 
treatment arms, then GSP change from baseline to EOT values will be analyzed as 
continuous data. The median of continuous GSP data from Visits 2, 3, and 4 will be used 
as the baseline value for a subject, and the median of continuous GSP data from Visits 
10, 11, and 12 will be used as the EOT value. For each subject, the difference between 
the baseline and EOT GSP values (EOT – baseline) will serve as the outcome value for 
the GSP ANCOVA analysis. 
Should the assumption of Normality be violated for either treatment arm, the GSP change 
from baseline to EOT values will be rank-transformed for both arms. For the rank-
transformation of GSP measurements at a particular timepoint, continuous data for all 
subjects 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. For 
determination of baseline value for a subject, the continuous GSP data will be ranked 
separately at each of Visits 2, 3, and 4; the median of the three ranks will be used as 
baseline value of the subject. Using the measurement data from Visits 10, 11, and 12, the 
rank-transformed GSP value at EOT will be derived in the same manner. For each 
subject, the difference between the rank-transformed baseline and EOT GSP values (EOT 
– baseline) will serve as the outcome value for the rank-based GSP ANCOVA analysis.     
Missing EOT GSP data (continuous data), for each of Days 41, 42, and 43 will be 
imputed before analysis is performed for subjects missing both axillae at all 3 visits. If at 
least one axillae is non-missing at Day 41, 42, or 43, then the EOT value will be 
considered non-missing. For continuous data, subjects with results (Section 8.2.1.2) 
meeting the criterion for “outlier” will be removed from imputation sampling database 
(i.e., data for vehicle subjects) prior to missing data imputation. From the appropriate 
imputation sampling database, multiple imputations of missing EOT sofpironium 
bromide gel, 15% arm GSP values will be performed using a CBI methodology (Section 
8.2.1.1 and Appendix 18.3). Multiple imputations assuming MAR will be performed for 
missing EOT data Vehicle subjects.  
The model specified is an ANCOVA model (either non-ranked or ranked). 
The following fixed effects are planned: 
x Treatment (class effect:  sofpironium bromide gel, 15% group, vehicle) 


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x Baseline GSP (either non-ranked or ranked) 
x Analysis center (see Section 8.2.2) 
The null hypothesis to be tested for the primary analysis of the GSP Co-primary endpoint 
is as below: 
H0: The GSP changes (or rank-based changes) from baseline to EOT are the same in the 
sofpironium bromide gel, 15%, and vehicle groups, i.e. 
H0: µA = µP ; 
where µA and µP represent the true mean change (or rank-based change) in GSP scores for 
Treatment A (sofpironium bromide gel, 15%) and Treatment P (vehicle), respectively. 
The null hypothesis will be tested against the two-sided alternative hypothesis as below: 
H1: The GSP changes (or rank-based changes) from baseline to EOT are not the same in 
the sofpironium bromide gel, 15%, and vehicle groups, i.e. 
H1: µA  µP ; 
The ANCOVA model used in this analysis will be the same, regardless of whether 
continuous or rank-based GSP data is used. Within the model specified above, a 
comparison will be made (using LS mean contrasts) to compare the change (or 
rank-based change) from baseline to EOT for GSP in the sofpironium bromide gel, 15%, 
and vehicle groups. The estimand of this co-primary efficacy analysis is the mean 
treatment difference, sofpironium bromide gel, 15%, versus vehicle, in change from 
baseline (or rank-based change from baseline) to EOT for GSP among all ITT subjects, 
regardless of treatment adherence. The comparison will be conducted using a two-sided 
test at an alpha = 0.05. 
For the primary endpoint of either ranked or continuous GSP (pending normality test 
results), a separate, site poolability analysis will be performed with analysis center-by-
treatment interaction terms added to the primary analysis model. The overall p-value for 
the analysis center-by-treatment interaction terms will be determined by averaging the 
F test statistics across the 20 imputations, then calculating the p-value based on that 
average. An overall p < 0.10 for the combined interaction terms will be regarded as an 
indication of potential heterogeneity among the analysis centers.  A mixed effect 
ANCOVA model analysis will then be performed with analysis center as a random effect 
to account for the potential heterogeneity. The overall p-value for the analysis center 
random effect will be derived from the covariance parameter estimates across the 20 
imputations.     
8.3.3 
Supportive Analysis of the HDSM-Ax-7 Co-Primary Endpoint 
As a supportive analysis of the HDSM-Ax-7 co-primary endpoint, change from baseline 
to EOT will be analyzed as a continuous measure. The analysis model will be an 
ANCOVA model with treatment, baseline HDSM-Ax-7 score, and analysis center as 


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covariates. The estimand for this analysis is the difference in mean baseline to EOT 
changes in HDSMAx-7 total scores between sofpironium bromide gel, 15%, and vehicle 
arms among all ITT subjects, regardless of treatment adherence.  
8.3.4 
Supportive Analysis of the GSP Co-Primary Endpoint 
Two supportive analyses will be performed for the GSP co-primary endpoint: 
(1) If the Shapiro-Wilk test for Normality of the GSP baseline to EOT data is violated, 
then, using the same methodology as described in Section 8.3.2, an ANCOVA analysis 
will be performed for the non-rank-transformed, continuous GSP data. The model will 
use the fixed effects of treatment, baseline GSP, and analysis center. If the Shapiro-Wilk 
test for Normality of the GSP baseline to EOT data is not violated and the continuous 
GSP is used for the co-primary endpoint, then the ranked GSP ANCOVA analysis will be 
performed as a supportive analysis. 
(2) To further address the potential large variations in GSP data, mixed model repeated 
measures (MMRM) analyses will be performed to estimate the average sofpironium 
bromide gel, 15% treatment effect over the 6 week course of treatment, i.e. the average 
sofpironium bromide gel, 15% versus vehicle difference from baseline to Days 8, 15, 22, 
29, 36, and EOT, using both rank-based and non-rank-based data. As the MMRM 
methodology is known to be robust to missing data, missing data will not be imputed for 
this analysis.   
The model specified is a REML-based analysis with an identity link. 
The following fixed effects are planned: 
x Treatment (class effect: sofpironium bromide gel, 15% group, vehicle) 
x Visit (visits will be coded as ordinal, where Visit 5 = 1, Visit 6 =2, Visit 7 = 3, 
Visit 8 = 4, Visit 9 = 5, EOT = 6) 
x Baseline GSP (ranked or non-ranked, depending on the model) 
x Analysis center 
x Baseline-by-visit interactions  
x Treatment-by-visit interactions 
Based on the Study BBI-4000 CL-203 results, significant treatment versus visit 
interactions are not expected. Nevertheless, should treatment versus visit interactions be 
significant (i.e. p<0.05), the estimated treatment effect at EOT will be reported. An 
unstructured correlation matrix will be used to model the variance and covariance of 
within-subject repeated measures and restricted maximum likelihood estimation. The 
Kenward-Roger method will be used for the denominator degrees of freedom. In order to 
arrive at the correct structure for the data, if the model fails to converge using an 
unstructured covariance matrix, other covariance structures will be tested as follows: 
heterogeneous Toeplitz (TOEPH), heterogeneous AR(1) (ARH1), heterogeneous 
compound symmetry (CSH), Toeplitz (TOEP), spatial power with numeric visit number 


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SP(POW)(VISn), autoregressive (1) (AR(1)), and compound symmetry (CS). The model 
that converges with the lowest Akaike Information Criterion (AIC) will be used. If the 
treatment-by-visit interactions are not significant overall, they will be removed from the 
final model; similarly for the baseline-by-visit interactions. 
8.3.5 
Sensitivity Analyses of the Co-Primary Efficacy Endpoints 
As stated in Section 8.2.1.1, multiple imputations procedures for missing HDSM-Ax-7 
and GSP values will be performed prior to the co-primary efficacy analyses under MAR 
and MNAR assumptions. In order to support the results of the co-primary GSP analysis, 
the ranked GSP and non-rank-transformed GSP ANCOVA analyses will be repeated 
without imputing missing data, and again after removing outlier data. To further explore 
the robustness of the primary analysis results to different missing data assumptions, 
analyses using two additional imputation methods will be performed as presented below. 
The first is an analysis of the HDSM-AX-7 co-primary endpoint with missing data 
imputed as failure/non-response. The second is a tipping point analysis on both co-
primary endpoints, using multiple imputations for missing data. Additionally, the 7 items 
in the HDSM-Ax-7 scale will be analyzed individually to support the primary analysis for 
this co-primary endpoint. The below sensitivity analyses will be performed using the ITT 
Population and the mITT Population. 
Table   8-2 
Summary of Sensitivity Analyses of the Co-Primary Efficacy 
Endpoints 
Sensitivity 
Analysis 
Number 
Co-Primary 
Efficacy Outcome 
Assessed 
Sensitivity Analysis 
Populations 
1 
GSP change from 
baseline to EOT 
Analysis performed on 
available data only 
without imputing 
missing data; using 
both ranked and non-
ranked data. 
ITT, mITT 
2 
GSP change from 
baseline to EOT 
Subjects with outlying 
data removed from 
analysis; using both 
ranked and non-ranked 
data (multiple 
ITT, mITT 


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imputations for missing 
data). 
3 
HDSM-Ax-7 2-
point improvement 
from baseline to 
EOT 
Missing data imputed 
as failure/non-response 
(single imputation 
only) 
ITT, mITT 
4 
HDSM-Ax-7 2-
point improvement 
and GSP change 
from baseline to 
EOT 
Tipping point analysis 
(multiple imputations 
for missing data) 
ITT, mITT 
5 
HDSM-Ax-7 2-
point improvement 
from baseline to 
EOT 
Analysis of the 
influence of the 7 
individual items in the 
HDSM-Ax-7 scale 
(multiple imputations 
for missing data) 
ITT, mITT 
 
 
8.3.5.1 
Sensitivity Analysis 1: GSP, All Available Data, no 
Imputations 
To further investigate the robustness of the GSP co-primary efficacy endpoint, the ranked 
and non-rank-transformed GSP analyses will be repeated on all available data only 
without imputing missing data. The exact same analysis models (ANCOVA) will be used 
on the observed ranked and non-ranked change in GSP from baseline to EOT. 
8.3.5.2 
Sensitivity Analysis 2: GSP, Outlying Data Removed, 
Multiple Imputations 
To further investigate the robustness of the GSP co-primary efficacy outcome, the ranked 
and non-rank-transformed GSP analyses will be repeated with outlier data (as defined in 
Section 8.2.1.2) removed from the analysis data set (both sofpironium bromide gel, 15% 
group and vehicle group) before any endpoint analysis is performed. The methodology 
will be similar to the primary analysis of the GSP co-primary endpoint. For missing data 


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imputation purposes, outlier data will also be removed from the imputation sampling 
database. The exact same analysis models (ANCOVA) will be used on the observed 
ranked and non-ranked change in GSP from baseline to EOT. This differs from the 
analysis of the GSP co-primary endpoint, in that outlier GSP data is kept in the primary 
analysis but removed for this sensitivity analysis.  
8.3.5.3 
Sensitivity Analysis 3: HDSM-Ax-7, Missing Data imputed to 
Failure/Non-Response 
In this analysis, missing EOT HDSM-Ax-7 cases will be analyzed as failure/non-
responder in both treatment groups. The same co-primary HDSM-Ax-7 logistic 
regression model will be re-run on the HDSM-Ax dataset subjects with missing data 
modelled as not having improved by at least 2 points. The treatment success proportions 
estimates will also be reported.  
8.3.5.4 
Sensitivity Analysis 4: HDSM-Ax-7 and GSP, Tipping Point 
Analysis 
A tipping point analysis will be conducted to investigate what type of missing data would 
cause a positive between-arm comparison of the outcomes of the co-primary efficacy 
endpoints to be non-significant. These analyses will be conducted separately for the 
HDSM-Ax-7 and GSP co-primary endpoints. 
For the GSP co-primary endpoint, missing data in the vehicle arm will be assumed to be 
MAR, while missing data from the sofpironium bromide gel, 15% arm will be imputed 
assuming that subjects with missing data have missing GSP data that are worse by a pre-
VSHFLILHGǻFRPSDUHGWRVLPLODUVXEMHFWVZLWKREVHUYHGGDWD0LVVLQJYDOXHVZLOOEH
PXOWLSO\LPSXWHGYLDWKLVPHWKRGZLWKLQFUHDVLQJǻYDOXHV $ǻLQFUHPHQWRI5 mg will 
be used for this study. The GSP co-primary efficacy outcome analysis methodology will 
be applied to the imputed datasets and repeated until statistical significance no longer 
holds. The tipping point at which the results are no longer significant will be identified 
and the results will be summarized graphically. 
For the HDSM-Ax-7 co-primary endpoint, identical imputation methodology to that 
described above for the GSP will be applied to the HDSM-Ax-7 total scores, and the 
resulting values will be dichotomized into responders using the 2-point improvement 
criteria. A ǻLQFUHPHQWRI0.5 (in a 0-4 scale) will be used for this study. The HDSM-Ax-
7 co-primary efficacy outcome analysis methodology will be applied to the imputed 
datasets and repeated until statistical significance no longer holds. The tipping point at 
which the results are no longer significant will be identified and the results will be 
summarized graphically. 


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8.3.5.5 
Sensitivity Analysis 5: Analysis of the Influence of 7 
individual items in the HDSM-Ax-7 scale 
Sensitivity analyses will be conducted on the missing data imputed ITT Population to 
investigate whether any of the individual items in the HDSM-Ax-7 scale are overly 
influencing changes observed in the total score. First, a subject will be counted as a 
responder if they achieve at least a 2-point improvement in the individual question from 
baseline to EOT. The logistic regression model for the primary analysis for HDSM-Ax-7 
will be repeated for each of the 7 individual items, and each individual question will be 
analyzed separately. Secondly, one of the 7 items will be omitted, and the HDSM-Ax-7 
total score will be calculated as the average of the remaining 6 items. The primary 
logistic regression analysis for 2-point improvement response rate will be performed on 
this 6-item scale. This process will be repeated 7 times, each time with a different item of 
the HDSM-Ax-7 scale removed from calculation of the overall score.  
8.3.6 
Secondary Efficacy Analyses 
The three secondary efficacy endpoints are described in Section 8.1.3. 
If both co-primary analyses yield statistically significant results in favor of the 
sofpironium bromide gel, 15% group, the three secondary efficacy endpoints will be 
tested in the ITT population in a fixed sequence in the order presented in Section 8.1.3. 
Testing will continue only if all previously tested null hypotheses have been rejected at 
the 2-sided alpha < 0.05 significance level in favor of sofpironium bromide gel, 15%. 
The analysis of the three responder secondary endpoints specified in Section 8.1.3 will be 
conducted using the same logistic regression model as that used for the HDSM-Ax-7 
co-primary efficacy analysis. For each model, the covariates include treatment, baseline 
parameter score, and analysis center. For the composite endpoints, both HDSM-Ax-7 
baseline and GSP baseline will be included as covariates.   
8.3.7 
Exploratory Efficacy Analyses 
The exploratory efficacy endpoints are fully described in Section 8.1.4. All exploratory 
efficacy endpoints that involve a proportion of responders will be analyzed using 
methods similar to what was described for the HDSM-Ax-7 co-primary endpoint. For 
each endpoint, a logistic regression model will be generated using planned covariates of 
treatment, baseline parameter, and analysis center. For the composite endpoints, both 
baseline HDSM-Ax and GSP will be included as covariates. 
All other exploratory endpoints that involve a change from baseline to a single timepoint 
for a continuous variable will be analyzed using methods similar to what is described for 
the GSP co-primary endpoint. For each endpoint, an ANCOVA model will be generated 
with fixed effects for treatment, baseline parameter, and analysis center. 


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Change in PGI-S from baseline and PGI-C score (only collected at Day 43) will be 
analyzed using a Cochran-Mantel Haenszel (CMH) test for ordinal data to compare the 
treatment arms at each visit.  
All exploratory efficacy analyses will be based on available data and missing GSP and 
HDSM-Ax EOT data imputed per Section 8.2.1. HDSM-Ax-11 will be calculated in the 
same manner as HDSM-Ax-7 at EOT, where the mean is derived from imputed sub-items 
for the EOT score. In addition, all continuous parameters will be summarized by visit on 
the ITT population.  
Data in the analysis of rank-based GSP change from baseline to each timepoint will be 
ranked in the same manner as that of the co-primary GSP endpoints (Section 8.3.2). 
Proportion of subjects achieving 1- and 2-point improvement from baseline in HDSM-
Ax-7 and HDSM-Ax-11 will be plotted at each timepoint. Similar plots will be generated 
for proportion of subjects achieving 50% and 70% reduction in GSP from baseline at 
each timepoint and for the secondary composite endpoints. Plots will be generated for 
change from baseline for continuous measures over time.  
In addition, a summary table of frequency of missing measurements at each visit will be 
generated for GSP and HDSM-Ax-7, separately.   
All secondary and exploratory efficacy endpoints will be analyzed for both the ITT and PP 
populations. The co-primary endpoint primary analyses will also be analyzed for the PP 
population as an exploratory analysis. Analyses completed on the PP population will not 
be multiply imputed. The PP population is a completers population and analyses based on 
this population will use observed data. P-values for exploratory efficacy endpoints will be 
provided for descriptive purposes only and no formal hypothesis testing will occur. 
8.4 
Examination of Subgroups 
While the study is not powered to show efficacy for pre-defined subgroups, the co-
primary efficacy end points will be further analyzed by subgroups of interest. All p-
values from the subgroup tables will be of an exploratory nature, as no formal hypothesis 
testing will occur.   
The primary analyses for the primary endpoints (see sections 8.3.1 and 8.3.2) will be 
repeated for the ITT population for the following subgroups:  
x Age group: < 17 yearsWR years years. 
x Gender: male, female.  
x Ethnicity: Hispanic or Latino, Not Hispanic or Latino or not reported. 
x Race: white, non-white or not reported. 


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Race and ethnicity categories have been combined due to potential small sample size. For 
age group, should the models fail to converge due to small cell size, age categories may 
be further collapsed. For all subgroup models, should the models fail to converge, NA or 
not assessable or similar will be displayed. 
 


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9. 
SAFETY EVALUATION 
9.1 
Overview of Safety Analysis Methods 
Safety analyses will be carried out for the Safety Population. Subjects who do not 
complete the study, for whatever reason, will have all available data up until the time of 
termination included in the analyses. 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 safety analyses. In general, all data will be associated with the nominal study 
visit for which it was collected. 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. No formal hypothesis testing will be 
performed. 
9.2 
Adverse Events 
Treatment-emergent adverse events (TEAEs) are defined as those adverse events (AEs) 
with onset during or 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 and severity.  
Partial or completely missing AE start 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. 
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. 
b. Otherwise, impute to January 1st of that year. 
3. If the date is completely missing, impute to treatment start date. 
Partial or completely missing AE end dates will be imputed in the same manner, with end 
of treatment date or end of study date. 
AE listings will display the imputed dates.  
Verbatim terms on case report forms will be mapped to preferred terms and system organ 
classes using the latest version of MedDRA. 


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At Visits 5, 6, 7, 8, 9, 12 (EOT), and 13 (Follow-up), treatment-emergent adverse events 
(TEAEs) in the Safety Population will be summarized by severity in the following tables: 
all reported TEAEs, all SAEs, all treatment-related SAEs, treatment-related TEAEs, 
severe TEAEs, TEAEs leading to dose interruption, TEAEs leading to study 
discontinuation, TEAEs of special interest, and anticholinergic TEAEs. Additionally, 
local site reaction TEAEs will be summarized in the Safety Population by severity at 
Visits 5, 6, 7, 8, 9, 12 (EOT), and Visit 13 (Follow-up). Local site reaction TEAEs are 
defined as AEs coded to the system organ class of general disorders and administration 
site conditions and, at a minimum, the following preferred terms:  
x Application site pruritus 
x Application site pain 
x Application site irritation 
x Application site dermatitis 
x Application site rash 
x Application site erythema 
x Application site discolouration 
x Application site dryness 
x Application site exfoliation 
x Application site reaction 
x Application site warmth 
Each of the above tables will be produced 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 visits, 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. 
Summaries that are displayed by system organ class and preferred terms will be ordered 
by descending incidence of system organ class in the total column and preferred term 
within each system organ class. The total column will not be displayed and will only be 
used for sorting. TEAEs of special interest include the following: 
x Vision blurred 
x Mydriasis (unilateral or bilateral) 
x Urinary hesitation 
An overall TEAE summary table by treatment group with the total number of TEAEs and 
the number and percentage of subjects with at least one of the following will be 
presented: TEAE, serious TEAE, treatment-related TEAE, treatment-related serious 
TEAE, severe TEAE, TEAE leading to dose interruption, TEAE leading to study 
discontinuation, TEAEs of special interest, anticholinergic TEAEs, anticholinergic 
TEAEs leading to study discontinuation, local site reaction TEAEs, local site reaction 
TEAEs leading to study discontinuation. The overall summary table will also display the 
number and percent of subject deaths, should any deaths occur. 


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The number of subjects with study discontinuations due to TEAEs, the number of 
subjects with study discontinuations due to anticholinergic TEAEs, and the number of 
subjects with study discontinuations due to AESIs will be plotted as a bar chart versus 
time on treatment. Time on treatment is defined as the earlier of treatment end date or 
study discontinuation date – treatment start date + 1. Time on treatment will be displayed 
in categories of 0 to 2 weeks, >2 to 4 weeks, >4 to 6 weeks. Weeks are defined as 7 days. 
The follow-up visit is excluded. 
The number of treatment-related TEAEs and the number of local site reaction TEAEs 
will be plotted versus time on treatment. The number of subjects with a treatment-related 
TEAE and the number of subjects with a local site reaction TEAE will be plotted versus 
time.  Time for these plots will be displayed as weeks 1-8 which includes the follow-up 
visit. 
Adverse event data will be presented in data listings by subject, treatment group, and 
event. SAEs, TEAEs leading to study discontinuation, TEAEs of special interest, and 
anticholinergic TEAEs 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. 
9.3 
Local Tolerability Assessments 
Local tolerability assessments are performed for both axillae individually at visits 4, 5, 6, 
7, 8, 9, 12 (EOT), and 13 (follow-up). Visit 4 data are the baseline. Should Visit 4 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, or 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.  For any symptoms, subject 
severity is the worst severity of the two axillae.  
Subject and Investigator assessments will be included in tables and listings. Tables will 
be presented by treatment arm. An overall summary table will be presented with subject 
incidences tabulated according to the worst severity experienced while on study. At each 
visit, local tolerability assessments will also be descriptively summarized by severity. 
Additionally, at each post-baseline visit, local tolerability will be summarized as 
cumulative shift 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. Local tolerability assessment results will 
also be plotted by severity, displaying counts for any symptom, burning, stinging, itching, 
scaling, and erythema. A symptom is counted if the severity scale is rated >0. . 
9.4 
Clinical Laboratory Evaluation 
Safety laboratory parameters (hematology, chemistry, urinalysis) will be collected at the 
Screening Visit and EOT Visit. Urine pregnancy results will be collected at visits 1, 4, 8, 


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and 12 (EOT). 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 subsequent visit. Unscheduled visits and early termination visits will be included. 
Laboratory parameters to be summarized and listed include hematology, clinical 
chemistry, and routine urinalysis. Urine pregnancy test results will be listed only. 
 
9.5 
Vital Signs, Physical Findings, and Other Observations Related to 
Safety 
9.5.1 
Vital Signs 
Vital signs measurements will be collected at Visits 4, 5, 6, 7, 8, 9, 12 (EOT), and 13 
(follow-up). Visit 4 data are the Baseline. Should Visit 4 data be missing, baseline will be 
derived as the last value prior to first dose (e.g. Screening), 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 
descriptively summarized for values at each visit and for changes from baseline at each 
subsequent visit. Vital signs will also be listed.  
9.5.2 
Physical Examinations 
Physical examination results will be collected at Visit 4 only. 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. 
9.5.3 
Other Safety Measures 
9.5.3.1 
Prior and Concomitant Medications 
Medications will be coded using the latest version of the World Health Organization 
(WHO) drug dictionary. Medications entered on the eCRF will be mapped to Anatomic 
Therapeutic Chemical (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 9.2. 
A prior medication is defined as any medication started prior to the date of the first dose 
of study drug. A concomitant medication is defined as any medication started on or after 
the date of the first dose of study drug.  
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, 


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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,) will be presented on the listing of 
prior and concomitant medications. 
Prior or concomitant therapies and procedures will be listed only. 
 
 
 


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10. 
PHARMACOKINETIC/PHARMACODYNAMIC EVALUATION 
Pharmacokinetic and pharmacodynamic analyses are not part of this study protocol. 
 
 
 
 


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11. 
OTHER ANALYSES 
11.1 
Psychometric Analysis of the HDSM-Ax-7 
In parallel to the traditional statistical analysis, psychometric evaluation of the HDSM-
Ax-7 will be carried out to confirm the most appropriate HDSM-Ax-7 scoring algorithm 
and to examine internal validity, construct validity (i.e., examination of the magnitude of 
correlation between the HDSM-Ax-7 total score and key variables such as Questions 4 
and 5 of the HDSM-Ax-7, PGI-S, PGI-C and GSP), 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. 
 


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12. 
INTERIM ANALYSES AND DATA MONITORING 
There are no interim analyses planned, nor is there a plan to establish a data monitoring 
committee for this study. 
 
 


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13. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
Due to the issue of duplicate subjects discussed in Section 3.3, the mITT analysis 
population was added.  Definition of local site reaction TEAEs and analysis of local site 
reaction TEAEs was added. 
 


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14. 
REFERENCES 
1. 
Rubin DB. Inference and missing data. Biometrika. 1976;63(3):581–590. 
 


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15. 
LIST OF PLANNED TABLES 
Number 
Title 
Population 
14.1.1.1.1 
Summary of Subject Disposition and Reasons for 
Discontinuation 
Safety 
14.1.1.1.2 
Summary of Subject Disposition and Reasons for 
Discontinuation 
Intent-to-treat 
14.1.1.1.3 
Summary of Subject Disposition and Reasons for 
Discontinuation 
Per-protocol 
14.1.1.1.4 
Summary of Subject Disposition and Reasons for 
Discontinuation 
Modified Intent-to-treat 
14.1.1.2 
Summary of Major Protocol Violations 
Safety 
14.1.2.1 
Summary of Demographic Characteristics 
Safety 
14.1.2.2 
Summary of Demographic Characteristics 
Intent-to-treat 
14.1.2.3 
Summary of Demographic Characteristics 
Per-protocol 
14.1.2.4 
Summary of Demographic Characteristics 
Modified Intent-to-treat 
14.1.3.1 
Summary of Baseline Characteristics 
Safety 
14.1.3.2 
Summary of Baseline Characteristics 
Intent-to-treat 
14.1.3.3 
Summary of Baseline Characteristics 
Per-protocol 
14.1.3.4 
Summary of Baseline Characteristics 
Modified Intent-to-treat 
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 
Co-Primary $QDO\VLV6XEMHFWV$FKLHYLQJ 2-point 
Improvement in HDSM-Ax-7 from Baseline to End of 
Treatment - Multiple Imputations 
Intent-to-treat 
14.2.1.1.2 
Co-Primary Analysis: Subjects Achieving  2-point 
Improvement in HDSM-Ax-7 from Baseline to End of 
Treatment - No Imputation 
Per-protocol 
14.2.1.1.3 
Co-Primary Analysis: Subjects Achieving  2-point 
Improvement in HDSM-Ax-7 from Baseline to End of 
Treatment - Multiple Imputations 
Modified Intent-to-treat 
14.2.1.1.4 
Co-Primary Analysis: ANCOVA Analysis of Change 
in [Ranked/Continuous]* GSP from Baseline to End of 
Treatment - Multiple Imputations 
Intent-to-treat 
14.2.1.1.5 
Co-Primary Analysis: ANCOVA Analysis of Change 
in [Ranked/Continuous]* GSP from Baseline to End of 
Treatment - No Imputation 
Per-protocol 
                                                 
* Primary GSP endpoint is dependent on normality test results. If the normality is violated, the primary GSP 
endpoint will use ranked data. If the normality is not violated, the primary GSP endpoint will use 
continuous data. 


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Number 
Title 
Population 
14.2.1.1.6 
Co-Primary Analysis: ANCOVA Analysis of Change 
in [Ranked/Continuous]* GSP from Baseline to End of 
Treatment - Multiple Imputations 
Modified Intent-to-treat 
14.2.1.1.7 
Summary of Normality Test Results for GSP 
Intent-to-treat 
14.2.1.2.1 
Supportive Analysis for HDSM-AX-7: ANCOVA 
Analysis of Change in HDSM-Ax-7 from Baseline to 
End of Treatment - Multiple Imputations 
Intent-to-treat 
14.2.1.2.2 
Supportive Analysis for HDSM-AX-7: ANCOVA 
Analysis of Change in HDSM-Ax-7 from Baseline to 
End of Treatment - Multiple Imputations 
Modified Intent-to-treat 
14.2.1.3.1 
Supportive Analysis 1 for GSP: ANCOVA Analysis of 
Change in [Ranked/Continuous]* GSP from Baseline 
to End of Treatment - Multiple Imputations 
Intent-to-treat 
14.2.1.3.2 
Supportive Analysis 1 for GSP: ANCOVA Analysis of 
Change in [Ranked/Continuous]* GSP from Baseline 
to End of Treatment - Multiple Imputations 
Modified Intent-to-treat 
14.2.1.4.1 
Supportive Analysis 2 for GSP: Mixed Model 
Repeated Measures Analysis of Change in Ranked 
GSP - No Imputation 
Intent-to-treat 
14.2.1.4.2 
Supportive Analysis 2 for GSP: Mixed Model 
Repeated Measures Analysis of Change in Ranked 
GSP - No Imputation 
Modified Intent-to-treat 
14.2.1.5.1 
Supportive Analysis 3 for GSP: Mixed Model 
Repeated Measures Analysis of Change in Continuous 
GSP - No Imputation 
Intent-to-treat 
14.2.1.5.2 
Supportive Analysis 3 for GSP: Mixed Model 
Repeated Measures Analysis of Change in Continuous 
GSP - No Imputation 
Modified Intent-to-treat 
14.2.1.6.1 
Sensitivity Analysis 1 for GSP: ANCOVA Analysis of 
Change in Ranked GSP from Baseline to End of 
Treatment - No Imputation 
Intent-to-treat 
14.2.1.6.2 
Sensitivity Analysis 1 for GSP: ANCOVA Analysis of 
Change in Ranked GSP from Baseline to End of 
Treatment - No Imputation 
Modified Intent-to-treat 
14.2.1.7.1 
Sensitivity Analysis 1 for GSP: ANCOVA Analysis of 
Change in Continuous GSP from Baseline to End of 
Treatment - No Imputation 
Intent-to-treat 
14.2.1.7.2 
Sensitivity Analysis 1 for GSP: ANCOVA Analysis of 
Change in Continuous GSP from Baseline to End of 
Treatment - No Imputation 
Modified Intent-to-treat 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-301 
 
30 July 2021 
 
Version:  2.0 
 
Page 51 of 74 
 
Number 
Title 
Population 
14.2.1.8.1 
Sensitivity Analysis 2 for GSP: ANCOVA Analysis of 
Change in Ranked GSP from Baseline to End of 
Treatment with Outliers Removed - Multiple 
Imputations 
Intent-to-treat 
14.2.1.8.2 
Sensitivity Analysis 2 for GSP: ANCOVA Analysis of 
Change in Ranked GSP from Baseline to End of 
Treatment with Outliers Removed - Multiple 
Imputations 
Modified Intent-to-treat 
14.2.1.9.1 
Sensitivity Analysis 2 for GSP: ANCOVA Analysis of 
Change in Continuous GSP from Baseline to End of 
Treatment with Outliers Removed - Multiple 
Imputations 
Intent-to-treat 
14.2.1.9.2 
Sensitivity Analysis 2 for GSP: ANCOVA Analysis of 
Change in Continuous GSP from Baseline to End of 
Treatment with Outliers Removed - Multiple 
Imputations 
Modified Intent-to-treat 
14.2.1.10.1 
Sensitivity Analysis 3 for HDSM-Ax: Subjects 
Achieving  2-point Improvement in HDSM-AX-7 
from Baseline to End of Treatment - Non-responder 
Imputation 
Intent-to-treat 
14.2.1.10.2 
Sensitivity Analysis 3 for HDSM-Ax: Subjects 
Achieving  2-point Improvement in HDSM-AX-7 
from Baseline to End of Treatment - Non-responder 
Imputation 
Modified Intent-to-treat 
14.2.1.11.1 
Sensitivity Analysis 4 for HDSM-Ax: Subjects 
Achieving  2-point Improvement in HDSM-Ax-7 
from Baseline to End of Treatment - Tipping Point 
Analysis 
Intent-to-treat 
14.2.1.11.2 
Sensitivity Analysis 4 for HDSM-Ax: Subjects 
Achieving  2-point Improvement in HDSM-Ax-7 
from Baseline to End of Treatment - Tipping Point 
Analysis 
Modified Intent-to-treat 
14.2.1.12.1 
Sensitivity Analysis 4 for GSP: ANCOVA Analysis of 
Change in [Ranked/Continuous]* GSP from Baseline 
to End of Treatment - Tipping Point Analysis 
Intent-to-treat 
14.2.1.12.2 
Sensitivity Analysis 4 for GSP: ANCOVA Analysis of 
Change in [Ranked/Continuous]* GSP from Baseline 
to End of Treatment - Tipping Point Analysis 
Modified Intent-to-treat 
                                                 
* Primary GSP endpoint is dependent on normality test results. If the normality is violated, the primary GSP 
endpoint will use ranked data. If the normality is not violated, the primary GSP endpoint will use 
continuous data. 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-301 
 
30 July 2021 
 
Version:  2.0 
 
Page 52 of 74 
 
Number 
Title 
Population 
14.2.1.13.1 
Sensitivity Analysis 5 for HDSM-Ax: Subjects 
Achieving  2-point Improvement in each HDSM-Ax-
7 Item from Baseline to End of Treatment - Multiple 
Imputations 
Intent-to-treat 
14.2.1.13.2 
Sensitivity Analysis 5 for HDSM-Ax: Subjects 
Achieving  2-point Improvement in each HDSM-Ax-
7 Item from Baseline to End of Treatment - Multiple 
Imputations 
Modified Intent-to-treat 
14.2.1.14.1 
Sensitivity Analysis 5 for HDSM-Ax: Subjects 
Achieving  2-point Improvement in HDSM-Ax 6-
item Total from Baseline to End of Treatment - 
Multiple Imputations 
Intent-to-treat 
14.2.1.14.2 
Sensitivity Analysis 5 for HDSM-Ax: Subjects 
Achieving  2-point Improvement in HDSM-Ax 6-
item Total from Baseline to End of Treatment - 
Multiple Imputations 
Modified Intent-to-treat 
14.2.1.15.1 
Site Poolability Analysis 1 for HDSM-Ax: Subjects 
Achieving  2-point Improvement in HDSM-Ax-7 
from Baseline to End of Treatment - Multiple 
Imputations 
Intent-to-treat 
14.2.1.15.2 
Site Poolability Analysis 1 for HDSM-Ax: Subjects 
Achieving  2-point Improvement in HDSM-Ax-7 
from Baseline to End of Treatment - Multiple 
Imputations 
Modified Intent-to-treat 
14.2.1.16.1 
Site Poolability Analysis 2 for HDSM-Ax: Subjects 
$FKLHYLQJ-point Improvement in HDSM-Ax-7 from 
Baseline to End of Treatment with Analysis Center as a 
Random Effect - Multiple Imputations 
Intent-to-treat 
14.2.1.16.2 
Site Poolability Analysis 2 for HDSM-Ax: Subjects 
$FKLHYLQJ-point Improvement in HDSM-Ax-7 from 
Baseline to End of Treatment with Analysis Center as a 
Random Effect - Multiple Imputations 
Modified Intent-to-treat 
14.2.1.17.1 
Site Poolability Analysis 3 for GSP: ANCOVA 
Analysis of Change in [Ranked/Continuous]* GSP 
from Baseline to End of Treatment - Multiple 
Imputations 
Intent-to-treat 
14.2.1.17.2 
Site Poolability Analysis 3 for GSP: ANCOVA 
Analysis of Change in [Ranked/Continuous]* GSP 
Modified Intent-to-treat 
                                                 
* Primary GSP endpoint is dependent on normality test results. If the normality is violated, the primary GSP 
endpoint will use ranked data. If the normality is not violated, the primary GSP endpoint will use 
continuous data. 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-301 
 
30 July 2021 
 
Version:  2.0 
 
Page 53 of 74 
 
Number 
Title 
Population 
from Baseline to End of Treatment - Multiple 
Imputations 
14.2.1.18.1 
Site Poolability Analysis 4 for GSP: ANCOVA 
Analysis of Change in [Ranked/Continuous]* GSP 
from Baseline to End of Treatment with Analysis 
Center as a Random Effect - Multiple Imputations 
Intent-to-treat 
14.2.1.18.2 
Site Poolability Analysis 4 for GSP: ANCOVA 
Analysis of Change in Ranked GSP from Baseline to 
End of Treatment with Analysis Center as a Random 
Effect - Multiple Imputations 
Modified Intent-to-treat 
14.2.2.1 
Secondary Analysis 1: Subjects Achieving  1-point 
Improvement in HDSM-Ax-7 from Baseline to End of 
Treatment - Multiple Imputations 
Intent-to-treat 
14.2.2.2 
Secondary Analysis 1: Subjects Achieving  1-point 
Improvement in HDSM-Ax-7 from Baseline to End of 
Treatment - No Imputation 
Per-protocol 
14.2.2.3 
Secondary Analysis 1: Subjects Achieving  1-point 
Improvement in HDSM-Ax-7 from Baseline to End of 
Treatment - Multiple Imputations 
Modified Intent-to-treat 
14.2.2.4 
Secondary Analysis 2: Subjects Achieving  2-point 
improvement in HDSM-Ax-7 and 70% Reduction in 
GSP from Baseline to End of Treatment - Multiple 
Imputations 
Intent-to-treat 
14.2.2.5 
Secondary Analysis 2: Subjects Achieving  2-point 
improvement in HDSM-Ax-7 and 70% Reduction in 
GSP from Baseline to End of Treatment - No 
Imputation 
Per-protocol 
14.2.2.6 
Secondary Analysis 2: Subjects Achieving  2-point 
improvement in HDSM-Ax-7 and 70% Reduction in 
GSP from Baseline to End of Treatment - Multiple 
Imputations 
Modified Intent-to-treat 
14.2.2.7 
Secondary Analysis 3: Subjects Achieving  1-point 
improvement in HDSM-Ax-7 and 50% Reduction in 
GSP from Baseline to End of Treatment - Multiple 
Imputations 
Intent-to-treat 
14.2.2.8 
Secondary Analysis 3: Subjects Achieving  1-point 
improvement in HDSM-Ax-7 and 50% Reduction in 
GSP from Baseline to End of Treatment - No 
Imputation 
Per-protocol 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-301 
 
30 July 2021 
 
Version:  2.0 
 
Page 54 of 74 
 
Number 
Title 
Population 
14.2.2.9 
Secondary Analysis 3: Subjects Achieving  1-point 
improvement in HDSM-Ax-7 and 50% Reduction in 
GSP from Baseline to End of Treatment - Multiple 
Imputations 
Modified Intent-to-treat 
14.2.3.1 
Subjects Achieving  1-point Improvement in HDSM-
Ax-7 by Visit 
Intent-to-treat 
14.2.3.2 
Subjects Achieving  1-point Improvement in HDSM-
Ax-7 by Visit 
Per-protocol 
14.2.3.3 
Subjects Achieving  2-point Improvement in HDSM-
Ax-7 by Visit 
Intent-to-treat 
14.2.3.4 
Subjects Achieving  2-point Improvement in HDSM-
Ax-7 by Visit 
Per-protocol 
14.2.3.5 
Subjects Achieving  2-point Improvement in HDSM-
Ax-7 and 70% Reduction in GSP by Visit  
Intent-to-treat 
14.2.3.6 
Subjects Achieving  2-point Improvement in HDSM-
Ax-7 and 70% Reduction in GSP by Visit  
Per-protocol 
14.2.3.7 
Subjects Achieving  1-point Improvement in HDSM-
Ax-7 and 50% Reduction in GSP by Visit 
Intent-to-treat 
14.2.3.8 
Subjects Achieving  1-point Improvement in HDSM-
Ax-7 and 50% Reduction in GSP by Visit 
Per-protocol 
14.2.3.9 
Mean and Mean Change from Baseline in HDSM-Ax-7 
by Visit 
Intent-to-treat 
14.2.3.10 
Mean and Mean Change from Baseline in HDSM-Ax-7 
by Visit 
Per-protocol 
14.2.3.11 
Summary of Frequency of Missingness for HDSM-Ax-
7 
Intent-to-treat 
14.2.3.12 
Summary of Frequency of Missingness for HDSM-Ax-
7 
Per-protocol 
14.2.3.13 
Subjects Achieving  1-point Improvement in HDSM-
Ax-11 by Visit 
Intent-to-treat 
14.2.3.14 
Subjects Achieving  1-point Improvement in HDSM-
Ax-11 by Visit 
Per-protocol 
14.2.3.15 
Subjects Achieving  2-point Improvement in HDSM-
Ax-11 by Visit 
Intent-to-treat 
14.2.3.16 
Subjects Achieving  2-point Improvement in HDSM-
Ax-11 by Visit 
Per-protocol 
14.2.3.17 
Subjects Achieving  2-point improvement in HDSM-
Ax-11 and 70% Reduction in GSP from Baseline to 
End of Treatment  
Intent-to-treat 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-301 
 
30 July 2021 
 
Version:  2.0 
 
Page 55 of 74 
 
Number 
Title 
Population 
14.2.3.18 
Subjects Achieving  2-point improvement in HDSM-
Ax-11 and 70% Reduction in GSP from Baseline to 
End of Treatment  
Per-protocol 
14.2.3.19 
Subjects Achieving  1-point improvement in HDSM-
Ax-11 and 50% Reduction in GSP from Baseline to 
End of Treatment  
Intent-to-treat 
14.2.3.20 
Subjects Achieving  1-point improvement in HDSM-
Ax-11 and 50% Reduction in GSP from Baseline to 
End of Treatment  
Per-protocol 
14.2.3.21 
Subjects Achieving  2-point Improvement in HDSM-
Ax-11 and 70% Reduction in GSP by Visit  
Intent-to-treat 
14.2.3.22 
Subjects Achieving  2-point Improvement in HDSM-
Ax-11 and 70% Reduction in GSP by Visit  
Per-protocol 
14.2.3.23 
Subjects Achieving  1-point Improvement in HDSM-
Ax-11 and 50% Reduction in GSP by Visit 
Intent-to-treat 
14.2.3.24 
Subjects Achieving  1-point Improvement in HDSM-
Ax-11 and 50% Reduction in GSP by Visit 
Per-protocol 
14.2.3.25 
Mean and Mean Change from Baseline in HDSM-Ax-
11 by Visit 
Intent-to-treat 
14.2.3.26 
Mean and Mean Change from Baseline in HDSM-Ax-
11 by Visit 
Per-protocol 
14.2.3.27 
Subjects Achieving  1-point Improvement in HDSM-
Ax Question 4 by Visit 
Intent-to-treat 
14.2.3.28 
Subjects Achieving  1-point Improvement in HDSM-
Ax Question 4 by Visit 
Per-protocol 
14.2.3.29 
Subjects Achieving  2-point Improvement in HDSM-
Ax Question 4 by Visit 
Intent-to-treat 
14.2.3.30 
Subjects Achieving  2-point Improvement in HDSM-
Ax Question 4 by Visit 
Per-protocol 
14.2.3.31 
Subjects Achieving  1-point Improvement in HDSM-
Ax Question 5 by Visit 
Intent-to-treat 
14.2.3.32 
Subjects Achieving  1-point Improvement in HDSM-
Ax Question 5 by Visit 
Per-protocol 
14.2.3.33 
Subjects Achieving  2-point Improvement in HDSM-
Ax Question 5 by Visit 
Intent-to-treat 
14.2.3.34 
Subjects Achieving  2-point Improvement in HDSM-
Ax Question 5 by Visit 
Per-protocol 
14.2.3.35 
Subjects Achieving at least 70% Reduction in GSP by 
Visit 
Intent-to-treat 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-301 
 
30 July 2021 
 
Version:  2.0 
 
Page 56 of 74 
 
Number 
Title 
Population 
14.2.3.36 
Subjects Achieving at least 70% Reduction in GSP by 
Visit 
Per-protocol 
14.2.3.37 
Subjects Achieving at least 50% Reduction in GSP by 
Visit 
Intent-to-treat 
14.2.3.38 
Subjects Achieving at least 50% Reduction in GSP by 
Visit 
Per-protocol 
14.2.3.39 
Mean and Mean Change from Baseline in Ranked GSP 
by Visit 
Intent-to-treat 
14.2.3.40 
Mean and Mean Change from Baseline in Ranked GSP 
by Visit 
Per-protocol 
14.2.3.41 
Mean and Mean Change from Baseline in Absolute 
GSP by Visit 
Intent-to-treat 
14.2.3.42 
Mean and Mean Change from Baseline in Absolute 
GSP by Visit 
Per-protocol 
14.2.3.43 
Mean and Mean Percent Change from Baseline in GSP 
by Visit 
Intent-to-treat 
14.2.3.44 
Mean and Mean Percent Change from Baseline in GSP 
by Visit 
Per-protocol 
14.2.3.45 
Summary of Frequency of Missingness for GSP 
Intent-to-treat 
14.2.3.46 
Summary of Frequency of Missingness for GSP 
Per-protocol 
14.2.3.47 
Mean and Mean Change from Baseline in DLQI by 
Visit 
Intent-to-treat 
14.2.3.48 
Mean and Mean Change from Baseline in DLQI by 
Visit 
Per-protocol 
14.2.3.49 
Patient Global Impression of Severity (PGI-S) by Visit 
Intent-to-treat 
14.2.3.50 
Patient Global Impression of Severity (PGI-S) by Visit 
Per-protocol 
14.2.3.51 
Patient Global Impression of Change (PGI-C) at End 
of Treatment 
Intent-to-treat 
14.2.3.52 
Patient Global Impression of Change (PGI-C) at End 
of Treatment 
Per-protocol 
14.2.3.53 
Subgroup $QDO\VLV6XEMHFWV$FKLHYLQJ-point 
Improvement in HDSM-Ax-7 from Baseline to End of 
Treatment - Multiple Imputations – by Age Group 
Intent-to-treat 
14.2.3.54 
6XEJURXS$QDO\VLV6XEMHFWV$FKLHYLQJ-point 
Improvement in HDSM-Ax-7 from Baseline to End of 
Treatment - Multiple Imputations – by Gender 
Intent-to-treat 
14.2.3.55 
6XEJURXS$QDO\VLV6XEMHFWV$FKLHYLQJ-point 
Improvement in HDSM-Ax-7 from Baseline to End of 
Treatment - Multiple Imputations – by Ethnicity 
Intent-to-treat 
14.2.3.56 
6XEJURXS$QDO\VLV6XEMHFWV$FKLHYLQJ-point 
Improvement in HDSM-Ax-7 from Baseline to End of 
Treatment - Multiple Imputations – by Race 
Intent-to-treat 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-301 
 
30 July 2021 
 
Version:  2.0 
 
Page 57 of 74 
 
Number 
Title 
Population 
14.2.3.57 
Subgroup Analysis: ANCOVA Analysis of Change in 
Continuous GSP from Baseline to End of Treatment -- 
Multiple Imputations – by Age Group 
Intent-to-treat 
14.2.3.58 
Subgroup Analysis: ANCOVA Analysis of Change in 
Continuous GSP from Baseline to End of Treatment -- 
Multiple Imputations – by Gender 
Intent-to-treat 
14.2.3.59 
Subgroup Analysis: ANCOVA Analysis of Change in 
Continuous GSP from Baseline to End of Treatment -- 
Multiple Imputations – by Ethnicity 
Intent-to-treat 
14.2.3.60 
Subgroup Analysis: ANCOVA Analysis of Change in 
Continuous GSP from Baseline to End of Treatment -- 
Multiple Imputations – by Race 
Intent-to-treat 
14.3.1.1 
Overall Summary of Treatment Emergent Adverse 
Events 
Safety 
14.3.1.2.1 
Number and Percentage of Subjects with Treatment-
Emergent Adverse Events Cumulative to Visit 5 (Day 
8) by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety 
14.3.1.2.2 
Number and Percentage of Subjects with Serious 
Treatment-Emergent Adverse Events Cumulative to 
Visit 5 (Day 8)  by System Organ Class, Preferred 
Term, and Maximum Severity 
Safety 
14.3.1.2.3 
Number and Percentage of Subjects with Serious 
Treatment-Related Treatment-Emergent Adverse 
Events  Cumulative to Visit 5 (Day 8)  by System 
Organ Class, Preferred Term, and Maximum Severity 
Safety 
14.3.1.2.4 
Number and Percentage of Subjects with Treatment-
Related Treatment-Emergent Adverse Events 
Cumulative to Visit 5 (Day 8)  by System Organ Class, 
Preferred Term, and Maximum Severity 
Safety 
14.3.1.2.5 
Number and Percentage of Subjects with Severe 
Treatment-Emergent Adverse Events Cumulative to 
Visit 5 (Day 8)  by System Organ Class, Preferred 
Term, and Maximum Severity 
Safety 
14.3.1.2.6 
Number and Percentage of Subjects with Treatment-
Emergent Adverse Events Leading to Dose 
Interruption Cumulative to Visit 5 (Day 8)  by System 
Organ Class, Preferred Term, and Maximum Severity 
Safety 
14.3.1.2.7 
Number and Percentage of Subjects with Treatment-
Emergent Adverse Events Leading to Study 
Discontinuation Cumulative to Visit 5 (Day 8)  by 
System Organ Class, Preferred Term, and Maximum 
Severity 
Safety 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-301 
 
30 July 2021 
 
Version:  2.0 
 
Page 58 of 74 
 
Number 
Title 
Population 
14.3.1.2.8 
Number and Percentage of Subjects with Treatment-
Emergent Adverse Events of Special Interest 
Cumulative to Visit 5 (Day 8)  by System Organ Class, 
Preferred Term, and Maximum Severity 
Safety 
14.3.1.2.9 
Number and Percentage of Subjects with 
Anticholinergic Treatment-Emergent Adverse Events 
Cumulative to Visit 5 (Day 8)  by System Organ Class, 
Preferred Term, and Maximum Severity 
Safety 
14.3.1.2.10 
Number and Percentage of Subjects with Local Site 
Reaction Treatment-Emergent Adverse Events 
Cumulative to Visit 5 (Day 8) by System Organ Class, 
Preferred Term, and Maximum Severity 
Safety 
14.3.1.3.1 
Number and Percentage of Subjects with Treatment-
Emergent Adverse Events Cumulative to Visit 6 (Day 
15) by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety 
14.3.1.3.2 
Number and Percentage of Subjects with Serious 
Treatment-Emergent Adverse Events Cumulative to 
Visit 6 (Day 15) by System Organ Class, Preferred 
Term, and Maximum Severity 
Safety 
14.3.1.3.3 
Number and Percentage of Subjects with Serious 
Treatment-Related Treatment-Emergent Adverse 
Events  Cumulative to Visit 6 (Day 15) by System 
Organ Class, Preferred Term, and Maximum Severity 
Safety 
14.3.1.3.4 
Number and Percentage of Subjects with Treatment-
Related Treatment-Emergent Adverse Events 
Cumulative to Visit 6 (Day 15) by System Organ 
Class, Preferred Term, and Maximum Severity 
Safety 
14.3.1.3.5 
Number and Percentage of Subjects with Severe 
Treatment-Emergent Adverse Events Cumulative to 
Visit 6 (Day 15) by System Organ Class, Preferred 
Term, and Maximum Severity 
Safety 
14.3.1.3.6 
Number and Percentage of Subjects with Treatment-
Emergent Adverse Events Leading to Dose 
Interruption Cumulative to Visit 6 (Day 15) by System 
Organ Class, Preferred Term, and Maximum Severity 
Safety 
14.3.1.3.7 
Number and Percentage of Subjects with Treatment-
Emergent Adverse Events Leading to Study 
Discontinuation Cumulative to Visit 6 (Day 15) by 
System Organ Class, Preferred Term, and Maximum 
Severity 
Safety 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-301 
 
30 July 2021 
 
Version:  2.0 
 
Page 59 of 74 
 
Number 
Title 
Population 
14.3.1.3.8 
Number and Percentage of Subjects with Treatment-
Emergent Adverse Events of Special Interest 
Cumulative to Visit 6 (Day 15) by System Organ 
Class, Preferred Term, and Maximum Severity 
Safety 
14.3.1.3.9 
Number and Percentage of Subjects with 
Anticholinergic Treatment-Emergent Adverse Events 
Cumulative to Visit 6 (Day 15) by System Organ 
Class, Preferred Term, and Maximum Severity 
Safety 
14.3.1.3.10 
Number and Percentage of Subjects with Local Site 
Reaction Treatment-Emergent Adverse Events 
Cumulative to Visit 5 (Day 15) by System Organ 
Class, Preferred Term, and Maximum Severity 
Safety 
14.3.1.4.1 
Number and Percentage of Subjects with Treatment-
Emergent Adverse Events Cumulative to Visit 7 (Day 
22) by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety 
14.3.1.4.2 
Number and Percentage of Subjects with Serious 
Treatment-Emergent Adverse Events Cumulative to 
Visit 7 (Day 22) by System Organ Class, Preferred 
Term, and Maximum Severity 
Safety 
14.3.1.4.3 
Number and Percentage of Subjects with Serious 
Treatment-Related Treatment-Emergent Adverse 
Events  Cumulative to Visit 7 (Day 22) by System 
Organ Class, Preferred Term, and Maximum Severity 
Safety 
14.3.1.4.4 
Number and Percentage of Subjects with Treatment-
Related Treatment-Emergent Adverse Events 
Cumulative to Visit 7 (Day 22) by System Organ 
Class, Preferred Term, and Maximum Severity 
Safety 
14.3.1.4.5 
Number and Percentage of Subjects with Severe 
Treatment-Emergent Adverse Events Cumulative to 
Visit 7 (Day 22) by System Organ Class, Preferred 
Term, and Maximum Severity 
Safety 
14.3.1.4.6 
Number and Percentage of Subjects with Treatment-
Emergent Adverse Events Leading to Dose 
Interruption Cumulative to Visit 7 (Day 22) by System 
Organ Class, Preferred Term, and Maximum Severity 
Safety 
14.3.1.4.7 
Number and Percentage of Subjects with Treatment-
Emergent Adverse Events Leading to Study 
Discontinuation Cumulative to Visit 7 (Day 22) by 
System Organ Class, Preferred Term, and Maximum 
Severity 
Safety 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-301 
 
30 July 2021 
 
Version:  2.0 
 
Page 60 of 74 
 
Number 
Title 
Population 
14.3.1.4.8 
Number and Percentage of Subjects with Treatment-
Emergent Adverse Events of Special Interest 
Cumulative to Visit 7 (Day 22) by System Organ 
Class, Preferred Term, and Maximum Severity 
Safety 
14.3.1.4.9 
Number and Percentage of Subjects with 
Anticholinergic Treatment-Emergent Adverse Events 
Cumulative to Visit 7 (Day 22) by System Organ 
Class, Preferred Term, and Maximum Severity 
Safety 
14.3.1.4.10 
Number and Percentage of Subjects with Local Site 
Reaction Treatment-Emergent Adverse Events 
Cumulative to Visit 7 (Day 22) by System Organ 
Class, Preferred Term, and Maximum Severity 
Safety 
14.3.1.5.1 
Number and Percentage of Subjects with Treatment-
Emergent Adverse Events Cumulative to Visit 8 (Day 
29) by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety 
14.3.1.5.2 
Number and Percentage of Subjects with Serious 
Treatment-Emergent Adverse Events Cumulative to 
Visit 8 (Day 29) by System Organ Class, Preferred 
Term, and Maximum Severity 
Safety 
14.3.1.5.3 
Number and Percentage of Subjects with Serious 
Treatment-Related Treatment-Emergent Adverse 
Events  Cumulative to Visit 8 (Day 29) by System 
Organ Class, Preferred Term, and Maximum Severity 
Safety 
14.3.1.5.4 
Number and Percentage of Subjects with Treatment-
Related Treatment-Emergent Adverse Events 
Cumulative to Visit 8 (Day 29) by System Organ 
Class, Preferred Term, and Maximum Severity 
Safety 
14.3.1.5.5 
Number and Percentage of Subjects with Severe 
Treatment-Emergent Adverse Events Cumulative to 
Visit 8 (Day 29) by System Organ Class, Preferred 
Term, and Maximum Severity 
Safety 
14.3.1.5.6 
Number and Percentage of Subjects with Treatment-
Emergent Adverse Events Leading to Dose 
Interruption Cumulative to Visit 8 (Day 29) by System 
Organ Class, Preferred Term, and Maximum Severity 
Safety 
14.3.1.5.7 
Number and Percentage of Subjects with Treatment-
Emergent Adverse Events Leading to Study 
Discontinuation Cumulative to Visit 8 (Day 29) by 
System Organ Class, Preferred Term, and Maximum 
Severity 
Safety 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-301 
 
30 July 2021 
 
Version:  2.0 
 
Page 61 of 74 
 
Number 
Title 
Population 
14.3.1.5.8 
Number and Percentage of Subjects with Treatment-
Emergent Adverse Events of Special Interest 
Cumulative to Visit 8 (Day 29) by System Organ 
Class, Preferred Term, and Maximum Severity 
Safety 
14.3.1.5.9 
Number and Percentage of Subjects with 
Anticholinergic Treatment-Emergent Adverse Events 
Cumulative to Visit 8 (Day 29) by System Organ 
Class, Preferred Term, and Maximum Severity 
Safety 
14.3.1.5.10 
Number and Percentage of Subjects with Local Site 
Reaction Treatment-Emergent Adverse Events 
Cumulative to Visit 8 (Day 29) by System Organ 
Class, Preferred Term, and Maximum Severity 
Safety 
14.3.1.6.1 
Number and Percentage of Subjects with Treatment-
Emergent Adverse Events Cumulative to Visit 9 (Day 
36) by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety 
14.3.1.6.2 
Number and Percentage of Subjects with Serious 
Treatment-Emergent Adverse Events Cumulative to 
Visit 9 (Day 36) by System Organ Class, Preferred 
Term, and Maximum Severity 
Safety 
14.3.1.6.3 
Number and Percentage of Subjects with Serious 
Treatment-Related Treatment-Emergent Adverse 
Events  Cumulative to Visit 9 (Day 36) by System 
Organ Class, Preferred Term, and Maximum Severity 
Safety 
14.3.1.6.4 
Number and Percentage of Subjects with Treatment-
Related Treatment-Emergent Adverse Events 
Cumulative to Visit 9 (Day 36) by System Organ 
Class, Preferred Term, and Maximum Severity 
Safety 
14.3.1.6.5 
Number and Percentage of Subjects with Severe 
Treatment-Emergent Adverse Events Cumulative to 
Visit 9 (Day 36) by System Organ Class, Preferred 
Term, and Maximum Severity 
Safety 
14.3.1.6.6 
Number and Percentage of Subjects with Treatment-
Emergent Adverse Events Leading to Dose 
Interruption Cumulative to Visit 9 (Day 36) by System 
Organ Class, Preferred Term, and Maximum Severity 
Safety 
14.3.1.6.7 
Number and Percentage of Subjects with Treatment-
Emergent Adverse Events Leading to Study 
Discontinuation Cumulative to Visit 9 (Day 36) by 
System Organ Class, Preferred Term, and Maximum 
Severity 
Safety 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-301 
 
30 July 2021 
 
Version:  2.0 
 
Page 62 of 74 
 
Number 
Title 
Population 
14.3.1.6.8 
Number and Percentage of Subjects with Treatment-
Emergent Adverse Events of Special Interest 
Cumulative to Visit 9 (Day 36) by System Organ 
Class, Preferred Term, and Maximum Severity 
Safety 
14.3.1.6.9 
Number and Percentage of Subjects with 
Anticholinergic Treatment-Emergent Adverse Events 
Cumulative to Visit 9 (Day 36) by System Organ 
Class, Preferred Term, and Maximum Severity 
Safety 
14.3.1.6.10 
Number and Percentage of Subjects with Local Site 
Reaction Treatment-Emergent Adverse Events 
Cumulative to Visit 9 (Day 36) by System Organ 
Class, Preferred Term, and Maximum Severity 
Safety 
14.3.1.7.1 
Number and Percentage of Subjects with Treatment-
Emergent Adverse Events Cumulative to Visit 12 (Day 
48, EOT) by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety 
14.3.1.7.2 
Number and Percentage of Subjects with Serious 
Treatment-Emergent Adverse Events Cumulative to 
Visit 12 (Day 48, EOT) by System Organ Class, 
Preferred Term, and Maximum Severity 
Safety 
14.3.1.7.3 
Number and Percentage of Subjects with Serious 
Treatment-Related Treatment-Emergent Adverse 
Events  Cumulative to Visit 12 (Day 48, EOT) by 
System Organ Class, Preferred Term, and Maximum 
Severity 
Safety 
14.3.1.7.4 
Number and Percentage of Subjects with Treatment-
Related Treatment-Emergent Adverse Events 
Cumulative to Visit 12 (Day 48, EOT) by System 
Organ Class, Preferred Term, and Maximum Severity 
Safety 
14.3.1.7.5 
Number and Percentage of Subjects with Severe 
Treatment-Emergent Adverse Events Cumulative to 
Visit 12 (Day 48, EOT) by System Organ Class, 
Preferred Term, and Maximum Severity 
Safety 
14.3.1.7.6 
Number and Percentage of Subjects with Treatment-
Emergent Adverse Events Leading to Dose 
Interruption Cumulative to Visit 12 (Day 48, EOT) by 
System Organ Class, Preferred Term, and Maximum 
Severity 
Safety 
14.3.1.7.7 
Number and Percentage of Subjects with Treatment-
Emergent Adverse Events Leading to Study 
Discontinuation Cumulative to Visit 12 (Day 48, EOT) 
by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety 


Brickell Biotech, Inc. 
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Statistical Analysis Plan 
Protocol No. BBI-4000-CL-301 
 
30 July 2021 
 
Version:  2.0 
 
Page 63 of 74 
 
Number 
Title 
Population 
14.3.1.7.8 
Number and Percentage of Subjects with Treatment-
Emergent Adverse Events of Special Interest 
Cumulative to Visit 12 (Day 48, EOT) by System 
Organ Class, Preferred Term, and Maximum Severity 
Safety 
14.3.1.7.9 
Number and Percentage of Subjects with 
Anticholinergic Treatment-Emergent Adverse Events 
Cumulative to Visit 12 (Day 48, EOT) by System 
Organ Class, Preferred Term, and Maximum Severity 
Safety 
14.3.1.7.10 
Number and Percentage of Subjects with Local Site 
Reaction Treatment-Emergent Adverse Events 
Cumulative to Visit 12 (Day 48, EOT) by System 
Organ Class, Preferred Term, and Maximum Severity 
Safety 
14.3.1.8.1 
Number and Percentage of Subjects with Treatment-
Emergent Adverse Events Cumulative to Visit 13 (Day 
57, Follow-up) by System Organ Class, Preferred 
Term, and Maximum Severity 
Safety 
14.3.1.8.2 
Number and Percentage of Subjects with Serious 
Treatment-Emergent Adverse Events Cumulative to 
Visit 13 (Day 57, Follow-up) by System Organ Class, 
Preferred Term, and Maximum Severity 
Safety 
14.3.1.8.3 
Number and Percentage of Subjects with Serious 
Treatment-Related Treatment-Emergent Adverse 
Events  Cumulative Visit 13 (Day 57, Follow-up) by 
System Organ Class, Preferred Term, and Maximum 
Severity 
Safety 
14.3.1.8.4 
Number and Percentage of Subjects with Treatment-
Related Treatment-Emergent Adverse Events 
Cumulative to Visit 13 (Day 57, Follow-up) by System 
Organ Class, Preferred Term, and Maximum Severity 
Safety 
14.3.1.8.5 
Number and Percentage of Subjects with Severe 
Treatment-Emergent Adverse Events Cumulative to 
Visit 13 (Day 57, Follow-up) by System Organ Class, 
Preferred Term, and Maximum Severity 
Safety 
14.3.1.8.6 
Number and Percentage of Subjects with Treatment-
Emergent Adverse Events Leading to Dose 
Interruption Cumulative to Visit 13 (Day 57, Follow-
up) by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety 
14.3.1.8.7 
Number and Percentage of Subjects with Treatment-
Emergent Adverse Events Leading to Study 
Discontinuation Cumulative to Visit 13 (Day 57, 
Follow-up) by System Organ Class, Preferred Term, 
and Maximum Severity 
Safety 
14.3.1.8.8 
Number and Percentage of Subjects with Treatment-
Emergent Adverse Events of Special Interest 
Safety 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-301 
 
30 July 2021 
 
Version:  2.0 
 
Page 64 of 74 
 
Number 
Title 
Population 
Cumulative to Visit 13 (Day 57, Follow-up) by System 
Organ Class, Preferred Term, and Maximum Severity 
14.3.1.8.9 
Number and Percentage of Subjects with 
Anticholinergic Treatment-Emergent Adverse Events 
Cumulative to Visit 13 (Day 57, Follow-up) by System 
Organ Class, Preferred Term, and Maximum Severity 
Safety 
14.3.1.8.10 
Number and Percentage of Subjects with Local Site 
Reaction Treatment-Emergent Adverse Events 
Cumulative to Visit 14 (Day 57, Follow-up) by System 
Organ Class, Preferred Term, and Maximum Severity 
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 
14.3.5 
Study Drug Administration Exposure and Compliance 
Safety 
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 
Shift in Worst Severity for Local Tolerability 
Assessments from Baseline to Each Visit 
Safety 
14.3.6.4 
Mean and Mean Change from Baseline in Vital Signs 
Values by Visit 
Safety 
14.3.6.5 
Summary of Concomitant Medications by Drug Class 
and Generic Drug Name 
Safety 
 


Brickell Biotech, Inc. 
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Statistical Analysis Plan 
Protocol No. BBI-4000-CL-301 
 
30 July 2021 
 
Version:  2.0 
 
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16. 
LIST OF PLANNED FIGURES 
Number 
Title 
Population 
14.2.1 
LS Mean ProSRUWLRQRI6XEMHFWV$FKLHYLQJ 1-point 
Improvement in HDSM-Ax-7 by Visit -- Bar Chart 
Intent-to-Treat 
14.2.2 
LS Mean Proportion of Subjects Achieving  1-point 
Improvement in HDSM-Ax-7 by Visit  -- Bar Chart 
Per-protocol 
14.2.3 
LS Mean Proportion of Subjects Achieving  1-point 
Improvement in HDSM-Ax-11 by Visit -- Bar Chart 
Intent-to-Treat 
14.2.4 
LS Mean Proportion of Subjects Achieving  1-point 
Improvement in HDSM-Ax-11 by Visit  -- Bar Chart 
Per-protocol 
14.2.5 
LS Mean Proportion of Subjects Achieving  2-point 
Improvement in HDSM-Ax-7 by Visit -- Bar Chart 
Intent-to-Treat 
14.2.6 
LS Mean Proportion of Subjects Achieving  2-point 
Improvement in HDSM-Ax-7 by Visit  -- Bar Chart 
Per-protocol 
14.2.7 
LS Mean Proportion of Subjects Achieving  2-point 
Improvement in HDSM-Ax-11 by Visit -- Bar Chart 
Intent-to-Treat 
14.2.8 
LS Mean Proportion of Subjects Achieving  2-point 
Improvement in HDSM-Ax-11 by Visit  -- Bar Chart 
Per-protocol 
14.2.9 
LS Mean Proportion of Subjects Achieving  1-point 
Improvement in HDSM-Ax Question 4 by Visit -- Bar Chart 
Intent-to-Treat 
14.2.10 
LS Mean Proportion of Subjects Achieving  1-point 
Improvement in HDSM-Ax Question 4 by Visit -- Bar Chart 
Per-protocol 
14.2.11 
LS Mean Proportion of Subjects Achieving  2-point 
Improvement in HDSM-Ax Question 5 by Visit -- Bar Chart 
Intent-to-Treat 
14.2.12 
LS Mean Proportion of Subjects Achieving  2-point 
Improvement in HDSM-Ax Question 5 by Visit -- Bar Chart 
Per-protocol 
14.2.13 
LS Mean Proportion of Subjects Achieving Composite 
Endpoint Response of  2-point Improvement in HDSM-Ax-7 
and 70% Reduction in GSP by Visit -- Bar Chart 
Intent-to-Treat 
14.2.14 
LS Mean Proportion of Subjects Achieving Composite 
Endpoint Response of  2-point Improvement in HDSM-Ax-7 
and 70% Reduction in GSP by Visit -- Bar Chart 
Per-protocol 
14.2.15 
LS Mean Proportion of Subjects Achieving Composite 
Endpoint Response of  2-point Improvement in HDSM-Ax-11 
and 70% Reduction in GSP by Visit -- Bar Chart 
Intent-to-Treat 
14.2.16 
LS Mean Proportion of Subjects Achieving Composite 
Endpoint Response of  2-point Improvement in HDSM-Ax-11 
and 70% Reduction in GSP by Visit -- Bar Chart 
Per-protocol 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-301 
 
30 July 2021 
 
Version:  2.0 
 
Page 66 of 74 
 
Number 
Title 
Population 
14.2.17 
LS Mean Proportion of Subjects Achieving Composite 
Endpoint Response of  1-point Improvement in HDSM-Ax-7 
and 50% Reduction in GSP by Visit -- Bar Chart 
Intent-to-Treat 
14.2.18 
LS Mean Proportion of Subjects Achieving Composite 
Endpoint Response of  1-point Improvement in HDSM-Ax-7 
and 50% Reduction in GSP by Visit -- Bar Chart 
Per-protocol 
14.2.19 
LS Mean Proportion of Subjects Achieving Composite 
Endpoint Response of  1-point Improvement in HDSM-Ax-11 
and 50% Reduction in GSP by Visit -- Bar Chart 
Intent-to-Treat 
14.2.20 
LS Mean Proportion of Subjects Achieving Composite 
Endpoint Response of  1-point Improvement in HDSM-Ax-11 
and 50% Reduction in GSP by Visit -- Bar Chart 
Per-protocol 
14.2.21 
LS Mean Change from Baseline in HDSM-Ax-7 by Visit -- 
Line Graph 
Intent-to-Treat 
14.2.22 
LS Mean Change from Baseline in HDSM-Ax-7 by Visit -- 
Line Graph 
Per-protocol 
14.2.23 
LS Mean Change from Baseline in HDSM-Ax-11 by Visit -- 
Line Graph 
Intent-to-Treat 
14.2.24 
LS Mean Change from Baseline in HDSM-Ax-11 by Visit -- 
Line Graph 
Per-protocol 
14.2.25 
LS Mean Proportion of Subjects Achieving 70% Reduction in 
GSP by Visit -- Bar Chart 
Intent-to-Treat 
14.2.26 
LS Mean Proportion of Subjects Achieving 70% Reduction in 
GSP by Visit -- Bar Chart 
Per-protocol 
14.2.27 
LS Mean Proportion of Subjects Achieving 50% Reduction in 
GSP by Visit -- Bar Chart 
Intent-to-Treat 
14.2.28 
LS Mean Proportion of Subjects Achieving 50% Reduction in 
GSP by Visit -- Bar Chart 
Per-protocol 
14.2.29 
LS Mean Change from Baseline in Rank-based GSP by Visit -- 
Line Graph 
Intent-to-Treat 
14.2.30 
LS Mean Change from Baseline in Rank-based GSP by Visit -- 
Line Graph 
Per-protocol 
14.2.31 
LS Mean Change from Baseline in Absolute GSP by Visit -- 
Line Graph 
Intent-to-Treat 
14.2.32 
LS Mean Change from Baseline in Absolute GSP by Visit -- 
Line Graph 
Per-protocol 
14.2.33 
LS Mean Percent Change from Baseline in GSP by Visit -- 
Line Graph 
Intent-to-Treat 
14.2.34 
LS Mean Percent Change from Baseline in GSP by Visit -- 
Line Graph 
Per-protocol 
14.2.35 
LS Mean Change from Baseline in DLQI Score -- Line Graph 
Intent-to-Treat 
14.2.36 
LS Mean Change from Baseline in DLQI Score -- Line Graph 
Per-protocol 
14.2.37 
Normality Test Results for GSP  
Intent-to-Treat 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-301 
 
30 July 2021 
 
Version:  2.0 
 
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Number 
Title 
Population 
14.2.38 
Plot of GSP Outliers 
Intent-to-Treat 
14.2.39 
Patient Global Impression – Severity (PGI-S) 
Intent-to-Treat 
14.2.40 
Patient Global Impression – Severity (PGI-S) 
Per Protocol 
14.3.1.1.1 
Number of Subjects with Study Discontinuation due to 
Treatment-Emergent Adverse Events by Time on Treatment 
Safety 
14.3.1.1.2 
Number of Subjects with Study Discontinuation due to 
Anticholinergic Treatment-Emergent Adverse Events by Time 
on Treatment 
Safety 
14.3.1.1.3  
Number of Subjects with Study Discontinuation due to 
Treatment-Emergent Adverse Events of Special Interest by 
Time on Treatment 
Safety 
14.3.1.1.4  
Number of Treatment-Related Treatment-Emergent Adverse 
Events over Time 
Safety 
14.3.1.1.5  
Number of Subjects with any Treatment-Related Treatment-
Emergent Adverse Event over Time 
Safety 
14.3.1.1.6 
Number of Local Site Reaction Treatment-Emergent Adverse 
Events over Time 
Safety 
14.3.1.1.7 
Number of Subjects with any Local Site Reaction Treatment-
Emergent Adverse Event over Time 
Safety 
14.3.1.2  
Summary of Local Tolerability by Severity from Baseline to 
Day 43 (EOT) 
Safety 
 
 


Brickell Biotech, Inc. 
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Statistical Analysis Plan 
Protocol No. BBI-4000-CL-301 
 
30 July 2021 
 
Version:  2.0 
 
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17. 
LIST OF PLANNED DATA LISTINGS 
Number 
Title 
Population 
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 
16.2.1 
Subject Disposition 
All Randomized 
16.2.2 
Protocol Deviations 
All Randomized 
16.2.3 
Analysis Populations 
All Randomized 
16.2.4.1 
Demographic and Baseline Characteristics 
All Randomized 
16.2.4.2 
Medical History 
Safety 
16.2.4.3 
Prior and Concomitant Medications 
Safety 
16.2.5.1 
Study Medication Dosing and Compliance 
Safety 
16.2.5.2 
Study Drug Accountability 
Safety 
16.2.5.3 
Exposure Parameters 
Safety 
16.2.6.1 
Hyperhidrosis Disease Severity Measure - Axillary Results 
All Randomized 
16.2.6.2 
Gravimetric Sweat Production 
All Randomized 
16.2.6.3 
Dermatology Quality of Life Index Results 
All Randomized 
16.2.7.1 
All Adverse Events 
Safety 
16.2.7.2 
Adverse Events of Special Interest 
Safety 
16.2.7.3 
Anticholinergic Adverse Events 
Safety 
16.2.7.4 
Screening Period Adverse Events 
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 
Pregnancy Results 
Safety 
16.2.9.1 
Local Tolerability Results 
Safety 
16.2.9.2 
Vital Signs Results 
Safety 
16.2.9.3 
Physical Examination Results 
Safety 
16.2.9.4 
Prior or Concomitant Therapies or Procedures 
Safety 
16.2.10 
Subject Study Visits 
All Randomized 
 
 
 


Brickell Biotech, Inc. 
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Statistical Analysis Plan 
Protocol No. BBI-4000-CL-301 
 
30 July 2021 
 
Version:  2.0 
 
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18. 
APPENDICES 
18.1 
Schedule of Events 
Visit  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10  
11  
12  
13  
PROCEDURE  
Screening 
Rescreening / 
Baseline 
End of 
Treatment 
Follow-up 
Gravimetric Timepoint  
 
GSP 
11 
GSP 
21 
GSP 
31 
 
 
 
 
 
GSP 
4 
GSP 
5 
GSP 
6 
 
Day  
(allowable window)  
Up to  
 31 
days 
prior 
to  
GSP1  
  
(Day 
1) 
Day   
8   
(± 2)  
Day  
15   
(± 2)  
Day  
22   
(± 2)  
Day  
29   
(± 2)  
Day  
36   
(± 2)  
Day  
41   
(±2)  
Day  
42   
(± 2)  
Day  
43   
(± 2)  
Day  
57   
(± 3)  
Informed Consent/Assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History, Demographics 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
Physical Exam 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Vital Signs (blood pressure, 
heart rate, respiratory rate, and 
temperature) 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
I/E Criteria 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
Gravimetric Assessments2,3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HDSM-Ax4,5 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DLQI6 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
Local Tolerability Assessments7 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization8 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Non-antiperspirant Deodorant 
Dispensed9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Investigational Product10 (IP) 
Dispensed / Returned 
 
 
 
X 
 
 
X 
 
 
 
   
X 
 
IP Weight11 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
Compliance Evaluation 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Safety Labs (hematology, 
chemistry, and urinalysis) 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
UPT (females of childbearing 
potential only)12 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Concomitant Medication 
Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Brickell Biotech, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. BBI-4000-CL-301 
 
30 July 2021 
 
Version:  2.0 
 
Page 70 of 74 
 
Visit  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10  
11  
12  
13  
PROCEDURE  
Screening 
Rescreening / 
Baseline 
End of 
Treatment 
Follow-up 
Gravimetric Timepoint  
 
GSP 
11 
GSP 
21 
GSP 
31 
 
 
 
 
 
GSP 
4 
GSP 
5 
GSP 
6 
 
Day  
(allowable window)  
Up to  
 31 
days 
prior 
to  
GSP1  
  
(Day 
1) 
Day   
8   
(± 2)  
Day  
15   
(± 2)  
Day  
22   
(± 2)  
Day  
29   
(± 2)  
Day  
36   
(± 2)  
Day  
41   
(±2)  
Day  
42   
(± 2)  
Day  
43   
(± 2)  
Day  
57   
(± 3)  
Optional End of Study Patient 
Survey13  
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviations: DLQI = Dermatology Life Quality Index; FOCBP = females of child-bearing potential; HDSM-Ax = 
Hyperhidrosis Disease Severity Measure-Axillae; I/E = inclusion/exclusion; IP = investigational product; PGI-C = 
Patient Global Impression of Change; PGI-S = Patient Global Impression of Severity; UPT = urine pregnancy test 
1 Visit 2 should occur no more than 31 days after the initial screening visit (Visit 1); both Visits 2 and 3 should occur 
within 14 days of rescreening/baseline Visit 4. Visit 4 will correspond to Day 1. 
2 Gravimetric assessments for all visits will be conducted from 7:00am-11:00am.  
3 One 5-minute gravimetric assessment will be conducted for each axilla.  
4 PGI-S will be administered as Question #6 of HDSM-Ax at every assessment; PGI-C will be administered as 
Question #7 of HDSM-Ax at the Day 43 visit only. 
5 Version of HDSM-$[TXHVWLRQQDLUHWREHDGPLQLVWHUHGDFFRUGLQJWRVXEMHFWDJHWRޒ\HDUVRU\HDUVRI
age). 
6 7KH'/4,ZLOOEHDGPLQLVWHUHGWRVXEMHFWV\HDUVRIDJH. 
7 Investigator assessments to be performed after the Subject assessments.  
8 Randomization will take place only after the subject is qualified at the Rescreening Visit (Visit 4).   
9 Non-antiperspirant deodorant will be dispensed at the Screening Visit (Visit 1) and resupplied as needed throughout 
the study. 
10 Pump container 1 of 2 to be primed, weighed, and dispensed to subject at Baseline (Visit 4). Pump 2 of 2 to be 
primed, weighed, and dispensed to subject at Day 22 (Visit 7). Written instructions for nightly dosing will be 
given to the subject. Subjects will apply their first dose of gel prior to bedtime the night of their Baseline visit. 
Instruct the subjects to return Pump container 1 of 2 at Day 22 (Visit 7) and Pump container 2 of 2 at Day 43 
(Visit 12, End of Treatment).    
11 Pump container 1 of 2 will be weighed with the applicator cap on after priming at Baseline prior to dispensing to the 
subject and upon return at Day 22 (Visit 7). Pump container 2 of 2 will be weighed with the applicator cap on after 
priming at Day 22 (Visit 7) prior to dispensing to the subject and upon return at Day 43 (Visit 12, End of 
Treatment).    
12 FOCBP for this study includes any premenopausal female capable of becoming pregnant who has not undergone 
successful surgical sterilization (hysterectomy, bilateral tubal ligation [t6 months prior to baseline], or bilateral 
oophorectomy) or is not postmenopausal (defined as amenorrhea t12 consecutive months). 
13 2SWLRQDOHQGRIVWXG\VXUYH\ZLOOEHRIIHUHGWRVXEMHFWV\HDUVRIDJH.   
 
 
 
 


Brickell Biotech, Inc. 
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Statistical Analysis Plan 
Protocol No. BBI-4000-CL-301 
 
30 July 2021 
 
Version:  2.0 
 
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18.2 
HDSM-Ax Imputation Flow Chart 
 
 
   


Brickell Biotech, Inc. 
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30 July 2021 
 
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18.3 
GSP Imputation Flow Chart 
 
 


Brickell Biotech, Inc. 
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Statistical Analysis Plan 
Protocol No. BBI-4000-CL-301 
 
30 July 2021 
 
Version:  2.0 
 
Page 73 of 74 
 
 
 
 
 


Brickell Biotech, Inc. 
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Statistical Analysis Plan 
Protocol No. BBI-4000-CL-301 
 
30 July 2021 
 
Version:  2.0 
 
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19. 
ATTACHMENTS 
None.